Familial Hypercholesterolemia: Genes and Beyond

ABSTRACT

Genetic disorders resulting in familial hypercholesterolemia (FH) include autosomal dominant hypercholesterolemia (ADH), polygenic hypercholesterolemia, as well as other rare conditions such as autosomal recessive hypercholesterolemia (ARH). All of these disorders cause elevations in low-density lipoprotein (LDL)-cholesterol (LDL-C) and, as a result, greatly increase the risk of cardiovascular disease (CVD). Genetic loci involved in ADH include the LDLR, which codes for the LDL receptor (LDLR), APOB, which codes for apolipoprotein B-100 (apoB-100), the major protein component of LDL, PCSK9, which codes for Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), the low abundance circulatory protein that terminates the lifecycle of the LDLR, and apolipoprotein E (APOE), which is an important constituent of triglyceride rich lipoproteins. Importantly, a large percentage of people with the severe hypercholesterolemic phenotype do not possess a readily identifiable gene defect and many likely have polygenic hypercholesterolemia. Thus, identification of a specific genetic pathologic variant is not a necessary condition for the diagnosis of a genetic hypercholesterolemia. Several formal diagnostic criteria exist for FH and include lipid levels, family history, personal history, physical exam findings, and genetic testing. As all individuals with severe hypercholesterolemia are at high risk for CVD, treatment is centered on dietary and lifestyle modifications and early institution of lipid-lowering pharmacotherapy. Treatment should initially be statin-based, but most patients require adjunctive medications such as ezetimibe and PCSK9 blocking monoclonal antibodies. Three large cardiovascular outcome trials have shown a reduction in atherosclerotic CVD when ezetimibe or PCSK9 blocking monoclonal antibodies were added to a background of statin therapy and consequently have assisted in shaping international guidelines and consensus recommendations. Novel therapeutics recently developed, include: inclisiran – a small interfering ribonucleic acid (siRNA)-based gene-silencing technology that inhibits PCSK9 production, bempedoic acid – an inhibitor of adenosine triphosphate (ATP)-citrate lyase with a large cardiovascular outcome trial demonstrating a reduction in CVD in patients with statin intolerance and is now FDA approved for a wide range of patients including heterozygous FH and patients with prior CVD (secondary prevention) or those at high-risk for CVD (primary prevention) and elevated LDL-C, and evinacumab – a fully human monoclonal antibody inhibiting angiopoietin-like 3 (ANGPTL3) (FDA approved for homozygous FH only). Patients with extreme and unresponsive elevations in LDL-C will require more aggressive therapies such as lipoprotein apheresis and agents for the treatment of severe hypercholesterolemia such as microsomal triglyceride transfer protein (MTP) inhibitors and evinacumab.

INTRODUCTION

Genetic disorders resulting in familial hypercholesterolemia (FH) consist of autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH), and polygenic hypercholesterolemia. The genetic architecture of FH is more complex than previously recognized and in fact is now believed to be associated with at least nine different genes with thousands of variants, the details of which are beyond the scope of this chapter. But briefly, the term “autosomal dominant hypercholesterolemia” refers to those patients with dominantly inherited severe hypercholesterolemia – low-density lipoprotein (LDL)-cholesterol (LDL-C) greater than 190 mg/dL, who likely harbor mutations in genes regulating serum LDL levels. Historically, the more common causes of ADH include “classic” FH, which is a codominant disorder involving aberrations in the LDL receptor (LDLR), as well as other codominant forms of “nonclassical” FH, which involve defects in two other genes that regulate plasma clearance of LDL, apolipoprotein B (APOB), which is the main protein of LDL (a ligand for the LDLR), and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), which synthesizes a low abundance circulatory protein that limits the LDLR lifespan (1,2). Autosomal dominant forms of ADH include mutations in apolipoprotein E (APOE), which synthesizes the main protein of triglyceride rich lipoproteins and signal transducing adaptor family member 1 (STAP1), whose function in cholesterol homeostasis remains largely unknown (2,3). However, recent data have determined that mutations in STAP1 are not a causative factor in FH (4-7). An autosomal recessive form of FH, ARH, is very rare and results from pathogenic variants in LDLR accessory protein 1 (LDL-RAP1). Other forms may be due to defects in lysosomal acid lipase (LIPA), ATP- binding cassette sub-family G member 5 and 8 (ABCG5/8), and cholesterol 7 alpha-hydroxylase (CYP7A1) (2,8). Finally, a common form of FH is attributable to multiple variations in several genes each with minor effects on cholesterol regulation (more than 50 loci identified, as opposed to a single large effect as seen in the textbook version of FH). Polygenic causes are relatively common and likely explain many of the patients who are genotype negative. In fact, up to 50% of patients referred to lipid clinics for possible or probable HeFH have a polygenic basis (2). Additionally, only approximately 2% of patients with an LDL >190 mg/dL and no additional clinical or family history compatible with FH have a pathogenic variant in one of the FH genes (9,10). Thus, having an elevated LDL-C does not necessarily indicate that the patient has ADH due to a pathogenic variation in the LDLR, APOB, PCSK9, or APOE genes. All forms of FH result in very high levels of LDL-C and increase the risk of early and accelerated coronary artery disease (CAD) (8). Yet, FH remains vastly underdiagnosed and thus, undertreated, representing an extraordinary missed opportunity for maintenance of cardiovascular health and prevention of cardiovascular events. It has been estimated that less than 10% of the patients in the US with FH have been diagnosed (11,12). This chapter will largely focus on the canonical forms of FH involving the traditional genetic loci described above.

GENETICS

The LDLR is an 893-amino acid cell surface glycoprotein that binds and internalizes LDL particles, primarily in the liver. Mutations in LDLR (i.e., “classic” FH) give rise to nearly 90% of cases of clinical ADH (13). Over 2000 such mutations in LDLR have been identified, including deletions, insertions, missense, copy number variants, and nonsense mutations (2). FH patients can be homozygous (traditionally with a prevalence thought to be 1 in 1,000,000 but based on contemporary genetic studies, the prevalence is thought to be closer to 1 in 300,000), carrying mutations in both alleles encoding for LDLR, or heterozygous (traditionally with a prevalence thought to be 1 in 500, with newer data suggesting as frequent as 1 in 200), possessing mutations in only one allele (2,14). Homozygous FH (HoFH) should be suspected when LDL-C exceeds 400 mg/dL, whereas heterozygous FH (HeFH) should be suspected when LDL-C is greater than 190 mg/dL in adults and 160 mg/dL in children (8). Patients with HoFH can be true FH homozygotes, with two identical mutations in each allele, versus compound heterozygotes, with a different mutation in each allele. In addition, FH can result in elevated levels of lipoprotein(a) (Lp[a]) through an unclear mechanism, not necessarily linked to the dysfunctional LDLR pathway (15-19). Elevated Lp(a), which historically was thought composed of 30-45% cholesterol by mass and reported as part of the LDL-C laboratory measurement, amplifies the already increased risk of incident CAD seen in those with FH (19). A more contemporary study suggests this range of cholesterol content contributed by Lp(a) to be more heterogenous with a range of 9-57% with a median value of approximately 15-20% in individuals with elevated Lp(a) (20). A recent evaluation of Lp(a) levels in a Danish Lipid Clinic found that elevated Lp(a) levels were common, with approximately 27% of individuals fulfilling a clinical diagnosis of FH due in part to elevated Lp(a)(21). This data suggests the LPA gene should be considered in the realm of possible causes for phenotypic FH and emphasize the importantance of Lp(a) testing. It is also important to be aware of “founder effects” in some populations. Founder effects influencing the type and frequency of mutations causing FH are seen among Afrikaners, French Canadians, Ashkenazi Jews, Christian Lebanese, and some Tunisian groups. Slimane et al. estimated the prevalence of individuals with HoFH and HeFH in Tunisia to be 1:125,000 and 1:165, respectively (22).

“Nonclassical” FH, which phenotypically resembles classic FH in presentation and severity, involves dominantly inherited gene defects in APOB, PCSK9, and APOE, which code for proteins that modulate ligand-LDL/LDL-like receptor interaction (2,23,24). ApoB is the major protein constituent of LDL and acts as a ligand for LDLR. Mutations in ApoB (most commonly a single base change at a position near amino-acid 3,500) block the binding of LDL containing the apoB-100 to LDLR, resulting in severely elevated levels of LDL-C. This condition was originally defined as “familial defective APOB-100” or FDAB (25). PCSK9, on the other hand, is a circulating protein that terminates the lifecycle of LDLR by binding to it and targeting it to lysosomal degradation. Gain-of-function (GOF) mutations in PCSK9 lead to a FH phenotype, whereas loss-of-function (LOF) mutations lead to lower LDL-C and protection from coronary atherosclerotic events (26,27). Absence of circulating PCSK9 has been reported in a few subjects, who were reportedly healthy and had LDL levels around 20 mg/dL (28,29). Collectively, these observations spurred a frenzy of targeted research that led to the development and FDA approval of therapeutic antibodies against PCSK9 to reduce LDL levels in individuals with atherosclerotic cardiovascular disease (ASCVD) and/or in FH. Mutations in ApoE (an in-frame three base-pair deletion at position 167 in exon 4) block the binding of triglyceride rich lipoproteins (i.e., chylomicrons, chylomicron remnants, very low-density lipoprotein [VLDL-C], intermediate-density lipoprotein [IDL-C]) to the E receptor (belongs to the LDLR superfamily), and limits clearance of these particles from plasma (30). The prevalence of ADH resulting from mutations in APOB, PCSK9, and APOE has been difficult to estimate, but it is agreed that these are 5-10%, <1%, and <<1% respectively (2).

Finally, an additional ultra-rare recessive genetic disorder causing hypercholesterolemia bears mentioning. It involves a homozygous deletion mutation in the gene CYP7A1. This gene codes for the enzyme cholesterol 7α-hydroxylase, which catalyzes the initial step in cholesterol catabolism and bile acid synthesis. The mutation results in loss of enzymatic function and high levels of LDL-C, and was first identified in three homozygotes within a single kindred of English and Celtic descent (31). There are a number of other rare recessive genetic disorders that are associated with hypercholesterolemia, see table 1 below and other Endotext chapters on these rare genetic disorders (32,33).

TABLE 1. RARE GENETIC DISORDERS THAT CAN BE CONFUSED WITH ADH
Disorder	Description
Sitosterolemia	Autosomal recessive disorder due to mutations in ABCG5/8. Manifestations include hypercholesterolemia, marked elevations of plasma plant sterols, tendon and tuberous xanthomas, and premature ASCVD
Lysosomal acid lipase deficiency	Autosomal recessive disorder due to mutations in LIPA, which codes for lysosomal acid lipase. Manifestations include moderate hypercholesterolemia with depressed high-density lipoprotein cholesterol (HDL-C), accelerated atherosclerosis, and progressive liver disease.
Deficiency of LDL receptor adapter protein 1	Autosomal recessive disorder due to mutations in LDL-RAP1. Typically presents with very high LDL cholesterol levels.
Deficiency of cholesterol 7-alpha hydroxylase	Autosomal recessive disorder due to mutations in CYP7A1, which codes for the enzyme that catalyzes the first step in bile acid synthesis, resulting in high intrahepatic cholesterol and reduced surface expression of LDLR.

An important practical point is that 30-50% of people with the FH phenotype have no readily identifiable defects in any of the genes that have been mentioned here; thus, diagnosing an individual with the FH phenotype does not necessarily mean the presence of a monogenic defect in the LDLR pathway (34). The genetic confirmation for FH-causing mutations in ADH varies considerably (2,10). The rate of positive genetics is related to clinical criteria - in patients with definite FH based on clinical criteria 60-80% are positive whereas in patients with possible FH based on clinical criteria only 21-44% are positive (35). Additionally, the LDL-C level is crucial. When LDL-C is very high (i.e., >310 mg/dL), the frequency of monogenic pathogenic variants is as high as 92% (36). In patients without an identifiable pathologic genetic variant the etiology may be due to an as-yet-unidentified genetic error or to polygenic, epigenetic, or non-genetic factors, including co-morbid and environmental modifiers. For those without a mutation, an elevated LDL-C still confers elevated cardiovascular disease (CVD) risk (37). However, for any given LDL-C strata, those with a causal mutation compared to those without have higher risk for CVD, likely due to lifelong exposure to high LDL-C (10,38). In addition, unintended consequences of genetic testing (i.e., genetic discrimination for life or long-term care insurance and increased expense) must be taken into account. For these reasons, genetic testing should not be mandated, but should involve a shared-decision making model between patient and provider, encompassing benefits and risks of genetic testing, as well as patient values and preferences (39). On the other hand, others advocate for routine genetic testing citing as the rationale 1) facilitate a definitive diagnosis; 2) identify pathogenic variants with higher cardiovascular risk and therefore needing more aggressive treatment; 3) increase initiation of and adherence to therapy; 4) facilitate insurance approval for novel lipid-lowering therapies; and 5) cascade testing of first-degree relatives (25). Cascade screening on the basis of LDL-C alone (i.e., ≥190 mg/dL) has low sensitivity and specificity, however, identification of a pathogenic variant with genetic testing followed by cascade screening results in very high sensitivity and specificity. This is likely due to missed diagnoses of FH with reduced penetrance where LDL-C is <190 mg/dL (35). Nonetheless, the reduced costs and more widespread availability of genetic testing warrant performance of this test to obtain information that can help the physician familiarize with genotype-phenotype correlations and identify subjects that can be studied for the discovery of novel pathways leading to severe hypercholesterolemia. It must be noted that the FDA does not mention genetic testing as a measure to define FH (either heterozygous or homozygous).

PATHOPHYSIOLOGY

Most circulating LDL particles end up in the liver. The LDLR pathway is the predominant method for LDL uptake (40,41). ApoB binds to a specific binding site on LDLR and the receptor-ligand complex is subsequently internalized from clathrin-coated pits on the cell membrane. The receptor-ligand complex undergoes endocytosis and is targeted to the lysosome, where LDL is released for degradation while the LDLR is recycled back to the cell surface approximately 100-150 times in its 24 hour life cycle (2). PCSK9 terminates LDLR lifespan by disallowing its recycling, thus providing a physiologic mechanism of protein removal much different from, and stronger than, that caused by inducible degrader of LDL, an E3 ubiquitin ligase (26,42). There are other nonspecific and constitutively active pathways of LDL-C clearance as well (40,43). In HeFH, though transport through the LDLR pathway is reduced by 50%, LDL-C clearance is doubled through these other, non-LDLR pathways. The same holds true for HoFH, where despite a near-absolute reduction in LDLR transport, total LDL-C clearance via non-specific pathways is increased by 4-fold (44). Excess LDL-C, which accumulates in liver cells, is then re-exported via the apoB system back into the plasma, secreted into bile unchanged, or transformed into bile acids. This increased production of LDL adds to inefficient clearance via LDLR to cause elevated serum LDL levels typical of the FH phenotype (45).

ADH can thus be further classified into subtypes 1, 2, and 3, based on which protein of the LDLR pathway is causative (Figure 1). ADH-1 comprises mutations within LDLR, the canonical form of FH. There are six major classes of ADH-1 (see table 2 below), based on the type of mutation. These include those that: inhibit synthesis of LDLR; impede exit of mature LDLR from the endoplasmic reticulum; affect the binding site of LDLR to apoB-100; prevent the ligand-receptor interaction; prevent endocytosis of the LDLR-apoB-100 complex; or inhibit recycling of LDLR to the cell surface for further rounds of lipid uptake (not shown). ADH-2 comprises mutations of APOB that block the association of apoB-100 to LDLR. ADH-3 is due to GOF mutations of PCSK9, which reduce LDLR recycling and accelerate its lysosomal degradation (12). Some authors have suggested that mutations that affect binding of apoB-100 to LDLR carry a less severe phenotype than those that affect LDLR directly (46-50).

FIGURE 1 (24): ADH-1 comprises mutations within LDLR. There are six major classes of ADH-1, affecting: a) synthesis of LDLR; b) exit of mature LDLR from the endoplasmic reticulum; c) binding site of LDLR to apoB-100; d) endocytosis of LDLR-apoB-100 complex; and recycling of LDLR to the cell surface (not shown). ADH-2 comprises mutations in apoB that block the association of apoB-100 to LDLR. ADH-3 is due to GOF mutations of PCSK9, which reduce LDLR recycling and accelerate its lysosomal degradation. Adapted from Calandra et al. J. Lipid Research 2011; 52: 1885-926.

TABLE 2. THE SIX CLASSES OF LDLR MUTATIONS (51)
Class 1: synthesis of receptor or precursor protein is absent	The so-called null allele is a prevalent class of mutations and is generally associated with very high LDL-C levels. The molecular basis of this type of mutation shows a wide variety: point mutations introducing a stop codon, mutations in the promoter region completely blocking transcription, mutations giving rise to incorrect excision of mRNA, and finally, large deletions preventing the assembly of a normal receptor.
Class 2: absent or impaired formation of receptor protein	This class comprises mutations in which the normal routing through the cell is not complete or is only very slowly completed. Usually, there is a complete blockade of transport, and LDL receptors are unable to leave the ER. The Golgi apparatus is not reached, and the increase of 40,000 Da in molecular weight does not take place. Truncated proteins, as a result of a premature stop codon, and misfolded proteins, as a result of mutations in cysteine-rich regions leading to free or unpaired cysteine residues, are retained in the ER. However, quality control by the ER is not perfect, given the observation that sometimes misfolded proteins leave the ER but are processed more slowly. Such mutations give rise to class 2B mutations, in contrast to class 2A mutations that cause complete retaining in the ER.
Class 3: normal synthesis of receptor protein, abnormal LDL binding	Receptors characterized by this class of alleles show the normal rate of synthesis, exhibit normal conversion into receptor protein, and are transported to the cell surface, but binding to LDL is impaired. It is obvious that mutations in the binding domain underlie this class of receptors.
Class 4: clustering in coated pits, internalization of the receptor complex does not take place	The receptors in this class lack the property to cluster in coated pits (class 4A). This phenomenon, which makes interaction of receptors with the fuzzy coat impossible, is caused by mutations in the carboxyterminal part of the receptor protein. These mutated receptors are synthesized normally, folding and transport are normal, but clustering in coated pits is impossible, and sometimes the receptors are secreted even after they have reached the cell surface (class 4B).
Class 5: receptors are not recycled and are rapidly degraded	All mutations in this class are localized in the EGF-precursor homologous domain of the LDL receptor protein. This domain seems to be involved in the acid-dependent dissociation of the receptor-ligand complex in endosomes, after which the receptor can be recycled. When the entire EGF-precursor homologous domain is deleted by site-directed mutagenesis or when such a deletion occurs naturally in a homozygous FH patient, the receptor is trapped in the endosomes, and rapid degradation subsequently is observed.
Class 6: receptors fail to be targeted to the basolateral membrane	The class of mutations was recently discovered and is caused by alterations in the cytoplasmic tail of the protein. Such receptors do not reach the liver cell membrane and are probably rapidly degraded.

*Adapted from Gidding SS, et al. Circulation 2015;132:2167-92.

CLINICAL MANIFESTATIONS

Lipid Abnormalities in Heterozygous Familial Hypercholesterolemia

LDL-C levels are frequently greater than the 90^th percentile for age and gender. The magnitude of the LDL-C elevation is affected by the specific mutations causing FH with mutations in the LDLR leading to greater elevations in LDL-C levels than mutations in ApoB or PCSK9 (36,46-49,52). Null mutations in the LDLR are more severe than non-null mutations (53). Additionally, other genes that regulate LDL-C and environmental factors, such as diet, also influence the magnitude of the elevation in LDL-C (54,55). It should be recognized that a significant number of patients with genetically diagnosed FH have LDL-C <190 mg/dL. In some studies, approximately 50% of patients with genetically diagnosed FH have LDL-C levels <190 mg/dL (9,10). HDL-C and triglyceride levels are usually normal or only modestly altered (56-63). Elevated triglycerides and/or low HDL-C do not rule out the diagnosis of FH. Lp(a) levels are frequently elevated in patients with FH and may contribute to the increased risk of ASCVD (15-19). One should exclude secondary causes of marked elevations in LDL-C particularly hypothyroidism, renal disease, autoimmunity, and iatrogenic conditions (see chapter on Approach to the Patient with Dyslipidemia) (64). Another pertinent secondary cause that should be evaluated, particularly given escalating global rates of adiposity and the myriad treatment approaches at curtailing these trends, include dietary interventions that may induce a hyperlipidemic state. One such contemporary dietary fad that has garnered traction in the weight loss community is the ketogenic diet, which includes low level of carbohydrates (sufficient enough to induce the formation of ketones), moderate protein intake and high fat intake. It is well-documented that the ketogenic diet results in modest LDL-C elevations in most, but for some, can induce marked elevations in LDL-C, to the degree of mimicking a FH phenotype (65).

Atherosclerotic Cardiovascular Disease in Heterozygous Familial Hypercholesterolemia

Patients with FH have a 3-13-fold higher risk of ASCVD, and a 20-fold higher risk for early onset ischemic heart disease (66,67). Untreated males with FH have a 50% risk for a fatal or non-fatal myocardial infarction by 50 years of age whereas untreated females have a 30% chance by age 60 (68,69). However, it should be recognized that there is heterogeneity of ASCVD risk and much of this risk is potentially modulated by variance in genetic factors (70,71). Other cardiovascular risk factors, such as male sex, BMI, diabetes, hypertension, smoking, low HDL-C levels, and Lp(a) levels modulate the risk of ASCVD (66). Patients with FH who have corneal arcus or xanthomas are more likely to have ASCVD (72-74). Of particular note, patients with mutations that result in FH have a greater ASCVD risk than patients with equivalent LDL-C levels (10,38). This is likely due to the LDL-C elevations being present from birth (lifelong exposure to elevated LDL-C). This concept is termed "cholesterol-years", which tabulates the cumulative exposure, both degree of cholesterol elevation and duration of cholesterol elevation, as a measure of area under the cholesterol curve. Those with a greater exposure (higher cholesterol for longer) of cholesterol, will go on to develop atherosclerosis at a much more aggressive rate (75,76). This concept also highlights an important framework for early FH detection and treatment as vital interventions for optimal ASCVD risk reduction (76).

Other Manifestations

Early onset corneal arcus (age < 45) and tendinous xanthomas, particularly the Achilles tendon and dorsum of hands, are classical abnormalities that occur in patients with FH. Xanthelasma (xanthomas in eyelids) and tuberous xanthoma may also be seen. However, it should be recognized that in the modern era with the increased treatment of elevated LDL-C levels these abnormalities are no longer frequently seen (only 5-35% of patients have xanthoma or corneal arcus currently) (77,78).

Homozygous Familiar Hypercholesterolemia

This is a rare disorder with untreated LDL-C levels that vary but are markedly elevated (usually > 300 mg/dL but often > 500 mg/dL) (79). Patients who are LDLR negative have higher LDL-C and a poorer clinical prognosis than LDLR defective patients (79). Lp(a) levels tend to be higher than observed in patients with HeFH (16). Additionally, HDL-C levels tend to be decreased in HoFH (79). Tendinous xanthoma, tuberous xanthomas, and arcus cornea may appear in childhood (79). If untreated >50% of patient with HoFH develop clinically significant ACVD by age of 30 and cardiovascular events can occur before age 10 in some patients (80). Almost 90% of patients with HoFH suffered a cardiovascular event by age 40 (80). Cholesterol and calcium deposits can lead to aortic stenosis and occasionally to mitral regurgitation (79,81-83).

DIAGNOSIS

FH, despite its different underlying gene abnormalities, leads to severe hypercholesterolemia and a distinct FH phenotype with markedly increased risk of developing CAD. In general, there are five major clinical criteria for diagnosing FH (see table 3): a family history of early CAD (less than age 55 in a first-degree relative in men, and less than age 65 in women), early CAD in the index case, elevated LDL-C (greater than 190 mg/dL), tendon xanthomas (especially in the Achilles and finger extensor tendons), and corneal arcus (which is highly specific in younger patients, but overall an insensitive finding). Mutations in any of the aforementioned genes of the LDLR pathway, when they are identified, are diagnostic.

TABLE 3. MAJOR CLINICAL CRITERIA FOR DIAGNOSING FH
When to Suspect FH
1) If LDL-C levels are > 190 mg/dL (4.92 mMol/L) or non-HDL-C levels are >220 mg/dL (5.70mMol/L)
2) Patients with premature ASCVD (<55 years of age in male and <65 years of age in females)
3) Family history of hypercholesterolemia
4) When there is a positive family history of premature ASCVD (<55 years of age in male and <65 years of age in females)
5) When tendon xanthomas or corneal arcus (< age 45) are present on physical exam

As has been mentioned in other chapters of this text, when evaluating a patient suspected of having FH, it is critical to rule out secondary causes of hypercholesterolemia, such as hypothyroidism, nephrotic syndrome, and liver disease. Another extremely rare cause of non-FH has been described, involving autoantibodies to LDLR that inhibit receptor-mediated binding and catabolism of LDL-C (84).

There are three sets of statistically validated criteria that are most commonly used in the diagnosis of FH: the Dutch Lipid Network criteria, Simon Broome Register criteria, and Make Early Diagnosis to Prevent Early Deaths (MEDPED) criteria (85,86). These are summarized in Table 4, below (87).

TABLE 4. SCORING SYSTEMS FOR DIAGNOSING FH
MEDPED Criteria (USA)
	FH diagnostic if total cholesterol (LDL-C) levels exceed these cut points in mg/dL
Age	1^st degree relative		2^nd degree relative	3^rd degree relative	General population
< 18	220 (155)		230 (165)	240 (170)	270 (200)
20	240 (170)		250 (180)	260 (185)	290 (220)
30	270 (190)		280 (200)	290 (210)	340 (240)
> 40	290 (205)		300 (215)	310 (225)	360 (260)
Simon Broome Criteria (UK)
Total cholesterol (LDL-C) 290 (190) mg/dL in adults, or 260 (155) mg/dL in children	AND	DNA mutation Definite FH
		Tendon xanthomas in patient or 1^st or 2^nd Probable FH degree relative
		Family history of MI at age < 50 in 2^nd Possible FH degree relative or < 60 in 1^st degree relative OR Family history of total cholesterol > 290 mg/dL in 1^st or 2^nd degree relative
Dutch Criteria (Netherlands)
1 point	1^st degree relative with premature CVD or LDL-C > 95^thpercentile, OR Personal history of premature peripheral or cerebrovascular disease, OR LDL-C 155-189 mg/dL					Definite FH (8 points or more) Probable FH (6-7 points) Possible FH (3-5 points)
2 points	1^st degree relative with tendon xanthoma or corneal arcus, OR 1^st degree relative child (< 18 years) with LDL-C > 95^thpercentile, OR Personal history of CAD
3 points	LDL-C 190-249 mg/dL
4 points	Presence of corneal arcus in patient < 45 years old
5 points	LDL-C 250-329 mg/dL
6 points	Presence of a tendon xanthoma
8 points	LDL-C > 330 mg/dL, OR Functional mutation of the LDLR gene

Adapted from Fahed et al., Nutrition & Metabolism 2011;8:23.

Unlike MEDPED criteria, which use only lipid levels, the Simon Broome and Dutch criteria also use family history, personal history, physical exam findings, and genetic testing to establish an FH diagnosis. Again, however, it should be emphasized that FH should be diagnosed phenotypically, as opposed to genetically—most FH patients are genotype-negative and do not possess a clear genetic substrate for their hyperlipidemic phenotype, but they clearly warrant aggressive intervention.

It is important to note that in the modern era of earlier recognition, wide-spread statin use and possibly improved dietary messages, it is often difficult to make a definitive or probable diagnosis of FH using clinical criteria (i.e., treatment reduces the development of xanthomas and corneal arcus and reduces or delays the occurrence of ASCVD events in patients and relatives). Similarly, it is often very difficult to know the before treatment LDL-C levels (35).

While genetic screening is not required for clinical management, lipid screening in family members should be undertaken in all individuals by age 20, starting as early as age 2 (42). Cascade screening—i.e., lipid screening of first-degree relatives of the proband—is infrequently employed but is recommended as the most economical method of identifying new cases of FH (43). It is the responsibility of the examining clinician to attempt identification of other cases when making the diagnosis of FH in any given patient.

A potential novel solution to the underdiagnosis and undertreatment issues that plague the FH community lies in leveraging health information technology. The FIND FH study demonstrated the use of a machine learning algorithm can successfully utilize medical profiles within the electronic health record to consistently identify individuals with probable FH (88). This new approach possesses the promise of identifying FH patients on a national scale and will hopefully lead to increased initiation of effective preventive therapies and at an earlier time-point as well.

TREATMENT

Goals of Therapy

In genetic disorders causing hypercholesterolemia, aggressive lipid-lowering through lifestyle modification, pharmacologic treatment, and invasive treatments such as apheresis has been shown to decrease angiographically-apparent CAD and reduce cardiovascular events (80,89,90). However, traditional risk assessment tools like the Framingham risk score or pooled cohort equation do not apply to FH patients. Recent guidelines suggest that drug therapy should be initiated when LDL-C is greater than 190 mg/dL in all patients, including children over the age of eight (91,92). Most recommend at least a 50% reduction in LDL-C with initiation of high-intensity statin therapy as a starting goal, with some advocating for targeting LDL-C less than 100 mg/dL without ASCVD, less than 70 mg/dL with ASCVD, and even less than 55 mg/dL with ASCVD and at very high-risk (92-95). Additionally, consideration of non-statin options (ezetimibe, bile-acid sequestrants, bempedoic acid, and PCSK9 inhibiting [PCSK9i] therapeutics – including both monoclonal antibodies preferentially but also small interfering RNA should these thresholds not be met (92-94). The European Atherosclerosis Society suggests LDL-C goals of less than 135 mg/dL in pediatric patients, less than 100 mg/dL in adults, and less than 70 mg/dL in adults with known CAD or diabetes mellitus(11).

TABLE 5. GUIDELINE RECOMMENDATIONS FOR TREATING FH
	NLA Expert panel on pediatric FH(91)	AHA/ACC 2018 cholesterol guideline(92)and ACC non-statin ECDP(94)	NLA Expert panel on adult FH(93)	EAS guideline on FH(11)
Age to initiate treatment	≥ 8 years (earlier in special cases i.e., HoFH)	≥ 20 years	Not specified – “After a confirmatory diagnosis of FH …adult FH patients should receive initial treatment”	≥ 8 years
Agent recommended	Statins are preferred Non-statin options (ezetimibe, BAS, fibrates, niacin) are discussed but not routinely recommended due to lack of FDA approval or adverse drug events	Statins are preferred Non-statin options (ezetimibe, BAS, bempedoic acid, PCSK9i therapeutics) are also recommended as add on therapy	Statins are preferred Non-statin options (ezetimibe, BAS, niacin) or LDL apheresis are also recommended as add on therapy or in statin intolerant patients	Statins are preferred Non-statin options (ezetimibe, BAS) or LDL apheresis are also recommended as add on therapy or in statin intolerant patients
Goal of therapy	≥ 50% reduction in LDL-C or LDL-C < 130 mg/dL	≥ 50% reduction in LDL-C or LDL-C < 100 mg/dL in those without ASCVD, < 70 mg/dL with ASCVD, and < 55 mg/dL with ASCVD and at very high-risk	≥ 50% reduction in LDL-C	LDL-C < 135 mg/dL in pediatrics, < 100 mg/dL in adults, < 70 mg/dL in adults with CAD or diabetes

AHA / ACC: American Heart Association / American College of Cardiology; EAS: European Atherosclerosis Society; ECDP: Expert Consensus Decision Pathway; NLA: National Lipid Association; BAS: bile-acid sequestrants.

In our view in FH patients without clinical ASCVD one should aim for an LDL-C level <100 mg/dL (2.59 mMol/L). In FH patients with clinical ASCVD the goal, at a minimum should be an LDL-C level <70 mg/dL (1.81 mMol/L) with many experts recommending LDL-C levels <55 mg/dL (1.4 2mMol/L), particularly when patients have additional risk factors (acute coronary syndrome, diabetes, polyvascular disease, etc.) (96,97). In patients without ASCVD but who are at high risk due to other risk factors such as diabetes, Lp(a) >50 mg/dL, smokers, a strong family history of premature ASCVD, etc. many experts would recommend an LDL-C goal of <70 mg/dL (1.81 mMol/L). While LDL-C goals continue to decline, attainment of these goals is increasing more difficult and seldom attained in most FH patients.

Treatment of Patients with Heterozygous Familial Hypercholesterolemia

As with almost all metabolic disorders we should encourage the patient to follow a lifestyle that will reduce disease manifestations. However, lifestyle changes are very rarely sufficient to lower LDL-C levels to the desired range in patients with FH and therefore cholesterol lowering drugs will be required (see figure 2 and tables 6 and 7) (for detailed information on cholesterol lowering drugs see the chapter on cholesterol lowering drugs (98). In patients with HeFH, statins are a mainstay of treatment, despite the dearth of randomized clinical trials of statin efficacy focused on this special population. Statins are FDA approved for use in pediatric FH patients beginning at age 8-10 years for HeFH and in the first year of life or at initial diagnosis for HoFH (51,79,96,99-103). Data from longitudinal observational studies suggest statin initiation in childhood is both safe and effective, reducing LDL-C burden and corresponding atherosclerosis rates over follow-up of up to 20 years (51,104). The major early statin trials (4S and WOSCOPS) likely had study populations that were enriched with FH patients, given that mean baseline LDL-C ranged from 189 to 216 mg/dL (105,106). Patients should be treated with atorvastatin 40-80 mg per day or rosuvastatin 20-40 mg per day (i.e., high-intensity statin therapy). As monotherapy, statins can reduce LDL-C by up to 60% in HeFH patients but typically display a blunted response (10-25%) in HoFH patients depending on LDLR functionality (79,95,107). Updated guidance on statin therapy during pregnancy was issued by the FDA during a drug safety communication in 2021, removing the strongest warning against using statins during pregnancy (108). Though statins should still be avoided in most women attempting contraception during pregnancy, particular during the first trimester, the available evidence suggest that statins are likely not teratogenic. The updated guidance allows for more flexibility for treating pregnant women as part of a shared decision-making process, particular those at the highest ASCVD risk, including those with FH (109).

The vast majority of patients, however, require additional pharmacotherapy. When intensive statin therapy does not result in an LDL-C level in the desired range additional therapy should be added. Given that ezetimibe is generic, relatively inexpensive, well tolerated, and has evidence for ASCVD risk reduction in a large cardiovascular outcome trial, this is frequently the next drug used (110). One can anticipate that ezetimibe 10 mg per day added to intensive statin therapy will result in an approximate 20% further reduction in LDL-C. If this is not sufficient one can then use a PCSK9i monoclonal antibody to achieve the desired cholesterol goal. Adding a PCSK9i monoclonal antibody will result in a further 50-60% decrease in LDL-C levels and in most patients will result in LDL-C levels in the desired range. In some instances, if the LDL-C level is far from goal (>25%) on intensive statin therapy one can skip treating with ezetimibe and proceed directly to adding a PCSK9i monoclonal antibody. Bempedoic acid (discussed in more detail below) is an acceptable third- or fourth-line add-on agent if additional LDL-C lowering is needed. It is worth noting that bempedoic acid also comes as a combination product with ezetimibe providing approximately 40% LDL-C reduction in one tablet. This may be pertinent for patients with FH for whom pill burden is a real concern. In certain instances, bile resin binders may be useful in the treatment of FH (for example pregnant and lactating patients).

FIGURE 2. Approach to the Pharmacologic Treatment of Patients with Heterozygous Familial Hypercholesterolemia.

PCSK9 inhibitors consist of two therapeutic modalities, 1) monoclonal antibodies (alirocumab and evolocumab) that work extracellularly to sequester the PCSK9 protein, and 2) inclisiran, a novel, small interfering ribonucleic acid (siRNA)-based gene-silencing technology that inhibits mRNA translation and intracellular production of PCSK9 by the liver (111).

The effect of PCSK9i monoclonal antibodies in patients with HeFH has been extensively studied and consistently demonstrate potent LDL-C lowering on the order of 50-60% (63,112-126). An analysis of the ODYSSEY trials (FH I, FH II, LONG TERM, and HIGH FH) evaluated alirocumab use (75 or 150 mg subcutaneously every 14 days) in 1,257 HeFH patients. The primary endpoint was LDL-C at 24 weeks; alirocumab resulted in a more than 55% reduction in LDL-C compared with placebo (122). In another trial, alirocumab 150 mg every 14 days in 62 apheresis patients reduced the primary endpoint, rate of apheresis treatments over 12 weeks, by 75%, with 63.4% of patients completely discontinuing apheresis treatments due to well controlled LDL-C values (121). The RUTHERFORD-2 trial evaluated more than 300 patients with HeFH randomized to evolocumab (140 mg subcutaneously every 2 weeks or 420 mg subcutaneously monthly) versus placebo. At both dosing regimens, evolocumab resulted in significantly reduced LDL-C at 12 weeks compared with placebo (>60%) (63). In all trials, PCSK9i monoclonal antibodies were well tolerated, with most demonstrating treatment-emergent adverse events (TEAEs) similar to placebo. Clinically, the most common adverse events include: injection site reactions, mild cold or flu-like symptoms, nasopharyngitis, and myalgias (127). Thus, PCSK9i monoclonal antibodies are very effective at lowering LDL cholesterol levels and safe in HeFH patients.

Additionally, there are two cardiovascular outcomes trials that evaluated the FDA approved monoclonal antibodies targeting PCSK9. The FOURIER trial evaluated almost 28,000 subjects with stable vascular disease (CAD, stroke, peripheral arterial disease) on optimized statin therapy and randomized them to either placebo or evolocumab. Evolocumab therapy was associated with a 60% reduction in LDL-C and a 15% reduction in the primary 5-point major adverse cardiovascular event (MACE) rate (128). The FOURIER had an open-label extension trial (FOURIER-OLE) which followed 6,635 patients from the parent trial and allocated all patients (those originally assigned placebo or evolocumab) to evolocumab and followed over a median and maximal exposure of 7.1 years and 8.4 years respectively. Those originally assigned evolocumab in the parents study continued to display significant reductions in ASCVD events and even cardiovascular death as compared to those assigned placebo - establishing the important notion of a legacy effect with PCSK9i, where earlier initiation of therapy provides cardiovascular prevention that cannot be achieved when delayed. This study represents the longest follow-up to date of PCSK9i monoclonal antibodies and confirms that attainment of low LDL (30 mg/dL) is both safe and effective for preventing cardiovascular events (129).

ODYSSEY OUTCOMES enrolled approximately 18,000 subjects with recent acute coronary syndrome (1-12 months prior to enrollment in the trial) who were on high-intensity statin therapy at baseline and randomized them to placebo or alirocumab. Alirocumab was also associated with a 15% reduction in the primary outcome, in this case a 4-point composite of MACE (130). Major guidelines, consensus documents, and expert recommendations suggest consideration of a PCSK9 inhibitor (in addition to background statin +/- ezetimibe therapy) in high-risk patients with established ASCVD and/or in patients with severe hypercholesterolemia when LDL-C values exceed 55/70 or 100 mg/dL respectively (92,94,96,97,131-134). Both monoclonal antibodies have an FDA labeled indication for ASCVD risk reduction in patients with established ASCVD. Despite potent LDL-C lowering, a good safety profile, and robust clinical data demonstrating cardiovascular benefit, PCSK9i monoclonal antibodies are significantly underutilized among both patients with established ASCVD and those with FH, with reports suggesting only 1% to 2% of eligible patients currently prescribe PCSK9 inhibitors (135,136).

Inclisiran has been thoroughly studied in the ORION clinical development program, a series of phase 1 to 3 trials designed to investigate the pharmacokinetics, pharmacodynamics, optimal dose, efficacy, and safety of inclisiran in specific populations (111). ORION-9 was a phase 3, randomized, double-blinded, placebo-controlled trial evaluating use of inclisiran 300 mg given subcutaneously on days 1, 90, 270, and 540, in 482 HeFH patients with baseline LDL-C of ≥100 mg/dL(137). Treatment with inclisiran produced a placebo-corrected LDL-C reduction of 47.9% (P<0.001) at day 510. Response based on genotype was as expected, with LDL-C reductions of 41.2% to 59.2% for all except PCSK9GOF variants which were associated with dramatic LDL-C reduction of 89.7%. Pre-specified exploratory cardiovascular event (CV death, cardiac arrest, non-fatal MI, or non-fatal stroke) rates were comparable in both treatment groups (4.1% inclisiran vs. 4.2% placebo). Inclisiran was tolerated well during the trial with adverse events similar between treatment groups, with most adverse reactions mild to moderate in nature. The most common adverse event was injection site reactions, which was 10-fold higher in the inclisiran group (17%) compared to placebo (1.7%), however, 90% of these were graded as mild severity. Future studies will evaluate inclisiran in an adolescent HeFH population in the ORION-16 trial (138). Inclisiran was FDA approved in December 2021 as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including HeFH, to reduce LDL-C(139).Pooled analyses of ORION-9 (patients with HeFH), ORION-10 (patients with ASCVD), and ORION-11 (patients with ASCVD or ASCVD risk equivalents) demonstrated durable LDL-C reduction of approximately 50% with a good safety profile with only injection site reactions, predominantly mild, and bronchitis as potentially drug-induced adverse effects (140,141). Additionally, prespecified exploratory analysis of MACE which was a non-adjudicated outcome and a safety event, and which should be regarded as hypothesis generating only, hinted at a reduction in atherosclerotic events with inclisiran (141). The question of whether inclisiran reduces cardiovascular events will be definitively determined with two large cardiovascular outcome trials – ORION-4 and VICTORIAN 2P, with estimated completion dates in 2026 and 2027 respectively (111). Though PCSK9 inhibition by monoclonal antibodies and inclisiran are comparable in LDL-C reducing capacity, there are important differences to acknowledge 1) inclisiran has a long biological half-life allowing for twice yearly dosing and possible medication adherence advantages, 2) PCSK9i monoclonal antibodies are administered by patients in their home and inclisiran is to be administered by a healthcare professional in a healthcare setting, and 3) while PCSK9i monoclonal antibodies have robust data proving reduction in ASCVD events, clinical outcome trials with inclisiran are still in progress. Additional considerations with the in-clinic administration of inclisiran include a new medication use process which includes procurement, storage, administration, and billing, which is a new workflow to the cardiovascular community and may take time to acclimate to. There are also the financial implications from the patient perspective as inclisiran is billed under medical insurance, not pharmacy benefits, which has the potential for reduced out-of-pocket expense for Medicare recipients specifically (142,143).

Novel approaches to inhibit PCSK9 action, termed third-generation PCSK9 inhibitors, are currently in various stages of clinical development. These include once orally administered macrocyclic peptide agents (i.e., MK-0616), monthly subcutaneous injection fusion protein binders (i.e., Lerodalcibep), CRISPR-based gene editing (i.e., VERVE-101), and PCSK9 vaccines (144). New PCSK9 modalities offer potential advantages such as oral administration, storage at room temp, and less frequent administration. The magnitude of LDL-C reduction with these technologies is similar to currently existing PCSK9 therapeutics, approximately 40%-60% lowering, except for vaccination, which appears less robust with approximately 10%-30% LDL-C reduction. Time will tell if and how these newer therapies position themselves among the ever-changing lipid-lowering landscape.

Bempedoic acid, a novel inhibitor of adenosine triphosphate (ATP)-citrate lyase (ACL), an enzyme upstream from 3–hydroxy–3–methylglutaryl coenzyme A (HMG–CoA) in the cholesterol synthesis pathway, is the newest orally administered lipid-lowering therapy (145). Bempedoic acid is a prodrug, that is converted into its active form (bempedoyl-CoA) by very long-chain acyl-CoA synthetase 1 (ACSVL1), which is expressed in hepatocytes but is undetectable in muscle. Development of this agent was designed to circumvent the myotoxicity commonly associated with historical lipid-lowering therapies, primarily statins. Bempedoic acid was FDA approved on February 21, 2020 for use in patients with established ASCVD and/or HeFH who require additional LDL-C lowering as an adjunct to dietary intervention and maximally tolerated statin therapy (146). Bempedoic acid was evaluated in over 3,600 patients in the phase 3 CLEAR program trials, of which, only 3.7% were HeFH patients (145). A pooled analysis from two phase 3 trials, CLEAR Harmony and CLEAR Wisdom, demonstrated a similarly modest placebo-corrected LDL-C reduction at 12 weeks of bempedoic acid treatment in the HeFH cohort (22.3%) as compared to the overall population (18.3%) (147). Overall bempedoic acid was well tolerated in the phase 3 trials but occurrence of TEAEs was higher in the HeFH cohort compared to those without HeFH but was not increased with bempedoic acid versus placebo. Similar reports of efficacy and safety were seen in an updated analysis of phase 3 data in HeFH as well (148). In a real-world analysis of bempedoic acid, which was enriched in patients with HeFH (64%) and statin intolerance (74%), the drug was associated with clinically meaningful LDL-C lowering (mean reductions 20.3% to 36.7%), but high rates of TEAEs (50%) and drug discontinuations (35.9%)(149). Bempedoic acid completed a large cardiovascular outcome trial in 2023 with publication of the CLEAR OUTCOMES (150). The trial enrolled 13,970 patients with established cardiovascular disease (70%) or at high risk for cardiovascular disease (30%) who were deemed statin intolerant. Over a median follow-up of 40.6 months, the mean baseline LDL-C was reduced from 139 mg/dL to a timed-averaged, placebo-adjusted reduction of 22 mg/dL in the bempedoic acid group. Is important to note there was a larger drop in LDL-C levels in the placebo arm than usually observed in clinical trials, which may have diluted the difference in LDL-C reduction between the 2 groups. Nevertheless, the primary endpoint which consists of a 4-point MACE including death from cardiovascular causes, nonfatal MI, nonfatal stroke, or coronary vascularization was reduced from 11.7% in the placebo group vs.13.3% in the bempedoic acid group, HR 0.87 (95% CI 0.79 to 0.96), with statistically significant reductions seen the non-mortality outcome measures. Interestingly, the greatest relative risk reduction was seen in the primary prevention cohort (32%) as compared to the secondary prevention cohort (9%), however the clinical significance of this remains to be seen. Bempedoic acid was well-tolerated with small increases in biomarkers such as serum creatinine, blood urea nitrogen, hemoglobin, aminotransaminases, and uric acid, and rates of gout (3.2% vs 2.2%), and cholelithiasis (2.2% vs 1.2%) (151). In response to the CLEAR OUTCOMES data, the FDA updated the label for bempedoic acid which now includes “to reduce the risk of myocardial infarction and coronary revascularization in adults who are unable to take recommend statin therapy, including those not taking a statin, with established ASCVD or at high risk for ASCVD” (146).

Treatment of Patients with Homozygous Familial Hypercholesterolemia

The initial therapy in patients with HoFH is identical to the treatment of patients with HeFH. However, statins and ezetimibe may prove relatively ineffective in the treatment of HoFH because the mode of action of these drugs largely depends on the upregulation of functional LDLR in the liver. In HoFH, measurable activity of both copies of the LDLR is absent or greatly reduced (80). Drug-induced LDL-C lowering is diminished by more than 50% comparing HeFH to HoFH – high intensity statins lower LDL-C 50-60% vs 10-25% and ezetimibe lowers LDL-C by 15-25% vs <10%, respectively (see table 6) (95,152).

In patients with HoFH, response to PCSK9i monoclonal antibodies varies depending on the specific gene defect. In the TESLA-B trial, 49 patients with HoFH were treated with evolocumab or placebo every four weeks for 12 weeks. LDL-C in the evolocumab treatment arm was significantly reduced by almost 31% compared with placebo. In addition to overall reduction in LDL-C, the trial investigators examined the treatment effect by LDLR mutation status. They found that the response to evolocumab aligns with the genetic cause of HoFH, with a greater reduction in LDL-C observed in subjects with two LDL receptor-defective mutations (i.e., abnormal receptor functionality in both alleles) when compared with those patients with even just one LDL receptor-negative mutation (i.e., nonexistent receptor functionality in one allele). Evolocumab was well tolerated among the HoFH patients (153). Similar results were seen in other HoFH trials examining the PCSK9i monoclonal antibody (alirocumab) and over longer follow up durations, providing confirmation of durable LDL-C efficacy and safety with this therapeutic class (154-156).

Inclisiran, dosed as 300 mg subcutaneously on days 1 and 90 (or 104 if PCSK9 level was suppressed by >70%), was evaluated in 4 HoFH patients enrolled in the ORION-2 trial (157). Patients were ages 50, 46, 23, and 29 years, 50% female, and had baseline LDL-C 540 mg/dL, 547 mg/dL, 614 mg/dL, and 189 mg/dL, respectively. All had biallelic causative genetic variants in LDLR, and all were on high-intensity statins and ezetimibe. Inclisiran-induced LDL-C reductions ranged 11.7% to 33.1% at day 90, and 17.5% to 37.0% at day 180 in three of the four patients, similar to results in prior trials of PCSK9i monoclonal antibodies in HoFH patients with residual LDLR function. One patient (LDLR c.681C/G [defective]) who had a history of hypo-responsiveness to both PCSK9i monoclonal antibodies (<20% lowering), also exhibited no change in LDL-C with inclisiran treatment. No adverse events were recorded over a 10 month follow up. A second, larger study of inclisiran use within the HoFH population was evaluated in a 2-part, phase 3 ORION-5 trial (158). Part 1 is a double-blind randomized study where patients were randomized in a 2-1 fashion to inclisiran and placebo respectively at days 1 and 90. Part 2 consisted of an 18-month open label single-arm extension trial in which all patients received inclisiran at day 180 and every 6 months thereafter until end of study at day 720. The study included 56 HoFH adults on stable lipid-lowering therapies including high-intensity statin 100%, ezetimibe 66.1%, and apheresis 35.7%. The median age was 42.7 years, 60.7% were women, and 67.9% had established ASCVD. The baseline mean LDL–C was 315.3 mg/dL with a higher value in the placebo group (356.7 mg/dL) as compared to the inclisiran group (294 mg/dL). Notably, more patients in the inclisiran group displayed the null/null LDLR genotypes which are known to produce blunted response to PCSK9 inhibition (27% versus 15.8%) – an important difference that may have confounded the treatment results. The primary endpoint, placebo–corrected percent change in LDL-C from baseline to day 150 was not statistically significant (-1.68%; P=0.90). The absolute placebo–corrected change in LDL-C level from baseline to day 150 was 6.47 mg/dL (P=0.87). The lack of statistically significant change in LDL values occurred despite a 60.6% reduction in plasma PCSK9 levels with inclisiran use. There were wide fluctuations in LDL-C reduction based on genotype: +26.6% with homozygous LDLR, -26.6% with compound heterozygous LDLR, and -22.5% with other genetic types. A post-hoc sensitivity analysis excluding patients with LDLR null/null genotypes and undergoing lipoprotein apheresis revealed greater reduction in LDL-C from 12.9% to 30%, indicating that inclsiran requires sufficient residual LDLR function to be effective within this population. There were no statistically significant changes in other proteins including apoB, non-HDL C, lipoprotein (a) and total cholesterol. Similar to prior evaluations of inclisiran, the medication was well-tolerated. The lack of positive treatment results from the ORION-5 cannot exclude a small sample size compared to those enrolled in the PCSK9i monoclonal antibody trials, an imbalance in genotypes in the present study, or differing mechanisms for PCSK9 intubation (159). The upcoming study of inclisiran in adolescent (ORION-13) HoFH patients, Which is estimated to be completed by December 2024, will shed further light on the use inclisiran in HoFH. (160).

Standard triple drug therapy (statin, ezetimibe, PCSK9 inhibitor) often does not result in a sufficient lowering of LDL-C due to the combination of the very high baseline LDL-C and the relative resistance of patients with HoFH to drug therapy. Currently, there are no published reports of bempedoic acid use within the HoFH population. Novel agents approved specifically for the treatment of severe hypercholesterolemia include microsomal triglyceride transfer protein (MTP) inhibitors and apoB-100 antisense oligonucleotides (ASO). MTP is involved in the transfer of lipid droplets to apoB as well as assembly and secretion of apoB-containing lipoproteins in the liver and gut. MTP inhibition thus reduces production and secretion of chylomicrons and VLDL-C. In one study, 29 patients with HoFH were treated with the MTP inhibitor lomitapide for 26 weeks and were followed until week 78. Average LDL-C reductions were 50% (to 166 mg/dl) at week 26, 44% (to 197 mg/dL) at week 52, and 38% (to 208 mg/dL) at week 78 (161). Real-world observational data of lomitapide from the LOWER registry suggest slightly less robust LDL-C lowering (33%) and LDL-C goal attainment (65.4% attaining LDL-C <100 mg/dL, 41.1% attaining LDL-C <70 mg/dL), likely a result of inadequate dose titration (mean dose 10 mg/d, range 5-40 mg/d) due to a high burden of adverse effects with nearly quarter of patients discontinuing treatment due to side effects (162). Though lomitapide displays potent LDL-C lowering capacity, use is limited as a result of a significant side effect profile consisting of severe gastrointestinal complications and hepatotoxicity risk, as well as high medication cost.

Anti-sense oligonucleotide (ASO) molecules bind to specific mRNAs and target them for degradation, reducing protein synthesis in the process. Mipomersen, which was removed from the market in June 2018, is an ASO that binds to apoB-100 mRNA and thus prevents the formation of apoB-100. Mipomersen results in decreased synthesis of apoB-containing lipoproteins, mostly VLDL-C, eventually leading to a drastic reduction of LDL-C levels in plasma. In one trial, 51 patients with either genetically defined HoFH, untreated LDL-C levels of >500 mg/dL plus xanthomas, or evidence of HeFH in both parents were randomized to placebo versus mipomersen for a treatment duration of 26 weeks. In the placebo group, baseline LDL-C was 402 mg/dL and declined to 390 mg/dL; in the treatment group, baseline LDL-C dropped from 440 mg/dl to 324 mg/dL (163).

Evinacumab is the newest addition to the lipid-lowering treatment armamentarium, receiving FDA approval in February 2021 as an adjunct to other LDL-lowering therapies for treatment of adults and pediatric patients originally ≥12 years of age with HoFH, with the age being reduced to ≥5 years of age in March 2023 (152). Evinacumab is a fully human IgG4 isotype monoclonal antibody targeting a novel, non-LDLR pathway for LDL-C lowering by inhibiting angiopoietin-like 3 (ANGPTL3) (164). ANGPTL3 inhibition overrides the inhibitory effect on lipoprotein lipase (LPL) and endothelial lipase (EL) increasing the activity of these enzymes, producing a panlipid-lowering effect of apo-B containing lipoproteins (with the exception Lp[a]), reducing lipoproteins by approximately 50% from baseline (152). Specifically, evinacumab promotes LDL-C lowering through EL-dependent VLDL-C processing and clearance by LDLR independent pathways, thereby decreasing formation of LDL-C from VLDL-C.(165) The magnitude of LDL-C lowering was seen in both HoFH and HeFH populations and was similar regardless of genotype. Serial coronary computed tomography angiography (CCTA) evaluations of two HoFH patients enrolled in the ELIPSE HoFH trial demonstrated reductions in coronary total plaque volume (TPV) of 76% to 85% over 10 months of treatment with evinacumab (166). Evinacumab is dosed at 15 mg/kg of body weight given over a 60 minute intravenous infusion (152). The drug is well tolerated with adverse effects being infrequent, mild, and transient, consisting primarily of injection site reactions, flu/cold-like symptoms, pain, and fatigue. The long-term safety of evinacumab remains unknown. A recent real-world analysis of evinacumab use across six US academic medical centers, demonstrated good tolerability, potent LDL-C lowering (50.8%), and LDL-C goal attainment (30.4% achieving LDL-C goals of <70 mg/dL) among 24 patients followed for up to 63 weeks (167). Additionally, a real-world analysis demonstrated that evinacumab can be a complementary therapy to apheresis. A single center US academic medical institution described the use of two patients undergoing apheresis for whom evinacumab was added achieving LDL-C lowering of 42% to 58%, and LDL-C goal attainment of <55 mg/dL in one patient. The study concluded that evinacumab presents a major advancement in the treatment of HoFH and will allow for improved LDL-C goal attainment. Evinacumab will be complementary to ongoing lipoprotein apheresis in many, but for those with less severe residual LDL-C elevation, may allow for reduced apheresis frequency or potentially replace its use altogether (168). The most recent study of evinacumab was published January 2024 and included an open-label 3-part series evaluating evinacumab use in pediatric patients age 5 to 11 years of age with HoFH (169). Part A was a pharmacokinetic study of 6 patients which determined that the 15 mg/kg intravenously administered dose utilized within the adult patient population was appropriate for pediatric patients. Part B was a phase 3, single-arm, 24-week open-label study assessing the efficacy, safety, and pharmacokinetics of evinacumab in 14 patients. Part C is an ongoing, phase 3, 48-week open-label extension study with a 24-week follow-up designed to assess the long-term safety and efficacy of evinacumab and will include all 20 patients from parts A and B. The mean age for patients in the part B trial was 9.1 years, 57.1% of which were females with 71% of patients having biallelic different LDLR variance, with 5 patient's carrying null/null alleles. Additionally, 11 of the 14 of patients already had aortic stenosis at this young age. Baseline LDL-C was 263.7 mg/dL, 85.7% were on any statin, 50% were on high-intensity statin, 100% were taking non-statins (none on PCSK9 inhibitor), 14.3% were taking lomitapide, and 50% were on apheresis. The primary endpoint, mean LDL-C percent change from baseline was reduced by 48.3% with an absolute LDL-C lowering of 131.9 mg/dL at week 24. LDL-C reduction was seen as early as week 1 with near full response witnessed by week 2. Response was independent of age, sex, ethnicity, LDLR genotype, or baseline apheresis use. Evaluation of other lipoprotein parameters included reductions of 41.3% in apoB, 48.9% in non-HDL-C, 49.1% in total cholesterol, and 37.3% in Lp(a). Similar to that seen in the adult population, evinacumab was well-tolerated with no treatment-related serious or severe TEAEs noted and no drug discontinuations due to adverse effects. Immunogenicity potential was minimal with only 1 patient developing treatment emergent antidrug antibodies but no neutralized antibodies. Evinacumab is poised to play a significant role in HoFH management as it offers one of the most potent LDL-C lowering capabilities among existing treatments. Use in HoFH will likely be as an add-on therapy after high-intensity statin, ezetimibe, and PCSK9 inhibition. However, potential barriers to use may include high cost, intravenous administration, and requirement for administration in a healthcare or home infusion setting. Future use of evinacumab may extend beyond HoFH and could entail use in other therapeutic areas such as HeFH and severe hypertriglyceridemia.

In patients in which drug therapy is either not successful at lowering LDL-C or not well tolerated one can consider lipoprotein apheresis or potentially even liver transplantation (170). The FDA has approved lipoprotein apheresis for subjects with CVD and LDL-C >200 mg/dL or without CVD and LDL-C >300 mg/dL (171). This threshold has been moved to 160 mg/dL, and more recently to 100 mg/dL with FH and ASCVD, thus increasing the target population for cholesterol dialysis at a time when arrival of stronger medications is curtailing patient entry into this therapeutic program. The process, which involves removing apoB-containing lipoproteins from plasma, is usually performed every two weeks and results in a 60-70% reduction of LDL-C and Lp(a) in the immediate post-procedure period, with time-averaged reductions of 20-50%. Levels tend to revert to baseline within two weeks. For more detailed information on lipoprotein apheresis see the Endotext chapter on this topic (172).

TABLE 6. COMMON LIPID-LOWERING TREATMENTS FOR FH
Agent	Niacin	BAS	Fibrate	Statin	Ezetimibe
FDA approval date	1997*	1973	1981† 1993	1987	2002
Administration	PO	PO	PO	PO	PO
Dosing	Daily	Daily	Daily	Daily	Daily
LDL-C lowering (HeFH)	10%-25%	15%-30%	10%-20%	20%-60%	15%-25%
LDL-C lowering (HoFH)	<10%	<10%	<10%	10%-25%	<10%
Lp(a) lowering	20-30%	N/A	N/A	N/A	N/A
Relative cost	+/++	++	+	+	+
Safety concerns	Flushing, moderate GI intolerance (abd pain, nausea, vomiting, peptic ulcer), hyperglycemia, gout, hepatotoxicity	Moderate GI symptoms (abd pain, constipation, bloating, nausea), hypertriglyceridemia, fat-soluble vitamin deficiencies	Myalgia, mild GI symptoms (abd pain, diarrhea), cholelithiasis, increased LFT	LFT elevation, myalgia, DM risk	Mild GI symptoms (loose stool, diarrhea, cramping), myalgia, increased LFT
Other consider-ations		High pill burden, separate from other meds (binding)	Primarily used for triglyceride lowering, renal dose adjustments	Usually well tolerated

Adapted from Warden BA, et al. Expert Rev Cardiovasc Ther. 2021;1-13.

*Approval date is for niacin extended-release. Niacin has been used clinically for hypercholesterolemia since the 1950’s.

†Gemfibrozil FDA approved in 1981, fenofibrate in 1993.

TABLE 7. ADVANCED LIPID-LOWERING TREATMENTS FOR FH
Agent	Lipoprotein apheresis	Lomitapide	PCSK9i*	Bempedoic acid	Evinacumab
FDA approval date	1996	2012	2015	2020	2021
Administration	IV	PO	SQ	PO	IV
Dosing	2-4x monthly	Daily	1-2x monthly	Daily	Monthly
LDL-C lowering (HeFH)	50-85% (acute) 23-50% (time-average)	N/A	50%-60%	15%-25%	49%
LDL-C lowering (HoFH)	50-85% (acute) 23-50% (time-average)	20%-50%	zero-30%†	Unknown	49%
Lp(a) lowering	50-75% (acute) 20-40% (time-average)	zero-30%	20-30%	N/A	N/A
Relative cost	++++	++++	+++	++/+++	+++++
Safety concerns	IV access issues, hypotension, vasovagal episodes, fatigue, bleeding, hypocalcemia, anemia	Severe GI intolerance (diarrhea, nausea, vomiting, abd pain, cramping), fat malabsorption, hepatic steatosis, hepatotoxicity (REMS)	ISR, flu/cold-like symptoms	Mild GI symptoms (diarrhea, abd discomfort), gout, tendon injury, transient lab changes (SCr, BUN, LFT, Hgb, HCT, uric acid)	Nasopharyngitis, ISR, flu-like symptoms, fatigue, pain, headache, rare hypersensitivity reaction
Other consider-ations	Lengthy and frequent treatments, need for patient travel, DDI (heparin, ACEi)	Significant DDI, renal dose adjustments	Access and cost issues	Improves glycaemia, option for patients with SAMS	Reduces all non-Lp(a) apoB-containing lipoproteins

Adapted from Warden BA, et al. Expert Rev Cardiovasc Ther. 2021;1-13.

*PCSK9i: represent PCSK9 blocking monoclonal antibodies and inclisiran, a novel small interfering ribonucleic acid (siRNA)-based medication.

†Response aligns with genetic cause of HoFH with no reduction was seen in those with null-null LDLR mutations.

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Fibrocalculous Pancreatic Diabetes

ABSTRACT

In tropical countries like India, there are several reports of a unique form of diabetes called fibrocalculous pancreatic diabetes (FCPD). In majority of the cases, FCPD occurs in young, lean individuals with diabetes, abdominal pain, and steatorrhea. Diabetes is typically ketosis resistant. Recent studies have shown that a proportion of the cases may have genetic factors and gene mutations that confer the risk of developing the disease. Recent studies have suggested a changing profile of the disease which could also be present in older individuals having a normal body mass index and better survival perhaps attributable to better exocrine and endocrine (diabetes) care being offered to people with FCPD. The management of exocrine insufficiency is by the same standards as in any other cause of chronic pancreatitis, and the same is true for diabetes management except for the need of insulin therapy in most cases. The most distinguishing and worrying feature of FCPD is the higher risk of developing pancreatic cancer for which vigilance is paramount.

INTRODUCTION

It is well known that diabetes in tropical and developing countries is different from that seen in the Western World. For example, people with diabetes in India are leaner, develop diabetes earlier than their counterparts, making the distinction between insulin deficient type 1 and insulin resistant type 2 diabetes challenging (1,2). In addition, some people with lean type diabetes in India could have a latent autoimmune diabetes of the adult (3). In earlier times, the leanness was attributable to factors like malnutrition (4), which has become less frequent over the years with increasing improvement in nutritional status in the Indian population, though not uniform (5). Type 2 diabetes in India has become associated with the “thin-fat” Indian concept, which describes the presence of visceral adiposity in thinly built persons, although not all lean diabetes in India conforms to this phenotype (2, 6,).

Another distinct subtype of diabetes seen with leanness in this population was eventually termed fibrocalculous pancreatic diabetes (FCPD) (7). It is included in the current WHO classification of Diabetes Mellitus of 2019 as a subtype within ‘other specific types of Diabetes’ (8). This form of diabetes typically occurs in young people, in people with a low body mass index (BMI), and with clinical features of malnutrition. It is unique because of structural changes identified in the pancreas described below and the associated pancreatic dysfunction. Before the onset of diabetes, there is a pre-diabetic phase of pancreatic damage referred to as tropical chronic pancreatitis, a term indicating its geographical association with tropical countries such as India.

This article will discuss the unique nature of FCPD, its pathogenesis, the changing clinical spectrum and aspects of managing the condition.

EPIDEMIOLOGY AND HISTORICAL ASPECTS

In 1959, Zudeima reported a series of patients, particularly in the lower socioeconomic groups, with features of undernutrition and presence of pancreatic calculi (9). However, it was the disease-characterization work of Dr Geevarghese a decade later that the disease became known worldwide as such (10), with several Indian states adding to the description over subsequent decades (11,12,13). India, Brazil, Thailand, and other tropical countries published observations similar to those reported by Zudeima over the next four decades (14,15).

Early reports indicated FCPD to be an important cause of diabetes in young, lean individuals with features of malnutrition. In 2008, a national prospective study involving 32

Centers across various regions of India established a comprehensive database of patients with chronic pancreatitis which yielded significant insight into the clinical profile FCPD at the time (16). The disease profile of FCPD appeared to overlap with idiopathic pancreatitis, and that leanness and malnutrition were not integral to chronic pancreatitis, perhaps reflecting improved treatment of the condition. These changes were substantiated in subsequent reports (17, 18). More recent reports indicate that FCPD accounts for only a small proportion of people with young-onset diabetes (19).

The life expectancy of people with chronic pancreatitis has increased compared to that in the past, though not yet returned to normal (20). It is universal knowledge that longer duration of, particularly uncontrolled, hyperglycemia leads to microvascular complications. Hence, with improved overall care, diabetes complications have been known to occur in patients with FCPD (21), though macrovascular complications are thought to be rare.

PATHOGENESIS

The exact pathogenesis of FCPD is unclear with oxidative stress, micronutrient deficiency, dietary toxins, and autoimmunity implicated inconclusively.

A disbalance between the oxidative stress and antioxidant responses in the body has been postulated in FCPD based on reduced levels of antioxidant markers found with heightened oxidative stress markers (22). The consumption of cassava being linked pathogenetically to FCPD (23) was later proved to be of doubtful significance (24). While malnutrition is associated with FCPD, later reports indicate it to be a consequence rather than cause of FCPD (13).

Human leukocyte antigen (HLA) associations as part of genetic susceptibility studies were inconclusive. Altered expression of genes such as serum protease inhibitor Kazal type 1 (SPINK1), cationic trypsinogen (PRSS1), anionic trypsinogen (PRSS2), and chymotrypsinogen C have been noted in FCPD and in the Indian population, the N34S variant of the SPINK gene appears to confer susceptibility in 33% (25). Two hit model with the first step being alteration of genes leading to supertrypsin formation in the acinar cells of pancreas, followed by a second hit involving unidentified genes leading to gross structural changes within the gland and/or manifestation of disease was proposed as a more plausible phenomenon over a decade ago (26).

In summary, a multitude of pathogenetic mechanisms for FCPD has been proposed based mostly on earlier evidence from a time when the disease was reportedly more prevalent, neither one of which alone may play a singular role and that a complex interaction, most likely of gene-environment, underlies disease evolution.

TABLE 1. PATHOPHYSIOLOGICAL FACTORS POSTULATED IN THE ETIO-PATHOGENESIS OF FCPD
Genes Identified In FCPD · Serum protease inhibitor Kazal type 1 (SPINK1)- especially N34S mutation · Cationic trypsinogen (PRSS1) · Anionic trypsinogen (PRSS2) · Chymotrypsinogen C	Factors Implicated With Inconclusive Evidence · Toxins e.g. Cassava consumption · Imbalance of oxidative stress and antioxidants · Malnutrition
Proposed Two-Hit Model · First hit: genetic mutation leading to alteration in pancreatic acinar cells · Second hit: unidentified genes leading to disease manifestation

TABLE 1. PATHOPHYSIOLOGICAL FACTORS POSTULATED IN THE ETIO-PATHOGENESIS OF FCPD

Genes Identified In FCPD

· Serum protease inhibitor Kazal type 1 (SPINK1)- especially N34S mutation

· Cationic trypsinogen (PRSS1)

· Anionic trypsinogen (PRSS2)

· Chymotrypsinogen C

Factors Implicated With Inconclusive Evidence

· Toxins e.g. Cassava consumption

· Imbalance of oxidative stress and antioxidants

· Malnutrition

Proposed Two-Hit Model

· First hit: genetic mutation leading to alteration in pancreatic acinar cells

· Second hit: unidentified genes leading to disease manifestation

PATHOLOGY OF DIABETES IN FCPD

While early evidence supported reduced mass and insulin secretion by beta cells, insulin resistance has been recognized to play a role in the pathogenesis of diabetes in FCPD.

Both basal insulin secretion and stimulated insulin levels in response to a glucose tolerance test are reduced in people with FCPD compared to controls (11,13). Preservation of some beta cell function is supported clinically by the relatively rare instances of ketoacidosis following withdrawal of insulin (27). Ketoacidosis may be less common due to not only some residual insulin secretory activity but also due to reduced glucagon reserve secondary to alpha cell destruction and reduced availability of non-esterified fatty acid substrate for ketogenesis due to lack of visceral fat (28). Studies have also suggested that exocrine function could correlate with endocrine dysfunction. While it is simple and logical to presume that any pancreatic pathology would reduce insulin production, the situation is more complex than meets the eye.

There is evidence of insulin resistance (IR) in people with FCPD when measured by mean glucose disposal rates and homeostasis model assessment-IR, independent of BMI (13,29). Deficiency of pancreatic polypeptide (PP) has been postulated to underlie IR in FCPD, particularly at the level of the liver where defects in the internalization of liver glucose transporter-2 as well as altered bioavailability/ function of hepatic insulin receptor have been observed. The role of glucagon and thereby preservation or otherwise of alpha cells is debatable. Reduced fat store in people with FCPD may lead to the storage of triglyceride in the liver, which could predispose to insulin resistance.

This century has seen groundbreaking work in understanding the pathophysiology of endocrine dysfunction following non-necrotizing pancreatitis, including prediabetes and diabetes (29). New mediators and their associations include increased interleukin-6 driving insulin resistance and reduced pro-glucagon gut peptides oxyntomodulin [capable of signaling through glucagon like peptide 1 (GLP-1) and glucagon receptors] and glicentin with the former showing potential as a biomarker to distinguish post-pancreatic diabetes from T2DM. These pathways may well be implicated in FCPD, at least in part.

CLINICAL FEATURES AND NATURAL HISTORY OF FCPD

The first symptom is abdominal pain, noted in the upper abdomen radiating to the back and relieved by stooping forward or lying in a prone position, typical of pancreatitis pain. The pain abates, both in frequency and severity, which is followed by development of oily and frothy stool due to fat malabsorption indicating exocrine pancreatic insufficiency, as in pancreatic involvement from other chronic pathologies. Rise in blood glucose and eventually diabetes results usually one to two decades after the onset of abdominal pain. Tropical chronic pancreatitis is the pre-diabetes phase of the disease, whereas FCPD is the term used once diabetes has been diagnosed by universal diagnostic criteria.

FCPD has been classically described in young, lean, malnourished people of low socioeconomic background residing in tropical countries. The onset of pancreatic disease is in childhood with diabetes developing between 15 and 35 years of age, requiring treatment with large doses of insulin for moderate to severe hyperglycemia, and usually no ketosis despite insulin withdrawal (7).

The clinical profile of FCPD and previously described criteria may no longer be strictly applicable as reported in a nationwide study of pancreatitis conducted in 32 centers in different regions of India, including a total of 1033 patients (16). According to that survey, which used original criteria including a low BMI, the disease-affected people had normal BMI and presentation was later in life, contrary to the original descriptions of this entity. In this study, tropical pancreatitis accounted for only 3.8% of chronic pancreatitis, suggesting a downward trend in its incidence or at least the diagnosis. Classical signs such as cyanotic hue, distended abdomen, and parotid gland swelling may also no longer be seen (12).

With appropriate diabetes care and good pancreatic enzyme supplementation, malnutrition is rare, as is death due to diabetes in adolescence (30). As is true in patients with chronic pancreatitis, people with FCPD are also now likely to have a relatively ‘normal’ BMI and not necessarily be ‘lean’ as per the original description of this entity. Severity of diabetes appears to be higher in lean individuals. Thus, in addition to the typical, young and malnourished patient with FCPD, it may be important to consider an “extended spectrum” of FCPD, with people being older, higher BMI, and at risk of diabetes vascular complications also being considered in the spectrum.

More research is needed to characterize FCPD beyond simple clinical criteria. These criteria alone may yield a disproportionately large number of these cases, and those that are limited to a geographical region. Hence, we call for development of newer criteria for FCPD, perhaps including a biological approach.

The natural history of FCPD begins with abdominal pain and progresses through a subclinical e.g. pancreatic calcification phase followed by exocrine and later endocrine pancreatic insufficiency. This has undergone a shift from earlier days of abdominal pain in childhood, diabetes in adolescence and death in early adulthood. Unlike the reports of early mortality in the past, it is well known that people with FCPD now live longer, with 80% living beyond 35 years since the onset of abdominal pain (21).

People with FCPD appear to be at risk of microvascular diabetes-related complications like retinopathy, nephropathy, and neuropathy as in other patients with diabetes, perhaps secondary to the longer life span that these patients enjoy (11). Macrovascular complications like stroke and peripheral vascular diseases are however relatively rare likely due to relative youth, lower cholesterol levels, and leanness at least in the majority of patients (3,12).

Modifiable mortality attributable to the standard vascular and non-vascular complications in FCPD remains the same as in T2DM and T1DM. The risk of death from pancreatic cancer is disproportionately high, particularly for women (31).

DIAGNOSIS AND WORK UP OF FCPD

As per the currently established criteria, FCPD should be suspected in young, lean people from tropical countries who have a history of abdominal pain and steatorrhea, particularly if they have features suggesting malnutrition along with diabetes and especially if the diabetes is ketosis resistant (30). Conventionally, the disease is thought to occur only in tropical countries, however currently, there is no evidence to link any geographical factor with the etiology of the disease. The absence of a single detectable secondary cause of chronic pancreatitis is important. Also, given the changing profile of the disease discussed above, it is not limited to people with a lower BMI and in an adolescent age group. FCPD is an important but increasingly less frequent cause of diabetes in the young (32).

The diagnosis of FCPD is made when diabetes mellitus is associated with characteristic abnormalities in the pancreas including large intraductal calculi, fibrosis, or ductal changes. The presence of large and discrete pancreatic stones is a classical feature of the diagnosis of FCPD (15). Computerized tomography, magnetic resonance imaging, or endoscopic retrograde cholangiopancreatography may be required to clinch the diagnosis if typical calculi are absent on standard modalities such as x ray or ultrasound.

Thorough diagnostic workup should include a gastroenterological and an endocrinological consultation, with the latter ensuring standard tests in the management of all types of diabetes, including regular measurement of glycosylated hemoglobin, renal function, lipid profile, urine albumin creatinine ratio, foot neurovascular assessment, retinal screening, and when indicated, screening for cardiovascular disease.

Endocrine tests, like the measurement of C-peptide, may help clinical management, when a low C-peptide level would signal the need for insulin therapy, but they have no specific role in the diagnosis of FCPD. However, CA-19.9 for the early diagnosis of pancreatic cancer assumes a more important role from the point of view of long-term prognosis. Exocrine pancreatic dysfunction may be assessed by several tests of which low fecal elastase-1 assay is of practical significance, as well as low fecal chymotrypsin. The secretin pancreozymin test, which is a more dynamic assessment of pancreatic secretory function in response to the hormone secretin, is more cumbersome involving an endoscope.

TABLE 2. DIAGNOSTIC CRITERIA FOR FCPD
1. Occurrence in a tropical country
2. Diabetes as per standard diagnostic criteria
3. Evidence of chronic pancreatitis: a. Pancreatic calculi on X-ray or b. At least 3 of the following: i. Abnormal pancreatic morphology by imaging ii. Chronic abdominal pain since childhood iii. Steatorrhea c. Abnormal pancreatic function test
4. Absence of other causes of pancreatitis like alcoholism, hyperparathyroidism, marked hypertriglyceridemia, hepatobiliary disease etc.

Figure 1. X-ray abdomen showing multiple tiny opacities in epigastric region, suggestive of pancreatic calcification.

Figure 2. Ultrasound of abdomen showing atrophic pancreas, with dilated main pancreatic duct and multiple calculi in main pancreatic duct.

Figure 3. CT scan of abdomen showing atrophic pancreas with few parenchymal foci of calcification. Main pancreatic duct is dilated along with hyper dense calculi.

Figure 4. MRI scan of abdomen (axial -T2 weight HASTE sequence) showing atrophic pancreas with dilated main pancreatic duct and few filling defects within, suggestive of calculi.

Figure 5. MRI scan of abdomen (coronal - T2 weight HASTE sequence): Atrophic pancreas with dilated main pancreatic duct and few filling defects within, suggestive of calculi.

Figure 6. Maximum Intensity Projection Image showing irregular dilatation of main pancreatic duct with calculi within.

MANAGEMENT

The management of FCPD includes management of diabetes, with special consideration for aspects of chronic pancreatitis. While diabetes can be managed with lifestyle changes and oral drugs in a few cases, insulin is required in many cases.

Nutritional Management

As in other form of diabetes, medical nutrition therapy is the cornerstone of FCPD management. As most FCPD patients are lean, calorie restriction should be avoided. A balanced diet with adequate carbohydrates, fat, and proteins must be ensured. A low-fat diet helps in the management of steatorrhea (33). A gastrointestinal consultation to assess correlation of steatorrhea and other gastrointestinal symptoms with various foods should help in planning appropriate meals. Foods with potential for toxic effect on the pancreas, such as cassava (tapioca) should be avoided, though no conclusive link between the two has been proven and the damage to the pancreas is advanced. Fat soluble vitamins should be replaced as their absorption may be limited in FCPD. If available, sublingual or parenteral formulations of vitamin D may be preferred, to guard against pancreatic osteodystrophy. Smoking and alcohol must be avoided altogether.

Pain Management

Pain is a common symptom of FCPD and can occur due to acute inflammation of the pancreas, increased pressure within the parenchyma and the ductal system, ischemia of the gland, microvascular complications such as neuritis, and due to the space-occupying effect of pseudocysts. Abdominal pain is ideally managed by non-opioid analgesic, though in later stages their judicious use may be necessary (34). Subcutaneous octreotide, a synthetic somatostatin analogue, has been used to reduce the pain of chronic pancreatitis. It inhibits pancreatic secretion and increases the contractility of the sphincter of oddi.

Multiple antioxidants have proven benefit in pain reduction when used together, also in combination with micronutrients (34). Pancreatic enzyme replacement therapy (PERT – discussed in detail in the next section), while important from the exocrine therapy perspective, may benefit pain only if high protease containing (>25,000 USP units per tablet) preparation, in an uncoated formulation, is prescribed multiple times a day. PERT degrades cholecystokinin-releasing peptide in the duodenum and facilitates inhibition of endogenous pancreatic activity and thus may help with pain reduction. Endoscopic interventions to remove stones and lithotripsy may be helpful (35). Severe pain may require surgical procedures such as ductal decompression, drainage procedures like pancreatojejunostomy, and ablative procedures like subtotal pancreatectomy in refractory cases. Coeliac blockage has also been tried as a pain-relieving intervention.

Management of Pancreatic Exocrine Insufficiency

Steatorrhea responds to pancreatic enzyme supplements, which also helps improve glucose control. PERT is necessary to ensure adequate nutrient absorption and prevent down- stream effects such as protein-energy and vitamin malnutrition. It is important to prescribe an optimal dose of PERT, at the right time. Enteric coated PERT is the preferred option, unless being used also for pain relief, as it prevents the contents from being denatured by the acidic medium of the stomach prior to reaching the duodenum (34). Standard approach includes initial doses of 500-1000 lipase units/kg of body weight with each meal, up to maximum of 2,500 lipase units/kg per meal. While doses may vary with meal content and portion, in practice, 10,000-20,000IU for a small meal with 40,000 to 50,000 for a main meal often suffice in persons with diabetes who may need lower doses when following low-fat diet (36).

Ideally, patients should take half the dose with first bite of a meal, and the remaining half in the middle or at the end. However, as most patients prefer a reduced pill burden, the entire dose can be taken with the first bite of food to ensure adherence and convenience. Patients should be advised to avoid copious quantities of water with the tablet to prevent rapid transit through the upper gut.

The adequacy of PERT replacement is determined clinically by enquiring about stool consistency, presence or absence of oily droplets in the stool, weight gain, muscle mass, and bone health. Fecal fat and breath tests to evaluate response to PERT are reserved for use in a research setting. Fecal elastase-1 is not impacted by PERT and cannot be used as a monitoring tool. PERT can be combined with proton pump inhibitors and/or histamine-2 blockers, as these increase the responsiveness to PERT by reducing acidic degradation of the formulations.

Diabetes Management

A balanced and healthy diet with whole grains and adequate micro-and macronutrient intake is important, with due care given to the quantity of carbohydrate intake in the presence of diabetes. Restriction of simple carbohydrates remains a key recommendation. Adequate protein intake is important. In the presence of steatorrhea, a low-fat diet is important. Adequate physical activity, like brisk walking, and stress reduction are beneficial lifestyle measures advisable for all patients (36).

Insulin levels have been noted to be lower in majority of FCPD patients and so insulin remains the drug of choice. Long-acting basal insulin and multiple doses of rapid acting insulin at mealtime is the ideal insulin regime in FCPD (Figure 7). Glycemic targets to be attained with anti-diabetes therapy are similar to those recommended for all types of diabetes. Cardio-metabolic risk factors, such as hypertension and dyslipidemia, should be approached in a standard manner. Very high triglyceride levels > 500 mg/dl put people with FCPD at risk of pancreatitis, and therefore may need medications such as fibrates (33).

FIGURE 7: Representative Ambulatory Glucose Profile of a patient with FCPD well controlled on basal-bolus insulin therapy (Time in range 87%; time above range 10% and time below range 3%; glucose management indicator 6.4%).

Oral anti-diabetes agents are useful only in a minority of patients with FCPD, as insulin is the medication of choice (36). Among secretagogues, short acting drugs like repaglinide, which stimulate insulin secretion may be considered. Metformin has the benefit of glucose control without hypoglycemia and may be beneficial in countering insulin resistance in some patients. In addition, there is evidence that metformin could protect against pancreatic cancer (37). However, metformin may worsen gastrointestinal symptoms and lead to diarrhea and undesirable weight loss, and hence cautious use is advised.

Oral antidiabetic agents that seem less favorable in FCPD include alpha glucosidase inhibitors due to gastrointestinal symptoms, thiazolidinediones due to the link with osteoporosis, and oral sodium glucose co-transporters due to the associated weight loss until more research indicating benefit becomes available. Incretin based drugs, including GLP-1 receptor agonists or dipeptidyl peptidase 4 inhibitors should not be prescribed in FCPD, given the link between incretin-based therapies and pancreatitis. In fact, there is data from India that GLP-1 increases two-fold in people with FCPD compared to people with type 2 diabetes and controls (38). Gastric inhibitory peptide receptor antagonist and oxyntomodulin antagonism are emerging concepts in the management of post-pancreatic diabetes, and may well apply to FCPD (39).

SUMMARY

FCPD, a subtype of type 3c diabetes of pancreatic origin, that is unique to tropical regions of the world. There is a need for further research into etiology. The clinical phenotype is changing, and is not limited to the classical young, malnourished subject to an “extended spectrum” including older people with higher BMI without malnutrition and predilection to both exocrine and endocrine (diabetes-related) complications. Approach to its management includes standard care for pancreatic exocrine insufficiency and for diabetes, with a preference for insulin therapy for most patients. Judicious use of oral anti-diabetes agents may be appropriate for a few due to the presence of insulin resistance independent of intra-abdominal adipose tissue, a fascinating area of future research. A critical aspect of managing FCPD is early detection of pancreatic cancer, for which no specific guidance is available to date other than vigilance towards it. Future research on the genetic and environmental aspects of FCPD causation will help uncover new therapeutic approaches that may hold promise for further improving lives of people with FCPD.

ACKNOWLEDGEMENT

We thank Dr. Abhishek B. Yashod, MD (Radio-Diagnosis), Chellaram Hospital: Diabetes Care & Multispecialty, Pune, for providing the CT scan and MRI images.

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Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes

ABSTRACT

While lifestyle changes such as dietary modification and increased physical activity can be very effective in improving glycemic control, over the long-term most individuals with Type 2 diabetes (T2DM) will require medications to achieve and maintain glycemic control. The purpose of this chapter is to provide the healthcare practitioner with an overview of the existing oral and injectable (non-insulin) pharmacological options available for the treatment of patients with T2DM. Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas, 2) meglitinides, 3) metformin (a biguanide), 4) thiazolidinediones (TZDs), 5) alpha glucosidase inhibitors, 6) dipeptidyl peptidase IV (DPP-4) inhibitors, 7) bile acid sequestrants, 8) dopamine agonists, 9) sodium-glucose transport protein 2 (SGLT2) inhibitors and 10) oral glucagon like peptide 1 (GLP-1) receptor agonists. In addition, glucagon like peptide 1 (GLP-1) receptor agonists, dual GLP-1 receptor and GIP receptor agonists, and pramlintide can be administered by injection. Medications from these distinct classes of pharmaceutical agents may be used as treatment by themselves (monotherapy) or in a combination of 2 or more drugs from multiple classes with different mechanisms of action. A variety of fixed combinations of 2 agents are available in the US and in many other countries. In this chapter we discuss the administration, mechanism of action, effect on glycemic control, other benefits, side effects, and the contraindications of the use of these glucose lowering drugs.

INTRODUCTION

Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas, 2) meglitinides, 3) metformin (a biguanide), 4) thiazolidinediones (TZDs), 5) alpha glucosidase inhibitors, 6) dipeptidyl peptidase IV (DPP-4) inhibitors, 7) bile acid sequestrants, 8) dopamine agonists, 9) sodium-glucose transport protein 2 (SGLT2) inhibitors and 10) oral glucagon like peptide 1 (GLP-1) receptor agonists (Table 1) (6-8). In addition, glucagon like peptide 1 (GLP-1) receptor agonists, dual GLP-1 receptor and GIP receptor agonists, and pramlintide can be administered by injection (Table 2) (6-8).

Table 1. Currently Available (USA) Oral Hypoglycemic Drugs to Treat Type 2 Diabetes
General Class Compound/Brand Name	Generic Available	Dose Range	Cost
1^st Generation Sulfonylureas
Chlorpropamide/ Diabinese	Yes	100-750mg qd	Low
Tolazamide/ Tolinase	Yes	100mg qd to 500mg bid	Low
Tolbutamide/ Orinase	Yes	500mg qd to 1000mg tid with meals	Low
Acetohexamide/ Dymelor	Yes	250mg qd to 750mg bid	Low
2nd Generation Sulfonylureas
Glyburide (Glibenclamide)/ Diabeta, Glynase	Yes	2.5mg qd to 10mg bid	Low
Glipizide/ Glucotrol, Glucotrol XL	Yes	2.5mg qd to 20mg bid	Low
Glimepiride/ Amaryl	Yes	0.5mg to 8mg qd	Low
Gliclazide/ Diamicron	Yes	40mg qd to 160mg bid	Low
Meglitinides
Repaglinide/ Prandin	Yes	0.5mg to 4 mg with meals. Max 16mg/day	Low
Nateglinide/ Starlix	Yes	60-120mg tid with meals	Low
Biguanide
Metformin/ Glucophage, Glucophage XR	Yes	500-2500mg qd or tid depending upon preparation	Low
Thiazolidinediones (TZDs)
Rosiglitazone/ Avandia	Yes	4-8mg qd	High
Pioglitazone/ Actos	Yes	15-45mg qd	Low
Alpha-glucosidase inhibitors
Acarbose/ Precose	Yes	25-100mg tid with meals	Low
Miglitol/ Glyset	Yes	25-100mg tid with meals	High
Voglibose/ Basen, Voglib	Yes	0.2mg tid with meals
Dipeptidyl peptidase-IV (DPP-4) inhibitors
Alogliptin/ Nesina	Yes	25mg qd	High
Linagliptin/ Tradjenta	No	5mg qd	High
Sitagliptin/ Januvia	No	25-100mg qd	High
Saxagliptin/ Onglyza	No	2.5-5mg qd	High
Vildagliptin/ Galvus	No	50mg qd
Bile Acid Sequestrant
Colesevelam/ Welchol	No	1875mg bid or 3.75-gram packet or bar qd	High
Dopamine Agonist
Bromocriptine/ Cycloset	No	0.8 - 4.8mg qAM	High
Sodium-glucose co-transporter-2 (SGLT2) inhibitors
Canagliflozin/ Invokana	No	100-300mg qd	High
Dapagliflozin/ Farxiga	No	5-10mg qd	High
Empagliflozin/ Jardiance	No	10-25mg qd	High
Ertugliflozin/ Stelgatro	No	5-15mg qd	High
Oral glucagon like peptide 1 (GLP-1) receptor agonists
Semaglutide/ Rybelsus	No	7-14mg qd	High

Table 2. Currently Available (USA) Injectable Hypoglycemic Drugs to Treat Type 2 Diabetes
General Class Compound/Brand Name	Generic Available	Dose Range	Cost
GLP-1 Receptor Agonist
Exenatide/ Byetta	No	5-10mcg bid	High
Exenatide/ Bydureon	No	2mg once weekly	High
Liraglutide/ Victoza	No	0.6-1.8mg qd**	High
Albiglutide/ Tanzeum*	No	30-50mg once weekly	High
Dulaglutide/ Trulicity	No	0.75-4.5mg once weekly	High
Lixisenatide/ Adlyxin	No	10-20mcg qd	High
Semaglutide/ Ozempic	No	0.25-2.0mg once weekly	High
Dual GLP-1 Receptor/GIP Receptor Agonists
Tirzepatide/ Mounjaro	No	5mg-15mg once weekly	High
Amylin Mimetic
Pramlintide/ Symlin	No	15-120mcg tid with meals	High

*Withdrawn from market

Medications from these distinct classes of pharmaceutical agents may be used as treatment by themselves (monotherapy) or in a combination of 2 or more drugs from multiple classes with different mechanisms of action (6-8). A variety of fixed combination of 2 agents are available in the US and in many other countries (examples shown in Table 3). There are even combinations that contains 3 drugs (Qternmet XR which contains dapagliflozin, saxagliptin, and metformin and Trijardy XR which contains empagliflozin, linagliptin, and metformin). Additionally, there are combinations of GLP-1 receptor agonists and insulin (Table 3). These combination products may be useful and attractive to the patient, as they provide multiple drugs in a single tablet or injection, offering convenience and increased compliance. In the US, they also enable patients to receive two medications for a single medical insurance co-payment. Most importantly, the addition of a second drug results in an additive improvement in glycemic control. When a patient is on drug A if drug B is added to drug A, there is an improvement in glycemic control. This concept can be extended by the addition of a third drug C, and even a fourth drug D (Figure 1).

Table 3. Oral Pharmacological Fixed Combination Therapies to Treat Type 2 Diabetes
Drug 1	Drug 2	Brand Name	Generic
Glyburide	Metformin	Glucovance (discontinued by manufacturer: generic available)	Yes
Glipizide	Metformin	Metaglip (discontinued by manufacturer; generic available)	Yes
Glimepiride	Pioglitazone	Duetact	Yes
Glimepiride	Rosiglitazone	Avandaryl	Yes
Sitagliptin	Metformin	Janumet	No
Saxagliptin	Metformin	Kombiglyze XR	No
Pioglitazone	Metformin	ACTOSplus Met; ACTOSplus Met XR	Yes
Repaglinide	Metformin	PrandiMet	Yes
Rosiglitazone	Metformin	Avandamet	Yes
Linagliptin	Metformin	Jentadueto	No
Alogliptin	Metformin	Kazano	Yes
Alogliptin	Pioglitazone	Oseni	No
Canagliflozin	Metformin	Invokamet	No
Dapagliflozin	Metformin	Xigduo XR	No
Dapagliflozin	Saxagliptin	Qtern	No
Empagliflozin	Linagliptin	Glyxambi	No
Empagliflozin	Metformin	Synjardy	No
Ertugliflozin	Metformin	Segluromet	No
Ertugliflozin	Sitagliptin	Steglujan	No
Lixisenatide	Glargine Insulin	Soliqua	No
Liraglutide	Degludec Insulin	Xultophy	No

Figure 1. Efficacy When Oral Agents are Used as Add-On Therapy. When a patient is on drug A and they are changed to drug B, C, or D, often no improvement in glucose control will be seen. However, if drug B is added to drug A, there is an improvement. This concept can often be extended by the addition of a third drug (C), or even a fourth drug (D). There is decreasing benefit for each additional drug as the baseline A1c level decreases. Note that there is limited data on the use of 4 drug combinations.

OVERVIEW OF DRUGS

There are a number of different abnormalities that contribute to the hyperglycemia that occurs in patients with T2DM (9). Therefore, the drugs used to treat patients with T2DM can have a number of different mechanisms by which they lower glucose levels. Figure 2 shows the various sites of action of the pharmacological therapies for the treatment of T2DM.

Figure 2. Sites of Action of Pharmacological Therapies for the Treatment of Type 2 Diabetes.

A broad overview of the most commonly used drugs to treat T2DM is shown in Table 4 and the effect of drugs on blood lipid levels is shown in Table 5.

Table 4. Benefits and Side Effects of Commonly Used Drugs
Drugs	Ability to Lower Glucose	Risk of Hypoglycemia	Weight Change	Effect on ASCVD	Effect on Heart Failure	Effect on Renal Disease
2^ndGeneration SU	High	Yes	Increase	Neutral	Neutral	Neutral
Metformin	High	No	Neutral- modest weight loss	Potential Benefit	Neutral	Neutral
TZDs	High	No	Increase	Potential Benefit (Pioglitazone)	Increased	Neutral
DPP-4 inhibitors	Intermediate	No	Neutral	Neutral	Potential Increase (saxagliptin and alogliptin)	Neutral
SGLT2 inhibitors	Immediate	No	Decrease	Potential Benefit	Benefit	Benefit- Reduced progression of renal failure
GLP-1 receptor agonists	High	No	Decrease	Benefit	Benefit	Benefit- Reduced progression of renal failure

Table 5. Effect of Glucose Lowering Drugs on Lipid Levels*
Metformin	Modestly decrease triglycerides and LDL-C
Sulfonylureas	No effect
DPP4 inhibitors	Decrease postprandial triglycerides
GLP1 analogues	Decrease fasting and postprandial triglycerides
Acarbose	Decrease postprandial triglycerides
Pioglitazone Rosiglitazone	Decrease triglycerides and increase HDL-C. Small increase LDL-C but a decrease in small dense LDL
SGLT2 inhibitors	Small increase in LDL-C and HDL-C
Colesevelam	Decrease LDL-C. May increase triglycerides
Bromocriptine-QR	Decrease triglycerides
Insulin	No effect

*These effects are beyond benefits of glucose lowering

Bloomgarden et al reported results from a meta-regression analysis of 61 clinical trials evaluating the efficacy of the five major classes of oral anti-hyperglycemic agents (10). The results demonstrated that there is a strong direct correlation between baseline A1c level and the magnitude of the decrease in fasting glucose and A1c induced by these drugs (i.e., significantly greater reductions in both fasting plasma glucose and A1c were observed in groups with higher baseline A1c levels). Thus, expectations for the overall magnitude of effect from a given agent might be modest when treating patients whose baseline A1c is <7.5-8.0% while in patients with elevated A1c levels the effect of drug therapy may be more robust (figure 3). A separate meta-analysis of 59 clinical studies reached similar conclusions (11). These results indicate that comparing efficacies among different anti-diabetic medications is challenging, when the baseline HbA1c is different in the studies being compared.

Additionally, the population of patients studied can impact the efficacy of a particular class of drug. For example, patients with limited beta cell function will have a decreased response to sulfonylurea drugs as these agents work via stimulating insulin secretion by the beta cells while TZDs are most effective in patients with insulin resistance. Another example would be the decrease in efficacy of SGLT2 inhibitors lowering A1c levels in patients with decreased renal function. A recent trial demonstrated that in individuals with a BMI > 30 pioglitazone reduced HbA1c levels better than sitagliptin while in individuals with a BMI < 30 sitagliptin was more effective (12). In individuals with an eGFR > 90 canagliflozin lowered HbA1c better than sitagliptin while in individuals with an eGFR between 60-90 sitagliptin was more effective (12). These results demonstrate that certain patient characteristics will influence the response to treatment with specific drugs indicating the ability to target drug therapy for the specific patient. Additionally, the variation in response of patients makes it difficult to compare the glucose lowering effects of different hypoglycemic drugs except in direct head-to-head comparison studies.

Figure 3. Relationship between baseline A1c level and the observed reduction in A1c with oral anti-hyperglycemic medications. Irrespective of drug class, the baseline glycemic control markedly influences the overall magnitude of efficacy. Data from Bloomgarden et al, Table 1 (10).

A recent model-based meta-analysis was used to compare glycemic control between a large number of drugs adjusted for important differences between studies, including duration of treatment, baseline A1c, and drug dosages (13). In this analysis 229 studies with 121,914 patients were utilized. Table 6 shows the estimated decrease in A1c levels for different drugs in patients that are drug naïve with an A1c of 8% and a weight of 90kg after 26 weeks of treatment. If one averages the effect on A1c of the highest doses for each drug in a specific drug class the reductions in A1c for each class of drug are metformin 1.09%, sulfonylureas 1.0%, TZDs 0.95%, DPP-4 inhibitors 0.66%, SGLT2 inhibitors 0.83%, and GLP-1 receptor agonists 1.24%. These data and the individual data for each drug in table 6 provides a rough estimate of the efficacy of various drugs and drug classes in lowering A1c levels. One should note that within a drug class there may be differences in the ability of different drugs to lower A1c levels. This is particularly true with the GLP-1 receptor agonist drugs. For additional information there is a website that provides updated comparisons of various agents to treat patients with T2DM (https://www.comparediabetesdrugs.com/). This website shows the effect of glucose lowering drugs on A1c levels, change in weight, and hypoglycemia.

Table 6. Estimated Efficacy of Hypoglycemic Drugs Available in US (13)
Drug	A1c % Decrease	Drug	A1c % Decrease
Metformin 2000mg	1.01	Dulaglutide 0.75	1.18
Metformin 2550mg	1.09	Dulaglutide 1.5mg	1.36
Glipizide 5-20mg	0.86	Exenatide 10ug BID	0.86
Glyburide 1.25-20mg	1.17	Exenatide 2mg QW	1.16
Glimepiride 1-8mg	0.97	Exenatide 2mg QWS	1.14
Pioglitazone 15mg	0.62	Liraglutide 0.6mg	0.88
Pioglitazone 30mg	0.85	Liraglutide 1.2mg	1.13
Pioglitazone 45mg	0.98	Liraglutide 1.8mg	1.25
Rosiglitazone 4mg	0.67	Lixisenatide 10ug	0.44
Rosiglitazone 8mg	0.91	Lixisenatide 20ug	0.66
Canagliflozin 100mg	0.84	Semaglutide 0.5mg	1.43
Canagliflozin 300mg	1.01	Semaglutide 1.0mg	1.77
Dapagliflozin 5mg	0.65	Alogliptin 12.5mg	0.58
Dapagliflozin 10mg	0.73	Alogliptin 25mg	0.66
Empagliflozin 10mg	0.69	Linagliptin 5mg	0.59
Empagliflozin 25mg	0.77	Saxagliptin 2.5mg	0.59
Ertugliflozin 5mg	0.73	Saxagliptin 5mg	0.67
Ertugliflozin 15mg	0.81	Sitagliptin 100mg	0.72

The decreases in A1c are modeled for drug naïve patients with an A1c of 8% and a weight of 90kg after 26 weeks of treatment.

The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study randomized approximately 5,000 patients with relatively recent onset of T2DM (4.2 years) on metformin therapy to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin (14). The primary outcome was the time to primary failure defined as an A1c ≥ 7% over an anticipated mean observation period of 5 years The results as expected demonstrated that the GLP-1 receptor agonist liraglutide was more effective than the sulfonylurea glimepiride and the DPP4 inhibitor sitagliptin in maintaining the A1c < 7% (GLP1 receptor agonist better than sulfonylurea better than DPP-4 inhibitor) (15). Liraglutide and glargine insulin were similarly effective in lowering A1c levels (15). Significantly the majority of patients regardless of drug assignment did not have an A1c level less than 7% (Glargine 67.4%, Glimepiride 72.4%, Liraglutide 68.2%, Sitagliptin 77.4%) demonstrating the progressive nature of diabetes and the difficulty in maintaining good glycemic control. It should be noted that the SGLT2 inhibitors and TZD drugs were not included in this study. The incidences of microvascular complications (renal disease and neuropathy) and death were not different among the four treatment groups (16). There was a suggestion of a decrease in cardiovascular disease in the liraglutide treated group (16,17).

SULFONYLUREAS

Introduction

Sulfonylureas were developed in the 1950s and have been widely used in the treatment of patients with T2DM (18,19). First generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, and tolbutamide) possess a lower binding affinity for the ATP-sensitive potassium channel, their molecular target (vide infra), and thus require higher doses to achieve efficacy (see table 1) (18,19). These first-generation sulfonylureas are currently rarely used. Subsequently, in the 1980s 2nd generation sulfonylureas including glyburide (glibenclamide), glipizide, gliclazide, and glimepiride were developed and are now widely used (18). The 2nd generation sulfonylureas are much more potent compounds (~100-fold). Sulfonylureas can be used as monotherapy or in combination with any other class of oral diabetic medications except meglitinides because they lower glucose levels by a similar mechanism of action (18,20).

Key characteristics of the different sulfonylureas are shown in Table 7 (18). Of clinical importance is the duration of action, which varies with the rate of hepatic metabolism and the hypoglycemic activity of drug metabolites. Drugs with a long duration of action are more likely to cause severe and prolonged hypoglycemia whereas short acting drugs need to be given multiple times per day (18). Additionally, drugs that are metabolized to active agents (for example glyburide) are also more likely to cause hypoglycemia (18). Most sulfonylureas are metabolized in the liver and are to some extent excreted by the kidney; therefore, hepatic and/or renal impairment increases the risk of hypoglycemia (18).

Table 7. Key Characteristics of Sulfonylureas
Drug	Duration of action	Metabolites	Excretion
Tolbutamide	6–12 h	Inactive	Kidney
Chlorpropamide	60 h	Active or unchanged	Kidney
Tolazamide	12–24 h	Inactive	Kidney
Glipizide	12–24 h	Inactive	Kidney 80% Feces 20%
Glipizide ER	>24 h	Inactive	Kidney 80% Feces 20%
Glyburide	16–24 h	Inactive or weakly active	Kidney 50%
Micronized glyburide	12-24 h	Inactive or weakly active	Kidney 50% Feces 50%
Glimepiride	24 h	Inactive or weakly active	Kidney 60% Feces 40%

Administration

Sulfonylureas should be taken 30 minutes before meals starting with a low dose with an increase in dosage until desired glycemic control has been achieved. In patients with a high risk of severe hypoglycemia a very low-dose can be the initial therapy while in patients with very high A1c levels one can initiate therapy at a higher dose.

The recommended starting dose of glipizide is 5 mg approximately 30 minutes before breakfast. Geriatric patients or those with liver or renal disease or other risk factors for severe hypoglycemia can be started on 2.5 mg. Patients with very high A1c levels may be started on a higher dose. Based on the glucose response the dose can be increased weekly by 2.5-5 mg. If a once-a-day dose is not satisfactory or the patient requires more than 15 mg per day one can give the drug before breakfast and dinner. The maximum daily dose is 40 mg per day.

The usual starting dose of extended-release glipizide is 5 mg per day with breakfast. Those patients who are at high risk of hypoglycemia may be started at a lower dose. The dose can be increased based on glucose or A1c measurements. The maximum dose is 20 mg per day.

The usual starting dose of glyburide is 2.5 to 5 mg daily with breakfast or the first main meal. Patients at high risk for hypoglycemia should be started on 1.25 mg per day. The dose should be increased weekly by 2.5 mg based on the glucose response. The maximum dose per day is 20 mg.

The usual starting dose of micronized glyburide is 1.5 to 3 mg daily with breakfast or the first main meal. Patients at high risk for hypoglycemia should be started on 0.75 mg per day. The dose should be increased weekly by 1.5 mg based on the glucose response. The maximum dose per day is 12 mg.

The recommended starting dose of glimepiride is 1 or 2 mg once daily. Patients at increased risk for hypoglycemia should be started on 1 mg once daily. The dose should be increased every 1-2 weeks in increments of 1 or 2 mg based upon the patient’s glycemic response. The maximum dose is 8 mg per day.

The recommended starting dose of gliclazide is 40 - 80mg once daily. Patients at increased risk for hypoglycemia should be started on 40 mg once daily. The dose should be increased every 1-2 weeks in increments of 40 or 80 mg based upon the patient’s glycemic response. The maximum dose is 160mg twice a day.

Mechanism of Action

Sulfonylureas are insulin secretagogues and lower blood glucose levels by directly stimulating glucose independent insulin secretion by the pancreatic beta cells (18,20). Through the concerted efforts of GLUT2 (the high Km glucose transporter), glucokinase (the enzyme that phosphorylates glucose), and glucose metabolism, pancreatic beta cells sense blood glucose levels and secrete the appropriate amount of insulin in response (21,22). Glucose metabolism leads to ATP generation and increases the intracellular ratio of ATP/ADP, which results in the closure of the ATP-sensitive potassium channel on the plasma membrane (18,21,23). Closure of this channel depolarizes the membrane and triggers the opening of voltage-sensitive calcium channels, leading to the rapid influx of calcium (18,24). Increased intracellular calcium causes an alteration in the cytoskeleton and stimulates translocation of insulin-containing secretory granules to the plasma membrane and the secretion of insulin (Figure 4) (18).

Figure 4. Mechanism by which glucose, sulfonylureas, and meglitinides stimulate insulin secretion by the beta cells.

The KATP channel is comprised of two subunits, both of which are required for the channel to be functional (24). One subunit contains the cytoplasmic binding sites for both sulfonylureas and ATP, and is designated as the sulfonylurea receptor type 1 (SUR1). The other subunit is the potassium channel, which acts as the pore-forming subunit (24). Either an increase in the ATP/ADP ratio or ligand binding by sulfonylureas or meglitinides to SUR1 results in the closure of the KATP channel and insulin secretion (19,24). Studies comparing sulfonylureas and non-sulfonylurea insulin secretagogues have identified several distinct binding sites on the SUR1 that cause channel closure. Some sites exhibit high affinity for sulfonylureas, while other sites exhibit high affinity for meglitinides.

In addition to binding to SUR1, sulfonylureas also bind to Epac2, a protein activated by cAMP (18). Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, indicating that Epac2 also plays a role in sulfonylurea induced insulin secretion (25).

In addition to inducing insulin secretion sulfonylureas have other effects that could play a role in lowering blood glucose levels (18). Specifically, sulfonylureas have been shown to decrease hepatic insulin clearance, inhibit glucagon secretion from pancreatic alpha-cells (this may be secondary to increasing insulin secretion), and enhance insulin sensitivity in peripheral tissues (this may be partially due to lowering glucose levels and reducing glucotoxicity) (18). The contribution and importance of these additional effects in mediating the glucose lowering effects of sulfonylureas is uncertain.

Glycemic Efficacy

When used at maximally effective doses, results from well-controlled clinical trials have not indicated a marked superiority of one 2nd generation sulfonylurea over another in improving glycemic control (26). Similarly, 2nd generation sulfonylureas exhibit similar clinical efficacy compared to the 1st generation agents (26). Sulfonylureas do not have a linear dose-response relationship and the majority of the A1C reduction occurs at half maximum dosage. The effect of sulfonylureas as monotherapy or when added to metformin therapy on A1c levels varies but typically results in reductions in A1c of approximately 0.50-1.5% (13,19,20,27,28). If A1c levels are very high decreases in the range of 1.5- 2.0% may be seen (19,20,26). Patients with a short duration of diabetes with residual beta cell function (high C-peptide levels) are likely to be most responsive to sulfonylurea therapy (26). Overtime many patients on sulfonylureas require additional therapies (secondary failure). In the ADOPT study, after 5 years 34% of the patients on glyburide monotherapy had fasting glucose levels > 180 mg/dl (i.e., secondary failure) (29). Similarly, in the United Kingdom Prospective Diabetes Study (UKPDS), only 34% of patients attained an A1c <7 % at 6 years treated with sulfonylureas (glyburide or chlorpropamide) and this number declined to 24 % at 9 years (18). This lack of durability of sulfonylurea therapy is likely to due to beta cell exhaustion. In addition, the weight gain induced by sulfonylurea therapy may also adversely affect glycemic control.

The results of the GRADE study, which compared glargine insulin, glimepiride, liraglutide, and sitagliptin added to metformin, were discussed earlier in the section entitled “OVERVIEW OF DRUGS”.

Other Effects

CARDIOVASCULAR DISEASE

Based on the University Group Diabetes Project (UGDP) sulfonylureas carry a “black box” warning regarding cardiovascular disease (30,31). However, the U.K. Prospective Diabetes Study Group (UKPDS) studied a large number of newly diagnosed patients with T2DM at risk for cardiovascular disease. In this study improved glycemic control with sulfonylureas reduced cardiovascular disease by approximately 16%, which just missed being statistically significant (p=0.052) (32). In the UKPDS, A1c was reduced by approximately 0.9% and the 16% reduction in cardiovascular disease was in the range predicted based on epidemiological studies. Thus, the reduction in cardiovascular events was likely due to improvements in glycemic control and not a direct benefit of sulfonylurea treatment. In support of this conjecture is that in the UKPDS, insulin treatment resulted in a similar decrease in A1c levels and reduction in cardiovascular events (32). Additionally, a large randomized cardiovascular outcome study (Carolina Study) reported that linagliptin, a DPP-4 inhibitor, and glimepiride, a sulfonylurea, had similar effects on cardiovascular events (hazard ratio 0.98) (33). Taken together these results suggest that sulfonylureas have a neutral effect on cardiovascular disease.

Side Effects

HYPOGLYCEMIA

The major side effect of sulfonylurea treatment is hypoglycemia, which is more likely to occur and is more severe with long- acting sulfonylureas (18,19). In the UKPDS severe hypoglycemia, defined by need for third-party assistance, occurred each year in 0.4–0.6/100 patients treated with a sulfonylurea while non-severe hypoglycemia was seen in 7.9/100 persons treated with a sulfonylurea (34). Other studies have found even higher rates of severe hypoglycemia with 20–40% of patients receiving sulfonylureas having hypoglycemia and severe hypoglycemia (requiring third-party assistance) occurring in 1–7% of patients (20,34). With continuous glucose monitoring 30% of well controlled patients with T2DM had episodes of hypoglycemia that were often asymptomatic and nocturnal (35). Of great concern these hypoglycemic events were associated with EKG changes, particularly QTc prolongation (35). Other studies have also observed a very high rate of hypoglycemia in patients with T2DM treated with sulfonylureas when monitored using continuous glucose monitoring (36).

Hypoglycemia typically occurs after periods of fasting or exercise. In light of this hypoglycemic risk, initiation of treatment with sulfonylureas should be at the lowest recommended dose and the dose slowly increased in patients with modestly elevated A1c levels. Older patients (> age 65) and patients with hepatic or renal disease are more likely to experience frequent and severe hypoglycemic reactions, particularly if the goals of therapy aim for inappropriately tight glycemic control (18). Many clinicians avoid the use of long acting sulfonylureas (glyburide) in these high-risk patients as glyburide has a higher risk of hypoglycemia compared to other sulfonylureas (37).

WEIGHT GAIN

In the UKPDS, sulfonylurea treatment caused a net weight gain of approximately 3 kg, which occurred during the first 3-4 years of treatment and then stabilized (19,32). Other studies have similarly observed weight gain with sulfonylurea treatment (26).

FIRST GENERATION SIDE EFFECTS

Chlorpropamide can induce hyponatremia and water retention due to inappropriate secretion of antidiuretic hormone (ADH) (18). In addition, tolbutamide and chlorpropamide, in certain susceptible individuals, is associated with alcohol-induced flushing (18). Because of an increased risk of side effects 1^st generation sulfonylureas are seldom used.

RARE SIDE EFFECTS

Intrahepatic cholestasis and allergic skin reactions, including photosensitivity and erythroderma may rarely occur (Package insert).

Contraindications and Drug Interactions

Sulfonylureas are best avoided in patients with a sulfa allergy who experienced prior severe allergic reactions (Package insert). Otherwise, cross-reactivity between antibacterial and nonantibacterial sulfonamide agents is rare.

In renal failure, the dose of the sulfonylurea agent will require adjustment based on glucose monitoring to avoid hypoglycemia (18). Because it is metabolized primarily in the liver without the formation of active metabolites, glipizide is the preferred sulfonylurea in patients with renal disease (38).

In the elderly, long acting sulfonylureas, such as glyburide, glimepiride and chlorpropamide are not recommended (39).

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency and therefore should be used with caution in such patients (Package insert).

Certain drugs may enhance the glucose-lowering effects of sulfonylureas by inhibition of their hepatic metabolism (antifungals and monoamine oxidase inhibitors), displacing them from binding to plasma proteins (coumarins, NSAIDs, and sulfonamides), or inhibiting their excretion (probenecid) (20).

Summary

While the ability of sulfonylureas to improve glycemic control is robust, the risk of hypoglycemia and weight gain reduce the desirability of this drug class. Additionally, the shorter durability of effectiveness is also a limiting factor. In patients at high risk for the occurrence of severe hypoglycemic reactions or in patients who are obese, using drugs other than sulfonylureas to treat T2DM is indicated if possible. Similarly, in patients with atherosclerotic cardiovascular disease, heart failure, or at high risk for cardiovascular disease or renal disease other hypoglycemic drugs have important advantages. Nevertheless, because sulfonylureas are generic drugs and very inexpensive, they continue to be used and play a role in the management of patients with T2DM.

Table 8. Summary of the Advantages and Disadvantages of Sulfonylureas
Advantages	Disadvantages
Inexpensive	Hypoglycemia
Rapid acting	Weight gain
Once a day administration possible	Limited durability
Long history of use	Need to titrate dose

MEGLINATIDES

Introduction

The meglitinides are non-sulfonylurea insulin secretagogues characterized by a very rapid onset and abbreviated duration of action (20,40). Repaglinide (Prandin), a benzoic acid derivative introduced in 1998, was the first member of the meglitinide class. Nateglinide (Starlix) is a derivative of the amino acid D-phenylalanine and was introduced to the market in 2001. Unlike sulfonylureas, repaglinide and nateglinide stimulation of insulin secretion is dependent on the presence of glucose (40,41). As glucose levels decrease, insulin secretion decreases, which reduces the risk of hypoglycemia compared with sulfonylureas.

Meglitinides are rapidly absorbed with maximum serum concentrations generally attained within 1 hour and then quickly metabolized by the liver cytochrome CYP3A4 and CYP2C8 pathways, producing inactive metabolites, resulting in a plasma half-life of around 1 h (20). This rapid onset and short duration of action results in the ability of this class of drugs to predominantly reduce postprandial glucose levels (40). Because of the rapid onset and short duration of action meglitinides are given 1-30 minutes prior to meals. The drug should not be administered if the patient is going to skip the meal.

The pharmacokinetics of meglitinides differ with nateglinide having a faster onset and shorter duration of action than repaglinide (41). Nateglinide stimulates early insulin release faster and to a greater extent than repaglinide with insulin levels returning to baseline levels more rapidly (40,41).

Administration

The recommended starting dose of nateglinide is 120 mg three times per day before meals (1-30 minutes). In patients who are near their glycemic goal when treatment is initiated the recommended starting dose of nateglinide is 60 mg three times per day before meals. The maximum dose of nateglinide is 120 mg three times per day before meals.

The recommended starting dose of repaglinide for patients whose A1c is less than 8% is 0.5 mg before each meal (1-30 minutes). For patients whose A1c is 8% or greater the starting dose is 1 or 2 mg orally before each meal. The patient’s dose should be doubled up to 4mg with each meal until satisfactory glycemic control is achieved (should wait one week between increasing dose). The maximum daily dose is 16 mg per day.

Mechanism of Action

Meglitinides bind to a different site on SUR1 in β cells that is separate from the sulfonylurea binding site (Figure 4) (20,40). The effect of meglitinide binding is similar to the effect of sulfonylureas with binding resulting in the closure of the KATP channel leading to cell depolarization and calcium influx resulting in insulin secretion (20,40,41). However, the relatively rapid onset and short duration of action of meglitinides suits their use as prandial glucose-lowering agents (20,40).

Glycemic Efficacy

Studies have shown that A1c reductions are similar to, or slightly less, than those observed with sulfonylurea or metformin treatment when meglitinides are used as monotherapy (20,40). In studies comparing repaglinide monotherapy with sulfonylurea or metformin therapy the decrease in A1c was similar (40,42). In contrast, a study comparing nateglinide with metformin demonstrated that metformin was more effective in lowering A1c levels (43). In a randomized trial comparing repaglinide and nateglinide in patients with T2DM previously treated with diet and exercise, repaglinide was more effective in lowering A1c levels (1.57% vs. 1.04%) (44). While postprandial glucose levels were similar repaglinide was more effective in reducing fasting glucose levels, probably due to its longer duration of action. These clinical findings can be incorporated into clinical decision making. For example, if the main issue for the patient is postprandial hyperglycemia, and fasting glucoses are near normal, an agent, such as nateglinide, that has a limited effect on the fasting glucose would be ideal. However, if one needs reductions in both fasting and postprandial glucose levels a longer acting agent such as repaglinide is a better choice.

Other Effects

CARDIOVASCULAR DISEASE

The Navigator study was a double-blind, randomized clinical trial in 9,306 individuals with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors who received nateglinide (up to 60 mg three times daily) or placebo (45). After 5 years, nateglinide administration did not alter the incidence of cardiovascular outcomes suggesting that meglitinides do not have adverse or beneficial cardiovascular effects. The effect of meglitinides on cardiovascular disease has not been studies in patients with T2DM.

Side Effects

Similar to sulfonylureas, meglitinides can cause hypoglycemia but the risk of severe hypoglycemia is less (20,40,42). The incidence of hypoglycemia is lower with nateglinide than for repaglinide and nateglinide is less likely to cause severe hypoglycemia (20). In one study, the occurrence of symptomatic hypoglycemia was 2% for nateglinide and 7% for repaglinide (41). Weight gain is also a common side effect of meglitinides (approximately 1-3 kg) with nateglinide leading to less weight gain than repaglinide (20,41).

Contraindications and Drug Interactions

Because meglitinides are metabolized by the liver these drugs should be used cautiously in patients with impaired liver function (Package insert).

Drugs that inhibit CYP3A4 (for example ketoconazole, itraconazole and erythromycin) or CYP2C8 (for example trimethoprim, gemfibrozil and montelukast) can result in the increased activity of meglitinides enhancing the risk of hypoglycemia and should be avoided if possible (42).

Summary

Meglitinides can be useful drugs when there is a need to specifically lower postprandial glucose levels (i.e., patients with fasting glucose in desired range but elevated post meal glucose levels). Additionally, because of their short duration of action meglitinides can be useful in patients who eat erratically as this class of drugs can be given only before meals and the duration of action will match the postprandial increase in glucose. The risk of severe hypoglycemia and weight gain is less than sulfonylureas but still must be considered in patients treated with meglitinides. The development of drugs that do not cause weight gain or severe hypoglycemia and lower postprandial glucose levels have resulted in the limited use of meglitinides.

Table 9. Summary of the Advantages and Disadvantages of Meglitinides
Advantages	Disadvantages
Decrease postprandial glucose	Hypoglycemia
Flexible dosing	Weight gain
Relatively inexpensive	Frequent dosing
Short action allowing for missing meals	Need to titrate dose

METFORMIN

Introduction

Metformin (Glucophage) is a synthetic analog of the natural product guanidine (20). Since its initial clinical use over 50 years ago, metformin has surpassed the sulfonylureas as the most widely prescribed oral agent for T2DM throughout the world because of its proven efficacy on glycemic control as monotherapy and in combination with many other available agents (20). The widespread acceptance of metformin evolved after the realization that lactic acidosis was not a major problem in individuals with normal renal function. Phenformin, a structural analog of metformin, was previously withdrawn from the market in many countries due its propensity to induce lactic acidosis (20).

Administration

The usual starting dose of metformin is 500 mg twice a day with meals. After 1-2 weeks the dose can be increased to 1500 mg per day (750 mg twice a day or 500 mg in AM and 1000 mg in PM). After another 1-2 weeks the dose can be increased to 1000 mg twice a day. The slow increase in dosage is to reduce GI side effects and the dose should not be increased if GI side effects are occurring. The maximum dose is 2550 mg per day which can be given as 850 mg three times per day with meals but most patients are treated with 1000 mg twice a day with breakfast and dinner.

The usual starting dose of metformin extended release is 500 mg with the evening meal (largest meal). The dose can be increased by 500 mg weekly depending upon tolerability. The maximum dose is 2000 mg with the evening meal.

Note the dose of metformin may need to be adjusted based on renal function (discussed below).

Metformin should be temporarily discontinued when patients are unable to eat or drink. Metformin is seldom used in hospitalized patients.

Mechanism of Action

Metformin decreases hepatic glucose production and improves hepatic insulin sensitivity but has only a modest impact on peripheral insulin-mediated glucose uptake (i.e., insulin resistance), which is likely due to a reduction in hyperglycemia, triglycerides, and free fatty acid levels (46,47). Hyperinsulinemia is reduced and the decrease in hepatic glucose production results in a decrease in fasting glucose levels (20). In addition, metformin also increases intestinal glucose utilization and stimulates GLP-1 secretion (46,47). Insulin secretion is not increased (20). The cellular and molecular mechanisms that account for these changes are not definitively understood.

LIVER

There are several lines of evidence indicating that the liver plays an important role in metformin’s ability to improve glycemic control (46). In humans and rodents, metformin is concentrated in the liver and blocking the uptake of metformin into the liver in mice prevents the ability of metformin to lower blood glucose levels (46,47). As noted above tracer studies in humans show that metformin lowers hepatic glucose production and increases hepatic insulin sensitivity (46). There are a number of proposed mechanisms by which metformin alters hepatic metabolism (46).

Metformin inhibits mitochondrial ATP production by inhibition of Complex I of the respiratory chain and/or inhibiting mitochondrial glycerophosphate dehydrogenase, which is required to carry reducing equivalents from the cytoplasm into the mitochondria for re-oxidation (46,47). The decrease in ATP production could decrease hepatic gluconeogenesis (47). This also leads to an increase in AMP.
Metformin increases hepatic AMP levels and AMP is a potent allosteric inhibitor of fructose 1,6-bisphosphatase, a key enzyme in gluconeogenesis (47). In addition, high AMP levels inhibit adenylate cyclase reducing cyclic AMP formation in response to glucagon, which also decreases glycogenolysis and gluconeogenesis (i.e., decreases glucagon activity) (47). The increase in AMP also activates AMP-activated protein kinase.
Metformin activates AMP-activated protein kinase, which activates catabolic pathways leading to decreased gluconeogenesis, decreased fatty acid synthesis, and increased fatty acid oxidation (46,47). The changes in fatty acid metabolism are thought to account for the improvement in hepatic insulin sensitivity and the decrease in serum triglyceride levels (46).
Metformin inhibits glycerol-3-phosphate dehydrogenase increasing the cytosolic redox state resulting in a decreased conversion of glycerol and lactate to glucose (48).

INTESTINE

Several lines of evidence indicate that the intestine plays an important role in explaining metformin’s ability to lower blood glucose levels. First, a decrease in hepatic glucose production can only partially account for the decrease in blood glucose (46). Second, in humans with loss-of-function variants in SLC22A1, which decrease the uptake of metformin into the liver, the ability of metformin to lower A1c levels is not impaired (46). Finally, a delayed-release metformin that is retained in the gut, with minimal systemic absorption, is as effective at lowering blood glucose as the standard metformin formulation in patients with T2DM (46,49). There are a number of proposed mechanisms for how the intestine accounts for the beneficial effects of metformin.

Metformin increases anaerobic glucose metabolism in the intestine resulting in increased intestinal glucose utilization and decreased glucose uptake into the circulation (46). This is likely due to the inhibition of mitochondrial ATP production described above. The increased utilization of glucose by anaerobic metabolism could contribute to metformin induced weight loss.
Metformin increases GLP-1 secretion, which could increase insulin secretion and decrease glucagon secretion (46). The increase in GLP-1 could also contribute to the weight loss or weight neutral effects of metformin.
Metformin alters the intestinal microbiome, which could alter glucose metabolism (46,50).

It is clear that there are multiple potential mechanisms by which metformin can improve glucose metabolism and further studies are required to elucidate the relative importance and contribution of these proposed mechanisms and others yet to be identified.

Glycemic Efficacy

Metformin is often used as the initial therapy in patients with diabetes in conjunction with lifestyle changes (6,7). The typical reduction in A1c with metformin therapy is in the range of 1 to 2.0% (20,51). The decrease in A1c induced by metformin is independent of age, weight, and diabetes duration as long as some residual β-cell function remains (20). One retrospective study has reported that African-Americans have a greater decrease in A1c with metformin compared to Caucasians (52). The effect of immediate release and extended release metformin on A1c levels is similar (53). In head-to-head trials, metformin has been shown to produce equivalent reductions in A1c as sulfonylureas and thiazolidinediones but is more potent than DPP-4 inhibitors (51).

The durability of glycemic control with metformin is more prolonged than with sulfonylureas but shorter than with TZDs (29). After 5 years of monotherapy, 15% of individuals on rosiglitazone therapy, 21% of individuals on metformin therapy, and 34% of individuals on glyburide (glibenclamide) therapy had fasting glucose levels above the acceptable range (29). The ability to maintain an A1c <7% was 57 months with rosiglitazone, 45 months with metformin, and 33 months with glyburide (glibenclamide) (29).

In addition to the ability to improve glycemic control in monotherapy, metformin in combination with sulfonylureas, meglinitides, TZDs, DPP-4 inhibitors, SGLT-2 inhibitors, insulin, and GLP-1 receptor agonists lowers A1c levels and often allows for patients to achieve their A1c goals (51). As shown in Table 3 there are a large number of combination tablets that include metformin with other glucose lowering drugs.

Hypoglycemia does not occur with metformin monotherapy (51). Hypoglycemia may occur with metformin during concomitant use with other glucose-lowering agents such as sulfonylureas and insulin.

Other Effects

WEIGHT

Metformin is weight neutral or can sometimes result in a modest weight loss (up to 4 kg) (51). When used in combination with sulfonylureas or insulin it blunts the weight gain induced by these agents.

LIPIDS

Metformin decreases serum triglyceride levels and LDL-C levels without altering HDL-C (54,55). In a meta-analysis of 37 trials with 2,891 patients, metformin decreased triglycerides by 11.4mg/dl when compared with control treatment (p=0.003) (54). In an analysis of 24 trials with 1,867 patients, metformin decreased LDL-C by 8.4mg/dl compared to control treatment (p<0.001) (54). In contrast, metformin did not significantly alter HDL-C levels (54). It should be noted that in the Diabetes Prevention Program 3,234 individuals with impaired glucose metabolism were randomized to placebo, intensive lifestyle, or metformin therapy (56). In the metformin therapy group no significant changes were noted in triglyceride, LDL-C, or HDL-C levels compared to the placebo group. Thus, metformin may have small effects on lipid levels.

CARDIOVASCULAR DISEASE

In the UKPDS, metformin, while producing a similar improvement in glycemic control as insulin or sulfonylureas, markedly reduced cardiovascular disease by approximately 40% (57). In the ten-year follow-up the patients randomized to metformin in the UKPDS continued to show a reduction in MI and all-cause mortality (58). Two other small randomized controlled trials have also demonstrated cardiovascular benefits with metformin therapy. A study by Kooy et al compared the effect of adding metformin or placebo in overweight or obese patients already on insulin therapy (59). After a mean follow-up of 4.3 years this study observed a reduction in macrovascular events (HR 0.61 CI- 0.40-0.94, p=0.02), which was partially accounted for by metformin’s beneficial effects on weight. In this study the difference in A1c between the metformin and placebo group was only 0.3%. Hong et al randomized non-obese patients with coronary artery disease to glipizide vs. metformin therapy for three years (60). A1c levels were similar, but there was a marked reduction in cardiovascular events in the metformin treated group (HR 0.54 CI 0.30- 0.90, p=0.026). These results suggest that metformin may reduce cardiovascular disease and that this effect is not due to improving glucose control. Metformin decreases weight or prevents weight gain and lowers lipid levels and these or other non-glucose effects may account for the beneficial effects on cardiovascular disease. Larger cardiovascular outcome studies are required to definitively demonstrate a beneficial effect of metformin on cardiovascular disease.

POLYCYSTIC OVARY SYNDROME (PCOS)

In patients with PCOS metformin lowers serum androgen levels, increases ovulations, and improves menstrual frequency (61). Metformin may also be associated with weight loss in some women with PCOS (61). Metformin combined with clomiphene may be the best combination in obese women with PCOS to improve fertility (61). For a detailed discussion of the treatment of PCOS see the chapter on polycystic ovary syndrome in Endotext (61).

CANCER

Multiple epidemiological studies have demonstrated an association between metformin treatment and a reduced cancer incidence and mortality (62,63). Treatment with metformin has been associated with a decreased risk of breast, colon, liver, pancreas, prostate, endometrium and lung cancer and marked reductions in cancer-specific mortality for colon, lung and early-stage prostate cancer and improvements in survival for breast, colon, endometrial, ovarian, liver, lung, prostate and pancreatic cancer (62,63). A wide variety of different mechanisms have been proposed that could account for metformin’s anti-tumor effects providing biological plausibility (63). However, data from large randomized controlled trials have not yet definitively demonstrated whether metformin can prevent the development of cancer or is useful in the treatment of cancer (62-65). Further studies are required to elucidate the potential role of metformin in oncology.

Side Effects

GASTROINTESTINAL

The most common side effects of metformin are diarrhea, nausea, and/or abdominal discomfort, which can occur in up to 50% of patients (20,51). These side effects are usually mild and disappear with continued drug administration. The GI side effects are dose-related and slow titration to allow for tolerance can reduce the occurrence of these symptoms (51). Administrating metformin three times a day with meals instead of twice a day may also reduce GI side effects. A small number of patients cannot tolerate the drug, even at low doses (51). Extended-release metformin [metformin XR]) causes fewer GI symptoms and can be used in patients who do not tolerate immediate release metformin (51).

Studies have shown that reduced function of plasma membrane monoamine transporter or organic cation transporter 1 leads to an increase in metformin GI side effects (66,67). Use of drugs that inhibit organic cation transporter 1 activity (including tricyclic antidepressants, citalopram, proton-pump inhibitors, verapamil, diltiazem, doxazosin, spironolactone, clopidogrel, rosiglitazone, quinine, tramadol and codeine) increased intolerance to metformin (66).

LACTIC ACIDOSIS

A very rare complication of metformin therapy is lactic acidosis (51). This complication was much more common with phenformin therapy, the initial biguanide, and the risk with metformin is estimated to be 20 times less (51). The estimated incidence of metformin-associated lactic acidosis is 3–10 per 100,000 person-years (51). This is a potentially lethal complication of metformin therapy that typically occurs when renal dysfunction results in very high blood metformin levels, which inhibit mitochondrial function resulting in the overproduction of lactate (51). In addition to renal disorders other risk factors for metformin associated lactic acidosis include sepsis, cardiogenic shock, hepatic impairment, congestive heart failure, and alcoholism (51). In some circumstances the lactic acidosis observed in patients treated with metformin may not be due to metformin but rather to underlying clinical disorders such as severe sepsis.

VITAMIN B12 DEFICIENCY

Studies have demonstrated that vitamin B12 malabsorption is a side effect of metformin therapy (51). A randomized controlled trial showed that metformin 850 mg three times per day for over 4 years resulted in a 19% decrease in B12 levels compared to placebo (68). Moreover, 9.9% of patients treated with metformin developed vitamin B12 deficiency (<150 pmol/l) vs. only 2.7% in the placebo group (68). The Diabetes Prevention Program Outcomes Study also demonstrated an increased risk of B12 deficiency with long term metformin use (69). It is now recommended that periodic testing of vitamin B12 levels should be considered in patients on long-term metformin therapy, particularly in the setting of anemia or neuropathy (70).

OVULATION AND PREGNANCY

As discussed above in the polycystic ovary section, treatment of premenopausal women with PCOS with metformin may induce ovulation and thereby result in unplanned pregnancies. In premenopausal anovulatory women started on metformin one needs to discuss the need for contraception.

Contraindications and Drug Interactions

Metformin is contraindicated in patients with advanced kidney or liver disease, acute unstable congestive heart failure, conditions marked by decreased perfusion or hemodynamic instability, major alcohol abuse, or conditions characterized by acidosis (51). Metformin therapy should be suspended during serious illness or surgical procedures. Metformin is seldom used in hospitalized patients.

RENAL DISEASE

A major contraindication to the use of metformin is renal disease (51). Metformin is not metabolized and is excreted intact by the kidneys and therefore kidney function is a major determinant of blood metformin levels. eGFR should be obtained prior to initiating therapy. In patients with renal dysfunction or at risk for developing renal dysfunction eGFR should be obtained more frequently. In patients with a eGFR < 30 mL/min/1.73 m² metformin therapy is contraindicated (51). In patients with an eGFR between 30-60mL/min/1.73 m² metformin can be used but one should consider using lower doses (51). In patients with eGFR < 45mL/min/1.73 m² the author typically uses ½ the maximal dose of metformin. In patients with labile renal disease, especially if frequent deteriorations in kidney function occur, metformin is best avoided.

IODINATED CONTRAST STUDIES

FDA guidelines indicate that metformin use should be withheld before iodinated contrast procedures if a) the eGFR is 30–60 mL/min/1.73 m², b) in the setting of liver disease, alcoholism, or heart failure, or c) if intra-arterial contrast is used. The eGFR should be checked 48 hours later and metformin restarted if renal function remains stable.

DRUG INTERACTIONS

Carbonic anhydrase inhibitors, such as topiramate or acetazolamide, can decrease serum bicarbonate levels and induce a non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin may increase the risk for lactic acidosis (Package Insert).

Certain drugs, such as ranolazine, vandetanib, dolutegravir, and cimetidine, may interfere with common renal tubular transport systems that are involved in the renal elimination of metformin and therefore can increase systemic exposure to metformin and may increase the risk for lactic acidosis (Package Insert).

Summary

Metformin is a commonly used as the first drug for the treatment of diabetes because of excellent efficacy, an outstanding safety profile, low cost, and a long history of use without significant problems.

Table 10. Summary of the Advantages and Disadvantages of Metformin
Advantages	Disadvantages
Inexpensive	GI side effects
No hypoglycemia	B12 deficiency
Once a day administration possible	Lactic acidosis (very rare)
Long history of use	Need to monitor renal function
No weight gain and maybe weight loss
May decrease cardiovascular disease

THIAZOLIDINEDIONES (TZDS)

Introduction

Troglitazone (Rezulin), pioglitazone (Actos), and rosiglitazone (Avandia) are members of the thiazolidinedione (TZD) class of insulin sensitizing compounds that activate PPAR gamma (20,71). Troglitazone was withdrawn from the US, European, and Japanese markets in 2000 due to an idiosyncratic hepatic reaction leading to hepatic failure and death in some patients (20,71). This idiosyncratic hepatic reaction has not occurred with pioglitazone or rosiglitazone (71). TZDs decrease insulin resistance and thereby enhance the biological response to endogenously produced insulin, as well as exogenous insulin (71).

Administration

Initiate pioglitazone at 15 mg or 30 mg once a day with or without food. Use 15 mg in patients where there is concern of fluid retention. If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily.

Initiate rosiglitazone at 4 mg once a day with or without food. If there is inadequate glycemic control, the dose can be increased to a maximum of 8 mg once daily.

Because the maximum effect of TZDs on glycemic control may take 10-14 weeks one should wait 12 weeks before deciding whether to increase the dose of TZDs.

Mechanism of Action

The primary effect of pioglitazone and rosiglitazone is the reduction of insulin resistance resulting in an improvement of insulin sensitivity (20,71,72). Pioglitazone and rosiglitazone are selective agonists for the PPAR gamma receptor, a member of the super-family of nuclear hormone receptors that function as ligand-activated transcription factors (71,72). In the absence of ligand, PPARs bind as hetero-dimers with the 9-cis retinoic acid receptor (RXR) and a multi-component co-repressor complex to a specific response element (PPRE) within the promoter region of their target genes (71,72). Once PPAR gamma is activated by ligand, the co-repressor complex dissociates allowing the PPAR-RXR heterodimer to associate with a multi-component co-activator complex resulting in an increased rate of gene transcription (71,72). Additionally, PPAR gamma can repress target gene expression by negative feedback on other signal transduction pathways, such as the nuclear factor kB (NF-kB) signaling pathway, in a DNA binding independent manner (71). The target genes of PPAR gamma include those involved in the regulation of lipid and carbohydrate metabolism and inflammation (71,72).

PPAR gamma is highly expressed in adipose tissue while its expression in skeletal muscle is low (71,72). In the liver PPAR gamma expression is low but increases in obesity and thus in obese individuals it is possible that TZDs directly affect the liver (73). It is likely that the primary effects of TZDs are on adipose tissue, followed by secondary benefits on other target tissues of insulin (71). TZDs promote fatty acid uptake and storage in adipose tissue resulting in a decrease in circulating fatty acids and a decrease in fat accumulation in liver, muscle, and pancreas leading to the protection of these tissues from the harmful metabolic effects of higher levels of fatty acids (20,71). This decrease in fat accumulation in liver and muscle leads to an improvement in insulin action and the decrease in the pancreas may improve insulin secretion. Additionally, PPAR gamma agonists increase the expression and circulating levels of adiponectin, an adipocyte-derived protein with insulin sensitizing activity (71). A decrease in the gene expression of other adipokines involved in induction of insulin resistance, such as TNF-alpha, resistin, etc. are likely to also contribute to the improvement in insulin resistance that occurs with TZDs (71). Finally, the activation of PPAR gamma in other tissues may contribute to the beneficial effects of TZDs.

Glycemic Efficacy

Pioglitazone and rosiglitazone decrease A1c levels to a similar degree as metformin and sulfonylurea therapy (typically a 1.0-1.5% decrease in A1c) (20,71). The decreases in fasting plasma glucose were observed as early as the second week of therapy but maximal decreases occurred after 10-14 weeks (20,74). This differs from other hypoglycemic drugs where the maximal effect occurs more rapidly. TZDs lower both fasting and postprandial glucose levels (71). TZDs are more effective in improving glycemic control in patients with marked insulin resistance (75).

TZDs are effective in combination with other hypoglycemic drugs including insulin (20,41,74). TZDs do not cause hypoglycemia when used as monotherapy or in combination with metformin (20,41). In combination with insulin or insulin secretagogues, TZDs can potentiate hypoglycemia. If hypoglycemia occurs one needs to adjust the dose of insulin or insulin secretagogues.

The durability of glycemic control with TZDs is more prolonged than with either sulfonylureas or metformin (18). After 5 years of monotherapy, 15% of individuals on rosiglitazone, 21% of individuals on metformin, and 34% of individuals on glyburide (glibenclamide) had fasting glucose levels above the acceptable range (18). The ability to maintain an A1c <7% was 57 months with rosiglitazone, 45 months with metformin, and 33 months with glyburide (glibenclamide) (18). Similar results were observed when pioglitazone therapy was compared to sulfonylurea therapy (76). After 2-years of therapy 47.8% of pioglitazone-treated patients and only 37.0% of sulfonylurea-treated patients maintained an A1c <8%. Studies have shown that TZDs improve and preserve beta cell function, which may account for their better durability (77-79).

Other Beneficial Effects

PROTEINURIA

A meta-analysis of 15 studies (5 with rosiglitazone and 10 with pioglitazone) involving 2,860 patients demonstrated that TZDs decreased urinary albumin excretion in patients without albuminuria, in patients with microalbuminuria, and in patients with proteinuria (80).

BLOOD PRESSURE

TZDs modestly lower BP. In a review of 37 studies TZDs lowered systolic BP by 4.70 mm Hg and diastolic BP by 3.79 mm Hg (81).

LIPIDS

The effect of TZDs on lipids depends on which agent is used. Rosiglitazone increases serum LDL cholesterol levels, increases HDL cholesterol levels, and only decreases serum triglycerides if the baseline triglyceride levels are high [66]. In contrast, pioglitazone has less impact on LDL cholesterol levels, but increases HDL cholesterol levels, and decreases serum triglyceride levels (82). In the PROactive study, a large randomized cardiovascular outcome study, pioglitazone decreased triglyceride levels by approximately 10%, increased HDL-C levels by approximately 10%, and increased LDL-C by 1-4% (83). It should be noted that reductions in the small dense LDL subfraction and an increase in the large buoyant LDL subfraction are seen with both TZDs (82). Treatment with pioglitazone for 12 weeks resulted in a significant increase in the ability of HDL to facilitate the efflux of cholesterol from cells (84).

In a randomized head-to-head trial, it was shown that pioglitazone decreased serum triglyceride levels and increased serum HDL cholesterol levels to a greater degree than rosiglitazone treatment (85,86). Additionally, pioglitazone increased LDL cholesterol levels less than rosiglitazone. In contrast to the differences in lipid parameters, both rosiglitazone and pioglitazone decreased A1c and C-reactive protein to a similar extent. The mechanism by which pioglitazone induces more favorable changes in lipid levels than rosiglitazone is unclear, but differential actions of ligands for nuclear hormone receptors are well described.

CARDIOVASCULAR DISEASE

Studies with pioglitazone have suggested a beneficial effect on cardiovascular disease. The PROactive study was a randomized controlled trial that examined the effect of pioglitazone vs. placebo over a 3-year period in patients with T2DM and pre-existing macrovascular disease (87). With regard to the primary endpoint (a composite of all-cause mortality, non-fatal myocardial infarction including silent MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle), there was a 10% reduction in events in the pioglitazone group but this difference was not statistically significant (p=0.095). It should be noted that both leg revascularization and leg amputations are not typical primary end points in cardiovascular disease trials and these could be affected by pioglitazone induced edema. When one focuses on standard cardiovascular disease endpoints, the pioglitazone treated group did demonstrate a 16% reduction in the main secondary endpoint (composite of all-cause mortality, non-fatal myocardial infarction, and stroke) that was statistically significant (p=0.027). In the pioglitazone treated group, blood pressure, A1c, triglyceride, and HDL cholesterol levels were all improved compared to the placebo group making it very likely that the mechanism by which pioglitazone decreased vascular events was multifactorial.

The IRIS trial was a multicenter, double-blind trial that randomly assigned 3,876 patients with insulin resistance but without diabetes and a recent ischemic stroke or TIA to treatment with either pioglitazone or placebo (88). After 4.8 years, the primary outcome of fatal or nonfatal stroke or myocardial infarction occurred in 9.0% of the pioglitazone group and 11.8% of the placebo group (hazard ratio 0.76; P=0.007). All components of the primary outcome were reduced in the pioglitazone treated group. Additionally, in the subgroup of patients with “prediabetes” pioglitazone therapy also reduced cardiovascular events (89). Fasting glucose, fasting triglycerides, and systolic and diastolic blood pressure were lower while HDL cholesterol and LDL cholesterol levels were higher in the pioglitazone group than in the placebo group. Although this study excluded patients with diabetes the results are consistent with and support the results of a protective effect of pioglitazone observed in the PROactive study.

In contrast to the above results, a study compared the effect of pioglitazone vs. sulfonylurea on cardiovascular disease and did not observe a reduction in events with pioglitazone treatment (TOSCA.IT) (90). Patients with T2DM (n= 3,028), inadequately controlled with metformin monotherapy (2-3 g per day), were randomized to pioglitazone or sulfonylurea and followed for a median of 57 months. Only 11% of the participants had a previous cardiovascular event. The primary outcome was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularization and occurred in 6.8% of the patients treated with pioglitazone and 7.2% of the patients treated with a sulfonylurea (HR 0.96; NS). Limitations of this study are the small number of events likely due to low-risk population studied and the relatively small number of participants. Additionally, 28% of the subjects randomized to pioglitazone prematurely discontinued the medication. Thus, the results of this study should be interpreted with caution. Additionally, it should be noted that when patients in this study were analyzed based on the risk of developing cardiovascular disease those at high risk had a marked reduction in events when treated with pioglitazone compared to the sulfonylurea (91).

Further support for the beneficial effects of pioglitazone on atherosclerosis is provided by studies that have examined the effect of pioglitazone on carotid intima-medial thickness. Both the Chicago and Pioneer studies demonstrated favorable effects on carotid intima-medial thickness in patients treated with pioglitazone compared to patients treated with sulfonylureas (92,93). Additionally, in patients with “prediabetes” pioglitazone also slowed the progression of carotid intima-medial thickness (94). Similarly, Periscope, a study that measured atheroma volume by intravascular ultrasonography, also demonstrated less atherosclerosis in the pioglitazone treated group compared to patients treated with sulfonylureas (95).

There are a large number of potential mechanisms by which pioglitazone might reduce cardiovascular disease (Table 11) (79). In addition to altering risk factors pioglitazone has direct anti-atherogenic effects on the arterial wall that could reduce cardiovascular disease (79).

Table 11. Effect of Pioglitazone on Cardiovascular Risk Factors
Cardiovascular Risk Factor	Effect of Pioglitazone
Visceral Obesity	Decreases
Hypertension	Lowers BP
High Triglycerides	Lower TG
Low HDL cholesterol	Increases HDL cholesterol
Small dense LDL	Converts small LDL to large LDL
Endothelial dysfunction	Improves
Hyperglycemia	Lowers A1c
Inflammation	Lowers CRP
PAI-1	Lower PAI-1
Insulin resistance	Reduces
Hyperinsulinemia	Lowers insulin levels

While the data from a variety of different types of studies strongly suggests that pioglitazone is anti-atherogenic, the results with rosiglitazone are different. Several meta-analyses of small and short-duration rosiglitazone trials suggested that rosiglitazone was associated with an increased risk of adverse cardiovascular outcomes (96,97). However, the final results of the RECORD study, a randomized trial that was specifically designed to compare the effect of rosiglitazone vs. either metformin or sulfonylurea therapy as a second oral drug in those receiving either metformin or a sulfonylurea on cardiovascular events, have been published and did not reveal a difference in cardiovascular disease death, myocardial infarctions, or stroke (98,99). Similarly, an analysis of patients on rosiglitazone in the BARI 2D trial also did not suggest an increase or decrease in cardiovascular events in the patients treated with rosiglitazone (100).

Thus, while the available data indicate that pioglitazone is anti-atherogenic, the data for rosiglitazone suggests a neutral effect. Whether these differences between pioglitazone and rosiglitazone are accounted for by their differential effects on lipid levels or other factors is unknown.

METABOLIC DYSFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH)

Studies have shown that pioglitazone has beneficial effects on MASLD and MASH (101). In an early study 55 patients with impaired glucose tolerance or T2DM and liver biopsy-confirmed MASH were randomized to pioglitazone 45 mg/day or placebo (102). After 6 months of therapy liver enzymes improved and hepatic fat decreased, measured by magnetic resonance spectroscopy. Moreover, histologic findings improved including steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008). However, fibrosis was unchanged. A more recent study randomized 101 patients with prediabetes or T2DM and biopsy-proven MASH to pioglitazone 45 mg/day or placebo for 18 months (103). The primary outcome was a reduction of at least 2 points in the MASLD activity score in 2 histologic categories without worsening of fibrosis. Pioglitazone treatment resulted in 58% of patients achieving the primary outcome vs. only 17% of the placebo group (p<0.001) and 51% had resolution of MASH compared to 19% of the placebo group (p<0.001). Moreover, pioglitazone treatment improved the fibrosis score.

A meta-analysis of 8 randomized controlled trials (5 using pioglitazone and 3 using rosiglitazone) with 516 patients with biopsy-proven MASH reported that TZD treatment was associated with improved advanced fibrosis (OR, 3.15; P = .01), fibrosis of any stage (OR, 1.66; P = .01), and MASH resolution (OR, 3.22; P < .001) (104). Similar results were observed in patients with and without diabetes. Pioglitazone was more effective in improving MASH than rosiglitazone.

These studies demonstrate that pioglitazone has beneficial effects on MASLD and MASH. Whether this will result in improved clinical outcomes will require additional studies. TZDs are not FDA approved for the treatment of MASLD or MASH.

POLYCYSTIC OVARY SYNDROME

TZDs by improving insulin sensitivity decrease circulating androgen levels, improve ovulation rates, and improve glucose tolerance in patients with PCOS (61). Small trials have shown some benefit of TZDs for the treatment of infertility, usually in conjunction with clomiphene (61). Concerns regarding toxicity have limited the use of TZDs for the treatment of PCOS but if a patient has diabetes and TZDs are chosen for treating the diabetes one can anticipate beneficial effects on the PCOS.

Side Effects

WEIGHT GAIN

TZDs lead to an increase in body weight of 2 to 3 kg for every 1 percent decrease in A1c levels (71). In some studies patients gained over 4 kg during a 26-week study (71). Weight gain to a similar degree occurred in monotherapy studies and in studies where TZDs were added to metformin, sulfonylureas, or insulin (71). However, in combination with an SGLT2 inhibitor or a GLP-1 receptor agonist the weight gain was blunted or prevented (105,106). In the ADOPT trial weight gain was greater with TZD therapy than with glyburide therapy (2.5 kg over 5 years) (29). The weight gain induced by TZDs is dose related and can be minimized by using low doses (107).

The TZD induced increase in body weight is due to an expansion of the subcutaneous fat depot whereas the mass of visceral fat remains unchanged or even decreases (71). While weight increases, waist circumference typically remains stable. Stimulation of PPAR gamma in subcutaneous adipocytes stimulates lipid accumulation (72). Fluid retention as discussed below may also contribute to the increase in weight.

FLUID RETENTION

Edema has been reported in 3.0 to 7.5% of patients treated with the TZDs compared with 1.0 to 2.5% in patients on placebo or treated with other oral antidiabetic therapy (108). The increase in fluid retention is dose related. The risk of developing edema is greatest when a TZD is used in combination with insulin (108). The occurrence of edema is reduced when a TZD is used in combination with an SGLT2 inhibitor (105).

TZD induced edema responds poorly to treatment with thiazide and loop diuretics but responds to diuretics that effect the distal tubules such as spironolactone, triamterene, and amiloride (107). Additionally, edema improves when TZD treatment is discontinued (108). The increased fluid retention can lead to an increase in plasma volume resulting in a modest decrease in hemoglobin levels (2-4%) (107).

The increase in fluid retention is likely due to TZDs activating PPAR gamma in the renal tubules leading to the increased expression of the epithelial Na(+) channel resulting in the increased resorption of sodium (109). TZDs have been shown to decrease urine sodium excretion and to increase plasma renin and aldosterone levels (110).

CONGESTIVE HEART FAILURE (CHF)

In a meta-analysis of seven studies with a total of 10,040 participants with 641 CHF events, pioglitazone treatment increased the risk of developing CHF by 33% (RR 1.33, 95% CI 1.14–1.54) (111). Another meta-analysis found that pioglitazone was associated with a 51% increased risk of CHF while rosiglitazone was associated with a 173% increase (112). In the RECORD trial, the rosiglitazone group had an increased rate of severe episodes of CHF resulting in hospital admission or death (OR 2.10, p = 0.001) (98). Similarly, in the PROactive trial, the pioglitazone group also had increased rates of CHF (6% vs. 4%, p = 0.007) (87). Patients treated with TZDs have a higher risk for CHF development if they have a history of cardiovascular disease (107). Interestingly, TZD-associated CHF has not been linked with increased mortality (87,113).

Although TZDs are associated with worsening of CHF or CHF development, they are not associated with adverse effects on cardiac function or structure (107). It is thought that the CHF is mainly due to fluid retention rather than TZDs inducing primarily cardiac dysfunction (107).

OSTEOPOROSIS

Large randomized trials have shown that TZDs increase fracture risk, particularly in women. In the ADOPT study, which compared rosiglitazone, metformin, and glyburide, there was no difference in the incidence of fractures in men (114). However, fractures in women at 5 years was increased in the group treated with rosiglitazone (rosiglitazone 15.1%, metformin 7.3%, and glyburide 7.7%) (114). The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and were seen predominantly in the lower and upper limbs (114). In the PROactive study there was a higher rate of bone fractures in females treated with pioglitazone vs. placebo (5.1% vs 2.5%) (115). In the RECORD trial upper and distal lower limb fracture rates were increased mainly in women in the rosiglitazone treatment group (98). Hip and femur fracture were not increased with rosiglitazone treatment (98). In the IRIS trial an increased risk of fracture was seen in both males and females (men 9.4% vs 5.2%; HR, 1.83; women 14.9% vs 11.6%; HR, 1.32) (116). In a meta-analysis of 22 randomized controlled trials with 24,544 participants with 896 fracture cases there was a significantly increased incidence of fracture in women (OR=1.94; P<0.001), but not in men (OR=1.02; P=0.83) treated with TZDs (117). The risk of a fracture was similar with rosiglitazone and pioglitazone treatment and appeared to be similar for participants aged <60 years old and older than ≥60 years of age (117). Of note, in the ACCORD trial the risk of fractures in the women treated with rosiglitazone decreased after discontinuing rosiglitazone therapy (118).

In mice, TZDs suppress bone formation and increase bone resorption resulting in decreased bone mass (85). Additionally, TZD administration in mice results in the massive accumulation of adipocytes in the bone marrow cavity (85). In a meta-analysis of 14 trials with 1,734 participants, treatment with TZDs for 3 to 24 months decreased bone mineral density measured by DEXA at the lumbar spine (difference -1.1%; p < 0.0001), total hip (-1.0%; p < 0.0001) and forearm (-0.9%; p = 0.007) (117). In five studies TZD therapy was discontinued and after 24-52 weeks there was no increase in bone mineral density indicating no restoration of bone mineral density with cessation of TZD treatment (117). In an observation study each year of TZD use was associated with greater bone loss at the whole body (additional loss of -0.61% per year), lumbar spine (-1.23% per year), and trochanter (-0.65% per year) in women, but not in men (119).The effect of TZD treatment on bone turnover markers varied considerably between individual studies (117). This reduction in bone mass induced by TZD treatment could contribute to the increase in fractures but it is possible that changes in the microarchitecture of bone also plays a role.

BLADDER CANCER

In preclinical studies pioglitazone administration increased bladder cancer in male rats but not in female rats or in mice, dogs, or monkeys (120). In the PROactive study there was a nonsignificant increase in the number of patients who developed bladder cancer (16 vs 6, p = 0.069) (87). In a number of instances, the development of bladder cancer could not plausibly be related to treatment due to the temporal sequence of drug exposure and cancer diagnosis. After eliminating these patients there were six patients with bladder cancer in the pioglitazone group and three patients in the placebo group (87). After 10 years of follow-up, bladder cancer was reported in 0.8% of patients (n = 14) in the pioglitazone versus 1.2% (n = 21) in the placebo group (relative risk 0.65) during the follow-up period (121). In the IRIS study bladder cancer occurred in 12 patients in the pioglitazone group and in 8 in the placebo group (P=0.37) (88). Thus, in large randomized trials the data do not definitively support that pioglitazone significantly increases the risk of bladder cancer. The short duration of the randomized studies and infrequent occurrence of bladder cancer make interpretation of these studies difficult.

Because of the preclinical data the FDA requested that the manufacturer of pioglitazone initiate a prospective study to examine the relationship between pioglitazone and bladder cancer. This 10-year study of 193,099 persons did not find any statistically significant association between pioglitazone treatment and bladder cancer (122). Additionally, in a multinational cohort of 1.01 million patients with T2DM there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men or women after adjustment for age, calendar year, diabetes duration, smoking, and any ever use of pioglitazone (123). Similarly, no association was observed between rosiglitazone and bladder cancer in men or women (123). In a careful review of 23 epidemiological studies Davidson concluded that there was little evidence that pioglitazone increased the risk of bladder cancer (120). The FDA still warns about the possibility of bladder cancer with pioglitazone use and recommends that pioglitazone not be used in diabetic patients with active bladder cancer or history of bladder cancer (package insert).

MACULA EDEMA

Macular edema has been reported in patients taking TZDs (124,125). Patients may present with blurred vision or decreased visual acuity or be diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed (125). Some patients had improvement in their macular edema after discontinuation of the TZD (125).

OVULATION AND PREGNANCY

As discussed above in the polycystic ovary section, TZD treatment of premenopausal women with PCOS may induce ovulation and thereby result in unplanned pregnancies. In premenopausal anovulatory women started on a TZD one needs to discuss the need for contraception.

Contraindications and Drug Interactions

TZDs are contraindicated in patients with NYHA Class III or IV heart failure. Pioglitazone should not be used in diabetic patients with active bladder cancer or history of bladder cancer.

Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone and rosiglitazone concentrations and one should limit pioglitazone dose to 15 mg daily (package insert).

Summary

TZDs are effective drugs in improving glycemic control and have significant benefits on disorders that occur commonly in patients with T2DM (cardiovascular disease, NAFLD/NASH, PCOS). Unfortunately, TZDs also have serious side effects, such as edema, CHF, osteoporosis, and weight gain, that limit their use. Clinicians need to balance the advantages and disadvantages of TZDs for the individual patient.

Table 12. The Advantages and Disadvantages of Thiazolidinediones
Advantages	Disadvantages
Once a day administration	Edema
Reduces CVD (pioglitazone)	Heart failure
Durable Effect	Weight gain
Reduces MASLD	Osteoporosis
No hypoglycemia	Bladder cancer (pioglitazone)?
Relatively inexpensive	Macula edema?
No dose adjustment for renal disease	Small increase in LDLc
Increase HDL-C and decrease triglycerides

ALPHA-GLUCOSIDASE INHIBITORS

Introduction

Acarbose (Precose, Glucobay), miglitol (Glycet), and voglibose (Basen, Voglib) are members of the α-glucosidase inhibitor class of oral anti-hyperglycemic compounds that were introduced in the 1990s (20).

Administration

The recommended starting dosage of acarbose and miglitol is 25 mg given orally three times daily at the start of each meal. The dose of acarbose and miglitol can be adjusted at 4 to 8-week intervals based on one-hour postprandial glucose or A1c levels, and on tolerance. The dosage can be increased from 25 mg tid with meals to 50 mg tid with meals. The maximum dose is 100 mg tid with meals. Note that the dose can be varied based on the amount of carbohydrate in the meal. In some patients one can initiate therapy once a day with the largest meal.

Mechanism of Action

Alpha-glucosidase inhibitors are competitive, reversible inhibitors of pancreatic α-amylase and membrane-bound intestinal α-glucosidase hydrolase enzymes (20,126). Inhibiting these enzymes prevents the metabolism of disaccharides and oligosaccharides into monosaccharides delaying carbohydrate digestion and absorption (20,126). Carbohydrate absorption occurs more distally in the intestine reducing the postprandial increase in glucose and lowering postprandial insulin levels (20,126). Acarbose and miglitol have minimal inhibitory activity against lactase and consequently will not prevent the increase in plasma glucose following the ingestion of milk or cause lactose intolerance (package insert). In addition to effecting carbohydrate absorption, alpha-glucosidase inhibitors increase postprandial GLP-1 secretion and reduce glucose-dependent insulinotropic polypeptide (GIP) secretion (20).

Glycemic Efficacy

The typical decrease in A1c levels is relatively modest with alpha-glucosidase inhibitors (0.5-1.0%) (41,126,127). The decrease in A1c is predominantly due to decreases in post meal glucose levels and alpha-glucosidase inhibitors have only modest effects on fasting glucose levels (20,126,127). Alpha-glucosidase inhibitors can be combined with other hypoglycemic drugs with additive effects and are particularly useful to lower postprandial glucose levels (41,126). Alpha-glucosidase inhibitors are most effective in patients who ingest a high carbohydrate diet and for this reason have been widely used and very effective in Asian populations (20).

These drugs do not cause weight gain and hypoglycemia is uncommon (20,41,127). If a patient experiences hypoglycemia while taking an alpha-glucosidase inhibitor in combination with insulin or sulfonylureas the patient should be instructed to use glucose (gel, tablets, etc.) as alpha-glucosidase inhibitors will prevent the breakdown of sucrose and delay glucose absorption resulting in a failure to quickly correct hypoglycemia. Severe hypoglycemia may require intravenous glucose or intramuscular glucagon administration.

Other Effects

CARDIOVASCULAR DISEASE

In the STOP-NIDDM trial 1,429 subjects with impaired glucose tolerance were randomized to placebo vs. acarbose and followed for 3.3 years (128). In the acarbose group a 49% relative risk reduction in the development of cardiovascular events was observed (hazard ratio 0.51; P =0.03). Among cardiovascular events, the major reduction was in the risk of myocardial infarction (HR 0.09; P =0.02). In a smaller trial, 135 patients hospitalized for the acute coronary syndrome who were newly diagnosed with IGT were randomly assigned to acarbose or placebo (129). During a mean follow-up of 2.3 years the risk of recurrent major adverse cardiovascular event was decreased significantly in the acarbose group compared with the control group (26.7% versus 46.9%, P < 0.05).

Despite these favorable observations a large trial failed to demonstrate a beneficial effect of acarbose in Chinese patients with impaired glucose tolerance (ACE trial) (130). In a randomized trial acarbose vs. placebo was compared in 6,522 patients with coronary heart disease and impaired glucose tolerance. The primary outcome was cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure and patients were followed for a median of 5 years. The primary outcome was similar in the acarbose and placebo groups (hazard ratio 0.98; p=0.73). No significant differences were seen for death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function.

Thus, whether acarbose favorably affects cardiovascular disease in patients at high risk for developing diabetes is uncertain. Moreover, the effect of acarbose on cardiovascular disease in patients with diabetes is unknown.

WEIGHT

Acarbose is may result in a very small decrease in weight (0.4kg) (131).

Side Effects

Gastrointestinal side effects of alpha-glucosidase inhibitors include flatulence, abdominal discomfort, and diarrhea and are very commonly encountered (20,41,127). These side effects can lead to the inability to tolerate these drugs. A high carbohydrate diet may worsen the GI adverse effects. Over time the GI symptoms tend to decrease as the intestines adapt (126). GI side effects are due to the mechanism of action of alpha-glucosidase inhibitors (126). The inhibition of carbohydrate digestion in the small intestine leads to the delivery of undigested carbohydrates to the large intestine where microorganisms metabolize them into short-chain fatty acids, methane, carbon dioxide, and hydrogen, that can cause abdominal discomfort, increased flatulence, and diarrhea (126).

Acarbose, particularly at doses in excess of 50 mg tid, may give rise to elevations of serum transaminases and, in rare instances, hyperbilirubinemia. It is recommended that serum transaminase levels be checked every 3 months during the first year of treatment with acarbose and periodically thereafter. If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist (package insert).

Contraindications and Drug Interactions

Acarbose and miglitol are contraindicated in patients with inflammatory bowel disease, colonic ulceration, intestinal obstruction or those predisposed to intestinal obstruction, patients with chronic intestinal disease, or conditions that will be worsened by the increased gas formation in the intestine (41) (package insert). Acarbose is contraindicated in patients with cirrhosis (package insert).

Acarbose and miglitol should not be used in patients with a creatinine > 2 mg/dl (package insert).

Summary

Alpha-glucosidase inhibitors are excellent drugs for lowering postprandial glucose levels. Unfortunately, because of their GI side effects many patients are unable to tolerate these drugs. Additionally, the need for three times a day administration makes it difficult for patients to comply with these drugs.

Table 13. Advantages and Disadvantages of Alpha-Glucosidase Inhibitors
Advantages	Disadvantages
No hypoglycemia	GI side effects
Weight neutral	Frequent dosing schedule
Decreases postprandial glucose	Avoid if renal disease (creatinine> 2mg/dL
Relatively inexpensive	Limited glucose lowering effect

SODIUM-GLUCOSE TRANSPORT PROTEIN 2 (SGLT2) INHIBITORS

Introduction

There are currently five SGLT2 inhibitors available (Canagliflozin/ Invokana; Dapagliflozin/ Farxiga; Empagliflozin/Jardiance; Ertugliflozin/ Stelgatro; Bexagliflozin/ Brenzavvy) (132). These drugs are very similar and there are only a few differences between these agents.

Administration

The recommended starting dose of canagliflozin is 100 mg once daily, taken before the first meal of the day. In patients tolerating canagliflozin 100 mg once daily who have an eGFR of 60 mL/min/1.73 m² or greater and require additional glycemic control, the dose can be increased to 300 mg once daily.

The recommended starting dose of dapagliflozin is 5 mg once daily, taken in the morning, with or without food. In patients tolerating dapagliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily.

The recommended starting dose of empagliflozin is 10 mg once daily in the morning, taken with or without food. In patients tolerating empagliflozin, the dose may be increased to 25 mg.

The recommended starting dose of ertugliflozin is 5 mg once daily, taken in the morning, with or without food. In patients tolerating ertugliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 15 mg once daily.

The recommended starting dose of bexagliflozin is 20 mg once daily, taken in the morning, with

or without food.

Before initiating SGLT2 inhibitor therapy one should assess renal function and volume status. The dose of SGLT2 inhibitors may need to be adjusted based on renal function (see below).

Mechanism of Action

SGLT2 is a low-affinity, high-capacity glucose transporter in the proximal tubules of the kidneys, which is responsible for the reabsorption of the majority of the filtered glucose (approximately 90%) entering the tubules (20,133). SGLT1, which is predominantly expressed in the intestines is also expressed in the kidneys, is a high-affinity, low-capacity glucose transporter in the proximal tubules, which makes a minor contribution to the reabsorption of filtered glucose (approximately 10%) (20,133). SGLT 1 and 2 transporters are capable of reabsorbing virtually all the filtered glucose when blood glucose levels are less than approximately 180mg/dL. When blood glucose levels are greater than approximately 180mg/dL, glucose begins to appear in the urine (i.e., glycosuria). The higher the blood glucose level the greater the quantity of glucose in the urine. Patients with T2DM express a greater number of SGLT2 transporters in the proximal tubule than do healthy individuals and hence glucose reabsorption from the glomerular filtrate is increased in patients with diabetes and glycosuria occurs at a higher blood glucose level (typically approximately 220mg/dl (134).

Inhibition of SGLT2 by drugs results in glycosuria and can lead to the excretion of 60–90 grams of glucose in the urine per day (Figure 5) (20). The amount of glucose excreted in the urine can vary considerably depending on renal function and the degree of hyperglycemia (20). Decreased renal function results in a decrease in filtered glucose and less glucose in the urine while high blood glucose levels increase filtered glucose and increases the loss of glucose in the urine (20). The ability of the inhibition of SGLT2 to lower blood glucose levels is not dependent on insulin action and hence is not affected by insulin levels or insulin resistance (20). As will be discussed below many of the non-glucose lowering benefits and side effects of SGLT2 inhibitors can be explained by the increase in glucose excretion in the urine. It should be recognized that glycosuria results in an osmotic diuresis. Additionally, because the SGLT2 transporters also facilitate the reabsorption of sodium from the filtrate there is also the loss of sodium in the urine.

Figure 5. Effect of SGLT2 Inhibitors on the Kidney.

Glycemic Efficacy

A meta-analysis of 66 randomized trials found that SGLT2 inhibitors decreased A1c levels by 0.4 to 1.1% (135). In comparison to other hypoglycemic drugs, it was found that SGLT‐2 inhibitors showed a greater efficacy than DPP‐4 inhibitors and similar or slightly less efficacy compared to metformin and TZDs (13,135). Sulfonylureas appeared to be superior to SGLT‐2 inhibitors at 12 weeks, but at 24- and 52-weeks efficacy was similar or slightly lower (13,135). However, SGLT‐2 inhibitors produced a greater reduction in HbA1c than sulfonylureas at 104 weeks perhaps due to the lack of durability of sulfonylurea therapy discussed earlier (135). The A1c lowering ability of the different SGLT2 inhibitors is similar but A1c is reduced to a slightly greater extent by high-dose canagliflozin, which is probably a result of its additional action of inhibiting SGLT1 in the intestine decreasing dietary glucose absorption (132,133,135). SGLT2 inhibitors when used as an add-on therapy to metformin, insulin, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas, or metformin ± DPP-4 inhibitor were similarly effective in reducing A1c levels as when used in monotherapy (20,133). The efficacy of SGLT2 inhibitors is dependent on renal function and as renal function decreases the ability of these drugs to lower A1c levels diminishes (20,133). SGLT2 inhibitors lower both fasting and postprandial glucose levels (133). In monotherapy SGLT2 inhibitors have a low risk of causing hypoglycemia but in combinations with insulin or sulfonylureas may potentiate the development of hypoglycemia (20). In patients in good glycemic control, one often decreases the insulin or sulfonylurea dose when initiating therapy with an SGLT2 inhibitor. If glucose levels are very high SGLT2 inhibitors can result in marked polyuria and nocturia that leads to uncomfortable symptoms and therefore many clinicians do not initiate SGLT2 inhibitor therapy in patients with high HbA1c levels until glucose control is in a more reasonable range.

Other Effects

WEIGHT

SGLT2 inhibitors lead to weight loss (20,133). In general patient’s lose approximately 1- 3 kg on these drugs (20,132,133). SGLT2 inhibitor-induced weight loss results primarily from a decrease in fat mass, including reductions in visceral and subcutaneous adipose tissue (133). The weight loss is due to the loss of glucose in the urine, which represents the loss of calories (133,136). The excretion of 50 grams of glucose in the urine is equivalent to the loss of 225 calories (50-grams X 4.5 calories per gram of glucose). However, the amount of glucose lost in the urine should result in a greater weight loss than is typically observed and a compensatory increase in food intake blunts the weight loss (136). There are likely to be other homeostatic mechanisms that also play a role in limiting weight loss with SGLT2 inhibitors.

GLUCOSE MONITORING

Monitoring glycemic control with 1,5-AG assay is not accurate as measurements of 1,5-AG are unreliable in patients taking SGLT2 inhibitors.

BLOOD PRESSURE

SGLT2 inhibitors decrease systolic BP by approximately 3-6 mmHg and diastolic BP by approximately 2-3 mmHg (20,133). Patients with poorly controlled BP at baseline experience the largest reduction in BP (132). SGLT2 inhibitors lower BP by promoting an osmotic diuresis and decreasing intravascular volume (133). Weight loss may also contribute to the decrease in BP.

LIPID LEVELS

SGLT2 inhibitors cause a small increase in LDL and HDL cholesterol levels. In the EMPA-REG outcome study, described in detail below, LDL cholesterol levels were increased by 2-4 mg/dL and HDL cholesterol by 2-3 mg/dL in the group treated with empagliflozin (137). Similarly, in the CANVAS outcome study, discussed in detail below, LDL cholesterol and HDL cholesterol were also marginally increased in the canagliflozin treated group (LDL cholesterol 4-5 mg/dL and HDL cholesterol 2-3 mg/dL) (138). In a meta-analysis of 43 randomized trials with 22,528 patient’s triglyceride levels were decreased by 2 mg/dL (139). In a meta-analysis of 48 randomized controlled trials SGLT2 inhibitors significantly increased LDL-C (3.8mg/dl, p < 0.00001), HDL-C (2.3mg/dl, p < 0.00001), and decreased triglyceride levels (8.8mg/dl, p < 0.00001) (140). It is unlikely that these small changes in LDL-C, HDL-C, and triglyceride levels are of clinical significance. The mechanism for these increases in LDL and HDL cholesterol is unknown but could be due to a decrease in plasma volume. The decrease in triglycerides might be secondary to weight loss.

URIC ACID

SGLT2 inhibitors lower blood uric acid levels (141). This decrease is due to an increase in uric acid excretion by the kidneys. In an observational study 47,905 individuals receiving an SGLT2 inhibitor and 183,303 receiving a DPP4 inhibitor it was observed that the incidence of gout was 20.26 per 1000 patient-years for SGLT2 inhibitor users and 24.30 per 1000 patient-years for

DPP4 inhibitor users (142). A similar study found that a gout flare was lower among SGLT2 inhibitor users than DPP-4 inhibitor users (52.4 vs. 79.7 events per 1000 person-years) (143). Additionally, an observations study found that the incidence of gout was lower among SGLT2i initiators than sulfonylurea initiators (HR 0.62; 95% CI, 0.48-0.80) (144).

CARDIOVASCULAR

There have been numerous large randomized studies of the effect of SGLT2 inhibitors on cardiovascular events published (others are in progress).

EMPA-REG Outcome Trial

In this study, 7,020 patients with established cardiovascular disease and T2DM were randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily and were followed for 3.1 years (137). In the combined empagliflozin treated groups there was a statistically significant 14% reduction in the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). As compared with placebo, empagliflozin treatment did not result in a significant difference in the occurrence of non-fatal myocardial infarction or strokes. However, empagliflozin resulted in a significantly lower risk of death from cardiovascular causes (HR 0.62), death from any cause (HR 0.68), and hospitalization for heart failure (HR 0.65). The beneficial effects of empagliflozin were noted to occur very rapidly and the beneficial effects on heart failure appeared to be the dominant effect compared to effects on atherosclerotic events. Decreases in cardiovascular outcomes and mortality with empagliflozin occurred across the range of cardiovascular risk (145). Additionally, the reduction in hospitalizations for heart failure and cardiovascular death were observed both in patients with and without heart failure at baseline (146).

CANVAS Trial

The effects of placebo vs. canagliflozin 100mg or 300mg per day were determined in two combined trials involving a total of 10,142 participants with T2DM and high cardiovascular risk (approximately 70% of patients had established cardiovascular disease) (138). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke and the mean follow-up was 188 weeks. The primary outcome was reduced in the canagliflozin group (HR 0.86; P=0.02). The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease and those with preserved kidney function (147). Death from any cause (HR 0.87; 95% CI 0.74-1.01) and death from cardiovascular disease (HR 0.87; 95% CI 0.72-1.06) were reduced but were not statistically significant. Similarly, canagliflozin treatment did not result in a significant difference in non-fatal strokes or non-fatal myocardial infarctions. As seen with empagliflozin, hospitalization for heart failure was markedly reduced (HR 0.67; 95% CI 0.52-0.87) and this beneficial effect occurred rapidly.

CREDENCE Trial

In a second canagliflozin trial that focused on patients with kidney disease, a decrease in cardiovascular events was also observed (148). In this double-blind trial 4,401 patients with chronic kidney disease and T2DM were randomized to canagliflozin 100mg per day or placebo and followed for a median of 2.62 years. All the patients had an eGFR of 30 to <90 ml per minute per 1.73 m² and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000). In this trial hospitalization for heart failure was reduced by 39%. The relative benefits of canagliflozin for cardiovascular outcomes was similar in individuals across the spectrum of eGFR levels (149)

DECLARE–TIMI 58 Trial

The effect of dapagliflozin on cardiovascular events has been reported (150). 17,160 patients with T2DM, including 10,186 without atherosclerotic cardiovascular disease, were randomized to dapagliflozin 10mg per day or placebo and followed for a median of 4.2 years. The primary outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. Dapagliflozin did not result in a lower rate of major adverse cardiovascular events (8.8% in the dapagliflozin group and 9.4% in the placebo group; HR 0.93; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; HR 0.83; P=0.005), which reflected a lower rate of hospitalization for heart failure (HR 0.73; 95% CI 0.61 to 0.88). Interestingly, in the patients with a history of a previous MI dapagliflozin reduced the risk of a MACE (HR 0.84; P=0.039), whereas there was no effect in patients without a previous MI (151). Dapagliflozin reduced the risk of heart failure in patients with and without a history of heart failure but the benefit was greater in patients with a history of heart failure (with heart failure HR 0.62; 95% CI 0.45-0.86; without heart failure HR 0.88; 95% CI 0.74-1.03) (152). Dapagliflozin also reduced the risk of heart failure in patients without a history of atherosclerotic cardiovascular disease (153).

VERTIS CV

Patients with atherosclerotic cardiovascular disease and T2DM were randomized to ertugliflozin 5mg (n=2752), 15mg (2747), or placebo (n=2747) and the primary composite outcome of cardiovascular death and non-fatal MI or stroke was determined after a mean duration of follow-up of 3.5 years (154). This trial did not demonstrate a significant difference in the primary endpoint (MACE) nor any components of the primary endpoint. However, heart failure hospitalizations were significantly reduced by 30% in the patients treated with ertugliflozin (HR 0.70; CI 0.54–0.90). The benefits on heart failure were observed in both patients with a history of heart failure (decreased 37%) and patients without a history of heart failure (decreased 21%) (155).

DAPA HF Trial

In this trial 4,744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to receive either dapagliflozin 10 mg once daily or placebo for a median of 18.2 months (156). The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. Of note only approximately 45% of the patients had T2DM. Treatment with dapagliflozin reduced the primary outcome (HR 0.74; 95% CI 0.65 to 0.85; P<0.001), heart failure (HR 0.70; 95% CI 0.59 to 0.83), and death from cardiovascular disease (HR 0.82; 95% CI 0.69 to 0.98). Symptoms of heart failure were also improved with dapagliflozin treatment. Additionally, dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death (157). The benefits of dapagliflozin were similar in patients with and without T2DM (158). This study demonstrates that an SGLT2 inhibitor is beneficial in patients with pre-existing heart failure and this occurs in both patients with and without T2DM.

EMPEROR-Reduced Trial

In this trial 3,730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to empagliflozin 10 mg once daily or placebo for a median of 16 months (159). The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. Approximately 50% of the patients had T2DM. Treatment with empagliflozin reduced the primary outcome (HR 0.75; 95% CI 0.65 to 0.86; P<0.001) and hospitalization for heart failure (HR 0.69; 95% CI 0.59 to 0.81) but did not reduce cardiovascular death (HR 0.92; 95% CI 0.75 to 1.12). The beneficial effects were observed in patients with and without diabetes. This study is concordant with the results observed in the DAPA HF trial and demonstrates that SGLT2 inhibitors are beneficial in patients with pre-existing heart failure and this occurs in both patients with and without diabetes. Notably, the beneficial effects of empagliflozin on heart failure decreased when the drug was stopped indicating that therapy needs to be continued (160)

DAPA CKD Trial

This trial randomized 4,304 participants with an eGFR of 25 to 75 ml/min/1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio 200 to 5000 mg/g to receive dapagliflozin 10 mg daily or placebo for a median of 2.4 years (161). Approximately 67% of the patients had diabetes. The composite of death from cardiovascular causes or hospitalization for heart failure was decreased in the dapagliflozin group (HR 0.71; 95% CI 0.55–0.92).

EMPEROR-Preserved Trial

This trial randomized 5,988 patients with heart failure with an ejection fraction of >40% to treatment with placebo or empagliflozin 10 mg daily (162). Empagliflozin decreased the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit by 23% (HR 0.77; P<0.0001). Moreover, this benefit occurred rapidly reaching statistical significance at 18 days after randomization. The benefit of empagliflozin was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. These results indicate that SGLT2 inhibitors are beneficial even in patients with a preserved ejection fraction.

Deliver Trial

This trial randomized 6,263 patients with heart failure and a left ventricular ejection fraction greater than 40% to receive dapagliflozin 10 mg once daily or placebo (163). Treatment with dapagliflozin reduced the risk of hospitalization for heart failure by 18% (HR 0.82; P<0.001). Similar benefit was seen in patients with and without diabetes. Additionally, in patients with a left ventricular ejection fraction greater than 60% or those with a left ventricular ejection fraction of less than 60% the results were similar. These results confirm the results of the EMPEROR Preserved Trial described above and further suggest that even patients with heart failure and an ejection fraction greater than 60% will benefit from SGLT2 inhibitors.

EMPACT-MI Trial

Patients hospitalized for an acute myocardial infarction were randomized to empagliflozin 10 mg daily (n=3260) or placebo (n=3262) for a median follow-up of 17.9 months (164). Patients were at high risk of heart failure with evidence of newly developed left ventricular ejection fraction <45% or signs or symptoms of congestion plus other factors such as age > 65 years or older, a newly developed ejection fraction < than 35%, T2DM, or an GFR < than 60. Approximately 32% of the participants were diabetic. The composite primary end point of hospitalization for heart failure or death from any cause occurred in 8.2% in the empagliflozin group and 9.1% in the placebo group (HR 0.90; 95% CI 0.76 to 1.06; P=0.21). Death from any cause was similar in both groups but first hospitalization for heart failure occurred in 3.6% in the empagliflozin group and in 4.7% in the placebo group (HR 0.77; 95% CI, 0.60 to 0.98). Total heart failure events were reduced by 33% (risk ratio 0.67; 95% CI 0.51- 0.89; P=0.006) and the decrease was similar in patients with and without diabetes (165). This study demonstrates that initiating SLT2 inhibitor therapy during hospitalization for a myocardial infarction will reduce the occurrence of heart failure in high-risk patients.

Summary

Thus, a large number of randomized trials of SGLT2 inhibitors demonstrated a robust decrease in heart failure with SGLT2 inhibitor therapy (table 14) without a consistent strong effect on myocardial infarctions or strokes (166-168). In a meta-analysis of eight of these trials (not including Emperor Preserved or the Deliver Trial) with 59,747 patients it was observed that SGLT2 inhibitors reduced the risk of all-cause mortality (HR 0.84; 95% CI 0.78-0.91), cardiovascular mortality (HR 0.84; 95% CI 0.76-0.93), hospitalization for heart failure (HR 0.69; 95% CI 0.64-0.74), and myocardial infarction (HR 0.91; 95% CI 0.84-0.99), but there was no significant effect on the risk of stroke (HR 0.98; 95% CI 0.86-1.11) (167). The reduction in heart failure was seen in patients with and without diabetes, patients with renal disease, and patients with and without a history of heart failure. The Emperor Preserved and Deliver trial demonstrated that patients with a preserved ejection fraction also benefit from treatment with a SGLT2 inhibitor. Finally, the EMPULSE trial demonstrated that starting empagliflozin during the hospitalization for heart failure was beneficial (169) while the EMPACT-MI Trial demonstrated that starting empagliflozin in patients hospitalized for a myocardial infarction who were at high risk for heart failure also reduced the risk of developing heart failure (164,165).

Table 14. Summary of Effect of SGLT2 Inhibitors on Heart Failure
	Number	Prior Heart Failure	Mean Follow-up (years)	*Hazard Ratio (95% CI)**	P value
EMPA-REG Empagliflozin	7,020	10.1%	3.1	0.65 (0.05-0.85)	0.002
CANVAS Canagliflozin	10,142	14.4%	3.6	0.67 (0.52-0.87)	--
DECLARE-TIMI 58 Dapagliflozin	17,160	10.0%	4.2	0.73 (0.61-0.88)	0.0007
VERTIS-CV Ertugliflozin	8,246	23.7%	3.0	0.70 (0.54-0.90)	0.006
CREDENCE Canagliflozin	4,401	14.8%	2.6	0.61 (0.47-0.80	0.001
DAPA-HF Dapagliflozin	4,774	100%	1.5	0.70 (0.59-0.83)	0.001
EMPEROR Empagliflozin	3,730	100%	1.3	0.69 (0.59-0.81)	<0.001
EMPEROR Preserved	5,988	100%	2.2	0.73 (0.61 to 0.88)	<0.001
DAPA-CKD	4,304	11%	2.4	0.71** (0.55–0.92)	<0.009

Modified from reference (167).

*Hospitalization for Heart Failure.

** Hospitalization for Heart Failure and death from cardiovascular disease.

A meta-analysis of the effect of SGLT2 inhibitors on patients with diabetes (n= 74,437) and various other disorders (ASCVD, heart failure, and chronic renal disease) is shown in table 15 (168). In patients with diabetes with or without ASCVD, heart failure, or chronic renal disease SGLT2 inhibitors reduced the risk of heart failure and decreased cardiovascular death (the decrease in cardiovascular death was not statistically significant in patients without ASCVD and without heart failure). These results indicate that treatment with an SGLT2 inhibitors will be beneficial in a wide spectrum of patients with diabetes.

Table 15. The Decrease in Key Outcomes in Patients with Diabetes Treated with SGLT2 Inhibitors
	First Hospitalization for Heart Failure	Cardiovascular Death
Overall	28%	15%
With ASCVD	29%	17%
Without ASCVD	37%	5%*
With Chronic Kidney Disease	34%	17%
Without Chronic Kidney Disease	27%	22%
With Heart Failure	28%	14%
Without Heart Failure	28%	13%*

Modified from reference (168).

*not statistically significant.

The mechanisms accounting for the beneficial effects of SGLT2 inhibitors on heart failure are uncertain (170). Glycemic control was better in the SGLT2 inhibitor treated patients but it is doubtful that this modest decrease in glucose could account for the observed results (additionally benefit in non-diabetics makes a glucose effect very unlikely). SGLT2 inhibitor treatment was associated with small reductions in weight, waist circumference, uric acid level, and systolic and diastolic blood pressure, with no increase in heart rate and small increases in both LDL and HDL cholesterol. Whether these changes played a role in reducing events remains to be determined but it is unlikely that these play a major role as other treatments that effect these factors do not markedly diminish the risk of heart failure events. It is possible that hemodynamic changes secondary to the osmotic diuresis induced by SGLT2 inhibitors contributed to the beneficial effects. In an analysis of the EMPA-REG OUTCOME trial, the change in hematocrit (~3% increase), corresponding to ~7% reduction in plasma volume, accounted for approximately 50% of the benefit of the drug on cardiovascular death (171). Additionally, SGLT2 inhibitors increase free fatty acid levels and glucagon secretion, which promotes the production of ketone bodies such as beta-hydroxybutyrate that are utilized by the heart for energy production (172). It is possible that this alternative source of energy could be protective for heart function. Finally, there may be direct effects of SGLT2 inhibition on myocardial and renal metabolism (170,173,174). Further studies are required to better elucidate the mechanism of the beneficial effects of SGLT2 inhibitors on heart failure.

RENAL DISEASE

The large randomized SGLT2 inhibitor cardiovascular outcome trials described above also examined the effect of these drugs on renal disease.

EMPA-REG Outcome Trial

The effect of empagliflozin on renal outcomes was studied in 4,124 patients with T2DM who were randomized to empagliflozin (10 mg or 25 mg) or placebo (175). The prespecified outcomes were progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease, and incident albuminuria. Worsening nephropathy occurred in 12.7% of patients in the empagliflozin group and in 18.8% of patients in the placebo group, a relative risk reduction of 39% (P<0.001). Progression to macroalbuminuria was reduced 38%, doubling of serum creatinine by 44%, and initiation of renal replacement therapy by 55% (all statistically significant). The renal benefit was seen regardless of baseline eGFR, occurring in individuals with an eGFR as low as 30 mL/min/1.73 m². While empagliflozin caused an initial decrease in eGFR over the long term eGFR decreased in the placebo group at a more rapid rate than the empagliflozin group. Additionally, patients treated with empagliflozin were more likely to convert from microalbuminuria to normoalbuminuria (HR 1.43; p<0.0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1.82; p<0.0001), and were less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0.84; p=0.0077) (176).

CANVAS Trial

Similar to the results seen with empagliflozin, canagliflozin has also been shown to decrease renal disease. 10,142 participants with T2DM and high cardiovascular risk were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks (138). Progression of albuminuria occurred less frequently in the canagliflozin group (HR 0.73; 95% CI 0.67 to 0.79). In addition, regression of albuminuria also occurred more frequently in the canagliflozin group (HR 1.70; 95% CI 1.51 to 1.91). Most importantly, the composite outcome of sustained 40% reduction in eGFR, the need for renal-replacement therapy, or death from renal causes occurred less frequently in the canagliflozin group (HR 0.60; 95% CI 0.47 to 0.77). Annual eGFR decline was slower (slope difference between groups 1.2 mL/min/1.73 m2 per year, 95% CI 1.0-1.4) and mean urinary albumin creatinine ratio was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo (177). The benefits of canagliflozin on renal disease occurred across a wide spectrum of eGFR ranging from 30-45 to ≥90 and in patients with moderate and severe albuminuria (147,178).

CREDENCE Trial

The CREDENCE Trial focused on patients with renal disease. In a double-blind trial 4,401 patients with T2DM and chronic kidney disease were randomized to canagliflozin or placebo and followed for a median of 2.62 years (148). All the patients had an eGFR of 30 to <90 and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. The primary outcome was 30% lower in the canagliflozin group (HR 0.70; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was 34% lower (HR 0.66; P<0.001), and the relative risk of end-stage kidney disease was 32% lower (HR 0.68; P = 0.002). Benefits were seen regardless of baseline eGFR.

DECLARE–TIMI 58 Trial

In this trial of 17,160 participants a secondary outcome was a renal composite outcome defined as a sustained decrease of 40% or more in eGFR to < 60, new end-stage renal disease, or death from renal or cardiovascular causes (150). As seen in the other SGLT2 inhibitor studies there was a decrease in the development of renal disease with the incidence of the renal outcome 4.3% in the dapagliflozin group vs. 5.6% in the placebo group (HR 0.76; 95% CI 0.67 to 0.87). Excluding death from cardiovascular causes as part of the composite endpoint, the reduction in renal events was even more impressive (HR 0.53 p<0.0001) (179). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (HR 0.41; p=0.012) (179).

VERTIS CV Trial

In VERTIS CV trial the renal composite end point of renal death, dialysis/transplant, or doubling of serum creatinine was reduced but not statistically significant in the ertugliflozin treated group (HR 0.81; CI 0.63–1.04) (154).

DAPA-HF Trial

EMPEROR-Reduced Trial

In this trial 3,730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to empagliflozin 10 mg once daily or placebo for a median of 16 months (159). The annual rate of decline in the eGFR was decreased in the empagliflozin group compared to the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001). Additionally, a composite renal outcome (chronic dialysis or renal transplantation or a profound, sustained reduction in the eGFR) was decreased in the empagliflozin group (HR 0.50; 95% CI 0.32 to 0.77).

DAPA-CKD Trial

In this trial 4,304 individuals with and without diabetes with an eGFR of 25 to 75 and a urinary albumin-to-creatinine ratio of 200 to 5000mg/g were randomized to dapagliflozin 10 mg/day or placebo for a median of 2.4 years (this study was stopped early by the data monitoring board) (161). The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes and this was reduced by 39% in the dapagliflozin group (HR 0.61; 95% CI 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19). All of the components of this primary outcome were decreased in the dapagliflozin group. A sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was reduced by 44% in the dapagliflozin group (HR 0.56; P<0.001). In the subgroup of patients with Stage 4 chronic kidney disease (eGFR< 30) the benefits of dapagliflozin were similar to those described above indicating that even in patients with severe renal disease dapagliflozin is beneficial (180) Finally, the benefits of dapagliflozin were similar in participants with T2DM (36% decrease) and in those without T2DM (50% decrease). Thus, similar to the CREDENCE trial, this trial demonstrates that dapagliflozin decreases renal disease progression in patients with pre-existing renal disease. Moreover, this benefit is seen in patients with and without T2DM. Finally, benefit was observed in the dapagliflozin group regardless of the type of kidney disease (diabetic, ischemic, hypertensive, glomerulonephritis, other, or unknown) (181).

EMPA-KIDNEY

6609 patients with chronic kidney disease who had an eGFR > 20 but < 45 or who had an eGFR > 45 but < 90 with a urinary albumin-to-creatinine ratio of at least 200 were randomized empagliflozin 10 mg/day or placebo (182). The primary outcome was a composite of progression of kidney disease (end-stage kidney disease, a sustained decrease in eGFR to <10, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. After a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 13.1% in the empagliflozin group and 16.9% in the placebo group (HR 0.72; 95% CI 0.64 to 0.82; P<0.001). Progression of kidney disease occurred in 11.6% in the empagliflozin group and 15.2 of the placebo group (HR 0.71; 95% CI 0.62–0.81). Similar benefits were seen in patients with or without diabetes and in patients with an eGFR < 30 and > 45. Empagliflozin slowed the rate of progression of chronic kidney disease regardless of the level of albuminuria or the cause of chronic kidney disease (183,184).

Summary

Multiple trials clearly demonstrate that SGLT2 inhibitors have beneficial effects on renal function and decrease the development and progression of renal disease (Table 16). In a meta-analysis of 8 trials with 59,747 patients there was a robust decrease in the composite end points of renal disease (HR 0.62; 95% CI, 0.56-0.70) (167). The benefits are observed in patients with and without diabetes, with and without renal disease, and also in patients with heart failure. In a smaller meta-analysis this renal disease benefit was seen in patients with and without atherosclerosis (185). These renal benefits are independent of improvement in glycemic control and occurs in patients without diabetes (186). A more recent meta-analysis of 13 studies reported that SGLT-2 inhibitors significantly reduced by 31% the occurrence of a composite primary renal outcome consisting of a doubling of serum creatinine, decline of eGFR > 50%, end-stage kidney disease, renal replacement therapy, transplantation, or renal death (HR 0.69; 95% CI 0.61–0.79) (187).

Table 16. Summary of SGLT2 Inhibitors on Renal Disease
	Number	Mean Follow-up (years)	*Hazard Ratio (95% CI)**
EMPA-REG; Empagliflozin	7,020	3.1	0.54 (0.40-0.75
CANVAS; Canagliflozin	10,142	3.6	0.60 (0.47-0.77)
DECLARE-TIMI 58; Dapagliflozin	17,160	4.2	0.53 (0.43-0.66)
VERTIS-CV; Ertugliflozin	8,246	3.0	0.81 (0.63-1.04)
CREDENCE; Canagliflozin	4,401	2.6	0.66 (0.53-0.81)
DAPA-HF; Dapagliflozin	4,774	1.5	0.71 (0.44-1.16)
EMPEROR; Empagliflozin	3,730	1.3	0.52 (0.32-0.77)
DAPA-CKD; Dapagliflozin	4304	2.4	0.56 (0.45-0.68)

*Renal composite outcomes.

The mechanism accounting for this effect is unknown but a leading hypothesis is that an increase of sodium chloride in the macula densa due to SGLT2 inhibition triggers a cascade that reduces GFR through constriction of the afferent glomerular arterioles (tubuloglomerular feedback) (133,186). This would reduce glomerular hydrostatic pressure and initially decrease GFR, an effect that is observed with SGLT2 treatment, but in the long run this decrease in GFR protects the kidney from damage resulting in improved kidney function long-term (133).

METABOLIC DYSFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH)

Numerous studies have shown that treatment with SGLT-2 inhibitors decrease liver enzymes (101,188-192). Moreover, studies have shown a decrease in liver fat and liver stiffness (101,188,189,191-193). A study of 5 patients showed an improvement in liver histology after 24 weeks of therapy with canagliflozin (194). Further studies are required to determine whether SGLT-2 inhibitors will result in clinical benefits in patients with MASLD and MASH.

MORTALITY

A meta-analysis of 21 randomized controlled trials with 70,364 individuals reported that all-cause mortality was decreased by 14% (195). The decrease in all-cause mortality was seen with all of the SGLT2 inhibitors but was not statistically significant with ertugliflozin.

EFFECT OF SGLT2 INHIBITORS IN PATIENTS ON GLP1 RECEPTOR AGONIST THERAPY

A meta-analysis of 12 randomized cardiovascular or renal trials of SGLT2 inhibitors where 3065 (4·2%) of 73,238 participants with T2DM were using GLP-1RA at baseline examined the effectiveness of combination therapy (196). SGLT2 inhibitors reduced the risk of major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in individuals both receiving and not receiving GLP-1RA (HR 0.81; 95% CI 0.63-1.03 vs 0.90; 0.86-0.94; p-heterogeneity=0.31). Similarly, the risk of hospitalization for heart failure or cardiovascular death (HR 0.76; 95%CI 0.57-1.01 vs 0.78, 0.74-0.82; p-heterogeneity=0.90), and chronic kidney disease progression (HR 0.65; 95%CI 0.46-0.94 vs 0.67; 0.62-0.72; p-heterogeneity=0.81) in individuals both receiving and not receiving GLP-1RA was reduced. Additionally, SGLT2 inhibitors decreased the rate of decline in eGFR as measured by chronic and total eGFR slope regardless of GLP-1RA use. These results are not surprising as SGLT2 inhibitors and GLP-1RA have different mechanisms of action. Thus, the beneficial effects of SGLT2 inhibitors occur even in patients on GLP1RA therapy.

Side Effects

In a meta-analysis of 51 randomized controlled trials involving 24,371 patients it was noted that the frequency of side effects was similar with high dose and low dose SGLT-2 inhibitors (197).

URINARY TRACT INFECTIONS

In some but not all studies an increased risk of urinary tract infections was observed with SGLT2 inhibitors (20,132). In the large randomized cardiovascular outcome trials, an increase in urinary tract infections were not observed (137,138,150). In a meta-analysis of 10 large outcome trials with 71,553 participants the relative risk of urinary tract infection was minimal (RR 1.06, 95% CI 1.00-1.12) (198). Similarly, another meta-analysis of 213 studies with 150,140 participants found only a small increased risk of urinary tract infections (OR 1.11; 95% CI 1.06- 1.16) (199). In contrast, a meta-analysis of 86 randomized trials with 50,880 patients an increase in urinary tract infections was not observed (200). The potential increase in the occurrence and severity of urinary tract infections is due to the glycosuria as glucose is an excellent substrate for the growth of micro-organisms.

GENITAL MYCOTIC INFECTIONS

Genital mycotic infections (mainly balanitis and vulvovaginitis) are increased with SGLT2 inhibitor treatment (132). The risk of genital mycotic infections is greater in women than men. In a meta-analysis that included over 2000 patients treated with canagliflozin 100 mg or 300 mg vs. placebo, genital mycotic infections were seen in greater than 10% of women (100mg-10.4%, 300 mg-11.4%, placebo-3.2%) and around 4% of men (100 mg-4.2%, 300 mg-3.7%, placebo- 0.6%) (201). In a large meta-analysis of 188 studies with 121,275 participants the risk of genital mycotic infections was markedly increased (OR 3.5; 95% CI 3.1-3.9) (199). In uncircumcised men the risk of genital mycotic infections is greater than in circumcised men. Genital mycotic infections are the most common side effect seen with SGLT2 inhibitors but fortunately these infections are generally mild and relatively easy to treat (20).

The increase in genital mycotic infections is due to the glycosuria as glucose is an excellent substrate for the growth of Candida.

FOURNIER GANGRENE

Fournier gangrene (FG) is a necrotizing fasciitis of the perineum that is characterized by a rapidly progressive necrotizing infection of the external genitalia, perineum, and perianal region (202). Many of the patients with FG have diabetes (32-66%) (202). FG occurs most commonly in males and is a rare condition with an incidence of 3.3 in 100,000 men aged 50 to 79 years (202). In a recent case series of 59 patients over a 10-year period at a single institution, the incidence was estimated at 32 cases per 100,000 admissions (203). Risk factors included very high A1c (mean 9.6%), obesity, immunocompromised state, and illicit drug use (203). FG is a urologic emergency and requires treatment with broad-spectrum antibiotics and immediate surgical intervention (202).

A recent report described 55 FG cases in patients treated with SGLT2 inhibitors in the last 6 years since they were approved for use in the US (202). In contrast, only 19 cases of FG were reported in 35 years among patients receiving other hypoglycemic drugs. All of the SGLT2 inhibitors were associated with FG except ertugliflozin, which is likely explained by this drug only recently being approved for the treatment of diabetes. However, the authors were unable to assess the incidence of FG or whether SGLT2 inhibitors were causative. A second study compared the occurrence of FG in patients treated with SGLT2 inhibitors (15.0 per 100,000 person-years) vs DPP4 inhibitors (9.7 per 100 000 person-years) in men 65 years and

older who have T2DM using large data bases (204). Other studies have not found an increased risk of FG with SGLT2 inhibitors (205,206). A major difficulty in determining if SGLT2 inhibitors actually increase the risk of FG is that FG is very rare making definitive studies difficult.

Early recognition of FG is essential to reduce morbidity and mortality. Typical presentations include systemic symptoms, such as fatigue, fever, and malaise, and local symptoms that include tenderness, erythema, and swelling (202). Pain out of proportion to the clinical findings is highly suggestive of necrotizing fasciitis (202).

HYPOVOLEMIA AND HYPOTENSION

SGLT2 inhibitors induce an osmotic diuresis (132). This effect can result in postural dizziness, orthostatic hypotension, falls, and dehydration, particularly in elderly individuals, patients with kidney disease, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers), and patients with low systolic blood pressure (132) (package insert). In a meta-analysis of 10 large outcome studies the risk of volume depletion was modestly increased (RR 1.14, 95% CI 1.06-1.23) (198). Volume status should be determined prior to initiating therapy with an SGLT2 inhibitor.

ACUTE KIDNEY INJURY

SGLT2 inhibitors have been reported to cause acute kidney injury (132). It is likely that volume depletion and hypotension lead to the acute kidney injury (132). In an analysis of two large health care utilization cohorts SGLT2 inhibitors were not associated with an increased risk of acute kidney injury (207). Similarly, in the cardiovascular outcome studies described earlier an increase in acute kidney injury was not observed. In fact, in a meta-analysis of 4 large studies (EMPA-REG, CANVAS, CREDENCE, and DECLARE-TIMI 58) a decrease in acute kidney injury was observed (Risk ratio 0.75; p<0.0001) (208). Similarly, a meta-analysis of 10 studies with 71,553 participants also did not observe an increase in acute kidney injury and in fact observed a decrease (RR 0.84, 95% CI 0.77-0.91) (198). Even in patients over age 75 years of age an increase in acute kidney injury was not observed with SGLT2 treatment (209).

Before initiating SGLT2 inhibitor therapy one should consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing SGLT2 inhibitors in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure) (package insert).

DIABETIC KETOACIDOSIS

Diabetic ketoacidosis (DKA) has been observed in patients with T2DM treated with SGLT2 inhibitors but is a rare side effect (20,132). In some instances, the glucose levels are not very elevated despite the patient having DKA (euglycemic DKA) and this can result in a delay in diagnosing DKA (132). SGLT2 inhibitors were associated with approximately twice the risk of diabetic ketoacidosis compared to treatment with DPP-4 inhibitors (210). Additionally, in several of the large cardiovascular studies described above an increase in DKA was observed (CANVAS Trial- canagliflozin 0.6 vs. placebo 0.3 participants with an event per 1000 patient-years; CREDENCE Trial- canagliflozin 2.2 vs. placebo 0.2 per with an event per 1000 patient-years; DECLARE–TIMI 58-dapagliflozin 27 episodes vs placebo 12 episodes; VERTIS trial 0.3% 5mg ertugliflozin, 0.4% 15mg dose, and 0.1% placebo group) (138,148,150,154). In a meta-analysis of 10 studies with 71,553 participants the risk of DKA was increased (RR 2.23, 95% CI 1.36-3.63) (198).

Many of the DKA events occurred in patients with T2DM treated with insulin who had reduced or stopped insulin or experienced an intercurrent illness that could precipitate DKA (20,211). In some instances, the patients were thought to have T2DM but actually had latent autoimmune diabetes of adults (LADA), a form of Type 1 diabetes (20). The hyperglycemia in DKA associated with SGLT2 inhibitors is typically mild because the SGLT2 inhibitors reduce blood glucose levels (20). SGLT2 inhibitors should be temporarily discontinued in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery) (package insert). DKA developing during hospitalizations has been described emphasizing the need for vigilance when continuing SGLT-2 inhibitors in patients admitted to the hospital (212). Patients should be educated regarding this potential complication and in high-risk patients (for example patients on insulin therapy with a history of poor glycemic control or DKA) one could provide the patient with methods to measure either blood or urine ketone levels at home to facilitate the early diagnosis of DKA.

A possible mechanism for the increased risk of DKA is SGLT2 inhibitors increasing plasma glucagon levels thereby increasing ketone production (132,211). In combination with the low insulin levels this could potentiate the development of DKA.

OSTEOPOROSIS AND FRACTURES

In the CANVAS cardiovascular outcome study, the rate of all fractures was higher in the canagliflozin group than in the placebo group (15.4 vs. 11.9 participants with fracture per 1000 patient-years; HR 1.26; 95% CI 1.04 to 1.52) (138). A similar trend was observed for low-trauma fracture events (canagliflozin 11.6 vs. placebo 9.2 participants with fracture per 1000 patient-years; HR 1.23; 95% CI 0.99 to 1.52) (138). The incidence of fractures in the CANVAS study was increased with canagliflozin vs. placebo across subgroups based on sex, age, duration of Type 2 diabetes, baseline eGFR, and prior fracture history (213). Notably, the increase in fractures associated with canagliflozin treatment began within weeks of drug initiation indicating that the increased risk occurs rapidly (213).

In contrast, both the EMPA-REG, VERTIS, and DECLARE cardiovascular outcome studies did not demonstrate an increase in fractures with empagliflozin or dapagliflozin, respectively (137,150,154). Additionally, in the CREDENCE outcome study, canagliflozin did not increase fracture risk in patients with chronic kidney disease defined as an eGFR of 30 to <90 and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) (148). Similarly, in a pooled analysis of 8 randomized canagliflozin studies with 5867 participants (CANVAS trial excluded) an increase in fractures was not observed (213). Moreover, in a meta-analysis of 27 randomized controlled trials with an average duration of 64 weeks that compared the efficacy and safety of SGLT2 inhibitors to a placebo in 20,895 participants there was no increased risk of fractures with SGLT2 inhibitor treatment (RR 1.02; 95% CI 0.81- 1.28) (214). Similarly, a meta-analysis of 10 large outcome studies also did not observe an increase in fractures (RR 1.03; 95% CI 0.95- 1.12) (198).

Several studies have examined the effect of SGLT2 inhibitors on bone mineral density. Canagliflozin was associated with a decrease in total hip bone mineral density over 104 weeks, (placebo-subtracted changes:100mg -0.9% and 300mg -1.2%), but did not result in changes in bone mineral density in the femoral neck, lumbar spine, or distal forearm (215). In a 2-year study dapagliflozin did not significantly affect bone mineral density at the lumbar spine, femoral neck, or total hip (216). In a 26-week study ertugliflozin also had no adverse effect on bone mineral density (217).

Thus, the evidence that SGLT2 inhibitors increase the risk of osteoporosis and fractures, with the possible exception of canagliflozin, is not very strong. One should recognize though, that hypoglycemia, hypovolemia, and hypotension could increase the risk of falls and thereby increase the risk of fractures in susceptible individuals.

AMPUTATIONS

In the CANVAS study described above, canagliflozin was associated with an increased risk of amputations (HR 1.97; 95% CI 1.41 to 2.75), which were primarily at the level of the toe or metatarsal (138). Amputation risk was strongly associated with baseline history of prior amputation and risk factors for amputation (peripheral vascular disease and neuropathy). The risk of amputation was low with 6.3 of participants per 1000 patients-years in the canagliflozin group having an amputation vs. 3.4 in the placebo group. The basis for the increase in amputations is unknown.

However, the EMPA-REG OUTCOME trial with empagliflozin, the DECLARE-TIMI 58 trial with dapagliflozin, and the VERTIS CV trial with ertuglifozin did not report an increase in amputations in the patients treated with an SGLT2 inhibitor(137,150,154,218). Moreover, in the CREDENCE trial, canagliflozin also did not cause an increase in amputations in the patients treated with the SLGT2 inhibitor (148). In a meta-analysis of 7 large cardiovascular/renal outcome trials described above (excluding CANVAS) there was no increased risk of amputations in the SGLT2 inhibitor treated group vs. placebo group (RR 1.09; CI 95% 0.94-1.26) (219). Given that only one of eight large randomized trials has demonstrated an increased risk of amputations it is unlikely that SGLT2 inhibitors significantly increase the risk of amputations.

Nevertheless, before initiating SGLT2 inhibitor therapy one should consider factors in the patient history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, severe neuropathy, and diabetic foot ulcers and weigh the risks and benefits of therapy (package insert).

ACUTE ILLNESS

Because of the risk of hypovolemia, hypotension, and DKA the administration of SGLT2 inhibitors should be suspended during acute illness or planned surgical procedures. SGLT2 inhibitor therapy may be resumed following recovery.

This view needs to be modified based on the results of the DARE 19 study and DEFENDER Trial (220,221). In the DARE 19 study patients hospitalized with COVID-19 and with at least one cardiometabolic risk factor (i.e., hypertension, T2DM, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease) were randomized to dapagliflozin 10 mg daily or placebo for 30 days (220). While dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, the drug was well tolerated indicating that SGLT2 inhibitors can be safely given to hospitalized patients if there are strong indications for their use. Additionally, The DEFENDER trial randomized intensive care unit patients to dapagliflozin (n = 248) or placebo (n = 259) hoping to improve outcomes (221). Unfortunately, the addition of dapagliflozin to critically ill patients did not improve clinical outcomes but also did not cause harm.

CANCER

A meta-analysis of seventy-six randomized trials with 116,375 participants followed for over 48 weeks did not find an increased risk of cancer or cancer mortality with SGLT2 inhibitors (222).

Contraindications and Drug Interactions

RENAL FUNCTION

The dose of SGLT2 inhibitors needs to be adjusted based on renal function. Therefore, renal function needs to be assessed prior to initiating therapy and periodically thereafter (because changes in the recommendation occur rapidly with SGLT2 inhibitors please check the most recent package insert for the latest guidelines).

Dosage recommendations for dapagliflozin and canagliflozin are shown in tables 17 and 18.

Table 17. Dose Recommendations for Dapagliflozin
eGFR > 45	To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control. For all other indications, the recommended starting dose is 10 mg orally once daily.
eGFR 25-45	10 mg orally once daily
eGFR < 25	Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death, and heart failure.
Dialysis	Contraindicated

Table 18. Dose Recommendations for Canagliflozin
eGFR > 60	100 mg orally once daily, taken before the first meal of the day. Dose can be increased to 300 mg once daily for additional glycemic control.
eGFR 30-60	100 mg once daily.
eGFR < 30	Initiation is not recommended, however patients with albuminuria greater than 300 mg/day may continue 100 mg once daily to reduce the risk of ESKD, doubling of serum creatinine, CV death, and hospitalization for heart failure
Dialysis	Contraindicated

Empagliflozin is not recommended for glycemic control in patients with an eGFR < 30 and is contraindicated in patients on dialysis. Data are insufficient to provide a dosing recommendation in patients who have T2DM and established cardiovascular disease with an eGFR less than 30 or who have heart failure with reduced ejection fraction with an eGFR less than 20.

Ertugliflozin is not recommended in patients with an eGFR less than 45 and is contraindicated in patients on dialysis.

Bexagliflozin is not recommended in patients with an eGFR less than 30.

Summary

SGLT2 inhibitors are effective at lowering glucose levels and even more importantly have beneficial effects on heart failure and renal disease. They have a number of potential side effects but many are not definitively associated with SGLT2 inhibitors (fractures, urinary tract infections, amputations, Fournier’s gangrene) or are rare (DKA). The major side effect is genital mycotic infections, which usually are mild and respond to treatment. In patients with pre-existing cardiovascular disease, at high risk for cardiovascular disease particularly heart failure, or with renal disease SGLT2 inhibitors are a leading therapeutic choice.

Table 19. Advantages and Disadvantages of SGLT2 Inhibitors
Advantages	Disadvantages
Weight loss	Urinary Tract Infections?
No hypoglycemia	Genital Mycotic Infections
Decrease heart failure	Increased LDL (small increase)
Decreases renal disease	Increased risk of DKA
Once a day administration	Postural hypotension/volume depletion
Decrease BP	Fractures/ Osteoporosis?
	Increased risk amputations (canagliflozin)?
	Fournier’s gangrene (rare)?
	Expensive

COMBINATION SGLT1 AND SGLT2 INHIBITORS

Introduction

Sotagliflozin (Zynquista, Inpefa) inhibits both SGLT1 and SGLT2 (223). Sotaglifozin’s effectiveness in inhibiting SGLT-2 is similar to that of the selective SGLT-2 inhibitors discussed above but it is > 10-fold more potent in inhibiting SGLT-1(224). In the US the drug was approved in 2023 to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in patients with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. Sotagliflozin was approved in Europe for the treatment of patients with type 1 diabetes but is no longer available. It was used in overweight patients (BMI> 27 kg/m2) when optimal insulin on its own does not achieve adequate glycemic control (package insert- https://www.ema.europa.eu/en/documents/product-information/zynquista-epar-product-information_en.pdf).

Administration

The starting dose of sotagliflozin is 200 mg daily which may be increased to 400 mg as tolerated. In patients with decompensated heart failure, begin dosing when patients are hemodynamically stable. Renal function and volume status should be assessed prior to initiating therapy. Studies with sotagliflozin did not include patients with an eGFR less than 25 or on dialysis and in these studies, sotagliflozin was discontinued if eGFR fell below 15 or chronic dialysis was initiated.

Because of an increased risk of diabetic ketoacidosis ketone monitoring in patients with type 1 diabetes and in others at risk for ketoacidosis (patients with type 2 diabetes on insulin therapy) should be considered, particularly when precipitating conditions for diabetic ketoacidosis occur such as acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, or alcohol abuse.

In order to avoid hypoglycemia in patients on insulin a reduction in insulin dose may be considered, particularly in patients with good glycemic control. Similarly, there is a risk of hypoglycemia in patients taking insulin secretagogues.

Mechanism of Action

The mechanism by which inhibition of SGLT2 decreases glucose levels was discussed in the prior section on SGLT2 inhibitors. Inhibition of SGLT1 will have additional effects. In the kidney SGLT1 is responsible for approximately 10% of the transport of luminal glucose and thus inhibiting SGLT1 may facilitate SGLT2 induced loss of glucose in the urine (223,225). Moreover, SGLT1 is expressed in the small intestine and facilitates the absorption of dietary glucose (223,225,226). SGLT1 expression in the small intestine is increased in patients with diabetes (225,226). Inhibition of SGLT1 delays, and perhaps reduces, glucose absorption, and enhances circulating levels of GLP-1 reducing post-prandial glucose excursions (223,226-228). Finally, SGLT1 is expressed in human heart capillaries and whether this plays a role in cardiac protection remains to be determined (224).

Glycemic Efficacy

TYPE 1 DIABETES (T1DM)

The inTandem1 trial was carried out in North American adults and randomized patients with T1DM to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) (229). Baseline A1c was 7.57% and the placebo-adjusted A1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P < 0.001). At 52 weeks the difference in body weight between the placebo group and 400mg sotagliflozin group was -4.32 kg (-5.00 to -3.64). Notably hypoglycemia was not increased with sotagliflozin treatment. However, DKA occurred more frequently with sotagliflozin treatment (placebo 0.4%, sotagliflozin 200mg 3.4%, sotagliflozin 400mg 4.2%).

The inTandem2 trial was carried out in European adults and randomized patients with T1DM to placebo (n = 258), oral sotagliflozin 200 mg (n = 261), or 400 mg (n = 263) (230). Baseline A1c was 7.7% and the placebo-adjusted A1c reductions were 0.37% and 0.35% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.21% and 0.37% at 52 weeks (all P < 0.001). At 52 weeks the difference in body weight between the placebo group and 400mg sotagliflozin group was −2.92 kg (-3.62 to −2.22). Hypoglycemia was not increased with sotagliflozin treatment. DKA occurred more frequently with sotagliflozin treatment (placebo 0%, sotagliflozin 200mg 2.3%, sotagliflozin 400mg 3.4%).

The inTandem3 trial was a multicenter world-wide study in patients with T1DM randomized to placebo (n=703) or sotagliflozin 400mg (n=699) for 24 weeks (231). The baseline A1c was 8.2% and sotagliflozin decreased A1 by −0.46% compared to placebo. Hypoglycemia with a blood glucose level < 55 mg/dL was significantly lower in the sotagliflozin group than in the placebo group (11.8 per person-year vs. 15.4 per person-year) but severe hypoglycemia (episode needing assistance from another person or resulting in loss of consciousness or a seizure) was similar. Notably the risk of DKA was increase with sotagliflozin treatment (sotagliflozin 3.0% and placebo 0.6%).

Thus, in patients with T1DM sotagliflozin causes a modest reduction in A1c and body weight but increases the risk of DKA.

TYPE 2 DIABETES

Studies of the effect of sotagliflozin on glycemic control in patients with T2DM have not been as extensive as in patients with T1DM. In a 12-week trial that compared placebo (n= 60), sotagliflozin 200mg (n= 60), or sotagliflozin 400mg (n= 60) in patients with T2DM on metformin monotherapy a decrease in A1c of -0.09%, -0.50, and -0.92% occurred in patients treated with placebo, sotagliflozin 200mg, and sotagliflozin 400mg, respectively (232). As expected, there was a decrease in body weight and an increase in urinary glucose excretion with sotagliflozin treatment. Of note a study has shown that in patients with T2DM sotagliflozin treatment is effective in lowering postprandial glucose levels even in patients with an eGFR < 45 mL/min/1.73 m² (233).

In a small study comparing the effect of sotagliflozin and empagliflozin the decrease in A1c levels were very similar as were measurements of glycemia using continuous glucose monitoring (234).

Other Effects

CARDIOVASCULAR

The SOLOIST-WHF Trial was a multicenter trial in which patients with T2DM who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin 200 mg once daily (with a dose increase to 400 mg, depending on side effects) (n= 608), or placebo (n= 614) (235). The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). Because of loss of funding from the sponsor the study was stopped early and the median duration of follow-up was only 9 months. The primary end-point was reduced in the sotagliflozin group vs. placebo group (HR 0.67; 95% CI, 0.52 to 0.85; P<0.001) as was hospitalizations or urgent visits for heart failure (HR 0.64; 95% CI, 0.49 to 0.83: P <0.001). Of particular note benefit was observed in patients with reduced or preserved ejection fractions (<50% or ≥50%). This study demonstrates benefits in patients with a reduced or preserved ejection fractions and that treatment initiated during an acute heart failure episode is beneficial. DKA was uncommon in both the sotagliflozin group (0.3%) and placebo group (0.7%) but severe hypoglycemia was increased (sotagliflozin 1.5% vs placebo 0.3%).

The SCORED trial was a multicenter trial in which patients with T2DM and chronic kidney disease (eGFR- 25 to 60 ml/min/1.73 m², albuminuria was not required), and risks for cardiovascular disease were randomized to sotagliflozin (200 mg once daily, with an increase to 400 mg once daily if unacceptable side effects did not occur) (n= 5292) or placebo (n= 5292) and followed for a median of 16 months (236). The primary end point was the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. Sotagliflozin treatment decreased the primary end point (HR 0.74; 95% CI, 0.63–0.88; P <0.001), hospitalizations or urgent visits for heart failure (HR 0.67; 95% CI, 0.55–0.82; P <0.001), and deaths from cardiovascular causes, nonfatal myocardial infarctions, and nonfatal strokes (HR 0.77; 95%CI 0.65–0.91). Sotagliflozin reduced the risk of renal disease defined as first event of sustained ≥50% decline in eGFR, eGFR <15, dialysis, or kidney transplant with 1.6% events in the sotagliflozin group and 2.6% events in the placebo group (HR 0.62; 95% CI 0.48 - 0.82; P < 0.001) (237). A1c was decreased by 0.42% compared to placebo.

DKA while infrequent was increased in the sotagliflozin group (0.6% vs 0.3%; P=0.02).

RENAL

As noted above in the SCORED trial in patients with T2DM there was a reduction in renal disease endpoints in the participants treated with sotagliflozin.

Side Effects

The side effects of sotagliflozin are similar to those described previously for SGLT2 inhibitors. In addition, sotagliflozin also causes diarrhea and flatulence due to the inhibition of SGLT1 mediated glucose uptake in the small intestine.

Contraindications and Drug Interactions

Patients at high risk for DKA should not be started on sotagliflozin. Sotagliflozin is not recommended during the second and third trimesters of pregnancy or during breastfeeding.

Summary

In patients with T1DM sotagliflozin modestly reduces A1c levels and body weight but increases the risk of DKA. In patient with T2DM sotagliflozin reduces A1c levels more effectively and decreases body weight with a relatively low risk of DKA.

While studies have shown beneficial effects of sotagliflozin on the development of heart failure and renal disease it is not clear whether this benefit is solely due to inhibition of SGLT2 or whether inhibition of SGLT1 plays a significant role.

DOPAMINE AGONIST (CYCLOSET)

Introduction

In 2009, a quick-release formulation of bromocriptine (Cycloset, bromocriptine-QR) was approved to improve glycemic control in patients with T2DM (238,239). Bromocriptine is a centrally-acting dopamine D2 receptor agonist that has been used for many years for the treatment of hyperprolactinemia and Parkinson’s disease (238,239). It can be used to improve glycemic control in patients with T2DM either as monotherapy or in combination with other hypoglycemic drugs (238,239).

Administration

Bromocriptine-QR should be initiated at one tablet (0.8 mg) within two hours after waking in the morning. The dose can be increased by one tablet per week until a maximum daily dose of 6 tablets (4.8 mg) or until the maximal tolerated number of tablets between 2 and 6 per day is reached. Taking bromocriptine-QR with food is recommended to decrease gastrointestinal side effects (238).

Mechanism of Action

Bromocriptine-QR decreases insulin resistance resulting in an increase in glucose disposal and a decrease in hepatic glucose production (238). Bromocriptine-QR does not increase insulin levels (238). Thus, the effectiveness of bromocriptine-QR will be greatest in patients that are insulin resistant and produce insulin (238). Based on animal studies it is thought that bromocriptine-QR acts on the central nervous system, particularly the hypothalamus, to increase insulin sensitivity in liver, muscle, and adipose tissue (238).

Glycemic Efficacy

In a 24 week monotherapy study the A1c level was 0.4% lower in the bromocriptine-QR group compared to placebo group (240). Both fasting and postprandial glucose levels were decreased with bromocriptine-QR treatment (240). Bromocriptine-QR treatment was associated with a decrease in triglyceride levels (32 mg/dL) but no significant change in LDL or HDL cholesterol levels or change in body weight (240). A trial adding bromocriptine-QR to sulfonylurea therapy demonstrated a 0.55% lower A1c in the bromocriptine-QR group compared to placebo (240). As in the monotherapy study fasting glucose, postprandial glucose, and triglyceride levels were decreased with no change in LDL or HDL cholesterol levels (240). Addition of bromocriptine-QR to other hypoglycemic drugs including insulin results in an approximate decrease in A1c of 0.5 to 1.0% (238,239). Hypoglycemia is a rare side effect with use of bromocriptine-QR alone, but is increased with use of insulin secretagogue therapy or insulin (239,240).

Other Effects

BLOOD PRESSURE

Bromocriptine-QR modestly decreases systolic and diastolic blood pressure (239,240).

LIPIDS

Bromocriptine-QR treatment decreases triglyceride levels but has no significant effect on LDL or HDL cholesterol levels (239,240). The decrease in triglyceride levels is thought to be due to a decrease in hepatic triglyceride synthesis, likely due to a decrease in adipose tissue lipolysis resulting in decreased blood free fatty acid levels and decreased delivery of fatty acids to the liver for triglyceride synthesis (238).

CARDIOVASCULAR DISEASE

A 52-week, randomized, double-blind, multicenter trial evaluated cardiovascular safety in 3,095 patients with T2DM treated with bromocriptine-QR or placebo (241). The composite end point of first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina or congestive heart failure occurred in 1.8% of the bromocriptine-QR treated vs. 3.2% of the placebo-treated patients resulting in a 40% decrease in cardiovascular events (HR 0.60; CI 0.37– 0.96). Clearly further studies to confirm this finding and to elucidate the mechanism of this beneficial effect are required.

Side Effects

The most common side effect of bromocriptine-QR therapy is nausea which is usually transient and improves with time (239,240). This side effect can be minimized by reducing the dose (239,240). In the pooled phase 3 trials adverse events leading to discontinuation occurred in 539 (24%) of the bromocriptine-QR treated patients and 118 (9%) of the placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea (package insert). Similarly, in the bromocriptine-QR safety trial adverse events leading to discontinuation of drug occurred in 24% of the bromocriptine-QR treated patients and 15% of the placebo-treated patients, a difference again driven mostly by gastrointestinal adverse events, particularly nausea (package insert).

Hypotension resulting in syncope can occur particularly in patients on anti-hypertensive medications (package insert). Other side effects include somnolence, fatigue, vomiting, headache, and dizziness (package insert).

Contraindications and Drug Interactions

Bromocriptine-QR is metabolized by the Cyp3A4 system and therefore the drug should not be used with strong CYP3A4 inhibitors (e.g., azole antimycotics, HIV protease inhibitors) and the dose should not exceed 1.6 mg during concomitant use of a moderate CYP3A4 inhibitor (e.g., erythromycin) (package insert).

Bromocriptine-QR is contraindicated in patients with syncopal migraine because it increases the likelihood of a hypotensive episode (package insert). The use of bromocriptine-QR in patients with severe psychotic disorders in not recommended as it may exacerbate the disorder or diminish the effectiveness of drugs used to treat the disorder (for example clozapine, olanzapine, ziprasidone) (package insert).

Summary

Bromocriptine-QR has modest effects on A1c levels by decreasing insulin resistance. In clinical trials the drug was often discontinued due to nausea. Because of the modest effects on A1c and the prominent side effects this drug is not widely used in the treatment of patients with T2DM. If further studies confirmed the decrease in cardiovascular events in patients treated with bromocriptine-QR the use of this drug would increase.

Table 20. Advantages and Disadvantages of Bromocriptine-QR
Advantages	Disadvantage
Decreases triglycerides	Need to titrate dose
Once a day dosing	Modest effect on A1c
Cardiovascular benefits?	Frequent discontinuation due to GI side effects
Decrease BP	Expensive
Neutral weight effect
Hypoglycemia uncommon

OVERVIEW OF THE INCRETIN SYSTEM

The incretin effect refers to a greater insulin stimulatory effect after an oral glucose load than from an intravenous (IV) glucose infusion when plasma glucose concentrations are matched (242). Thus, glucose and other nutrients delivered via the gastrointestinal tract potentiates the ability of the beta cells in the pancreas to produce insulin resulting in greater insulin secretion than with IV glucose (243). The increase in insulin levels with IV glucose is only approximately one‐third of that elicited by oral glucose. The majority of the incretin effect is due to two GI hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon like peptide-1 (GLP-1) with GIP having a dominant role (Figure 6) (242). The basal plasma levels of the incretin hormones are low but after eating the levels increase reaching concentrations that augment the insulin secretory responses if glucose levels are high but are ineffective at low glucose concentrations (i.e. glucose dependent effect) (242).

Patients with T2DM have a significant reduction of the incretin effect but GLP-1 and GIP levels in the blood after meals are not reduced in patients with T2DM (242). Rather decreased functional beta cell mass and resistance to the effects of GLP-1 and GIP in patients with T2DM accounts for the decreased incretin effect (242). Infusion of GIP or GLP-1 has a decreased effect on insulin secretion in patients with T2DM (resistance to effect of GIP and GLP-1) compared to normal individuals likely secondary to decreased functional beta cell mass (242). Achieving near-normoglycemia by intensified insulin regimens improved beta cell responsiveness to exogenous GIP and GLP-1, although the increase in insulin secretion was still much lower than in individuals without diabetes (242). The reduced incretin effect in patients with T2DM occurs after the diagnosis of diabetes is established, suggesting this abnormality is secondary to the diabetic state rather than the cause of diabetes (243).

Glucagon Like Peptide-1 (GLP-1)

GLP-1 is cleaved from the pro-glucagon molecule by pro-hormone convertase enzymes in the intestine (243). GLP-1 is stored in the L-cells of the intestine, predominantly in the ileum and colon, and is released at mealtime in response to neurohormonal signals and the presence of food in the gut (242,243). GLP-1 affects postprandial glucose levels through several mechanisms, including enhancing insulin secretion by the beta cells and inhibiting postprandial glucagon secretion by the alpha cells in a glucose-dependent manner (i.e. GLP-1 does not stimulate insulin secretion or inhibit glucagon secretion unless glucose levels are elevated) (243). This glucose dependent effect accounts for why incretin-based drugs do not cause serious hypoglycemia. Activation of GLP-1 receptors on beta cells increases cAMP levels, which potentiates insulin release in the presence of elevated glucose concentrations. In addition, GLP-1 slows the rate of gastric emptying, which is often paradoxically accelerated in patients with diabetes (243). GLP-1 also acts as a postprandial satiety signal through neurohormonal networks that signal the brain to suppress appetite and food intake, which can lead to weight loss (243). Animal studies suggest that exogenous GLP-1 has the ability to increase islet size, enhance beta-cell proliferation, inhibit beta-cell apoptosis, and regulate islet growth (244). The administration of GLP-1 intravenously increases insulin secretion, reduces glucagon secretion, and decreases glucose levels during fasting and in the post-prandial state (242). GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) into inactive peptides (half-life is minutes) (Figure 6).

Figure 6. Incretin Hormone Secretion and Effect on Pancreas

Glucose-Dependent Insulinotropic Peptide (GIP)

Within minutes after ingestion of food, GIP is secreted from the K-cells located in the proximal region of the jejunum (242,243). GIP helps maintain normal glucose homeostasis by stimulating an increase in insulin secretion by the beta cells (Figure 6). Studies have suggested that the increase in insulin with food intake (Incretin effect) is primarily mediated by GIP (242). In contrast to GLP-1, GIP does not inhibit glucagon secretion, and in fact may stimulate glucagon secretion during euglycemic states. Additionally, GIP has no effect on gastric emptying. GIP concentrations in patients with T2DM are either normal or slightly increased following a meal indicating that the failure to secrete is not the explanation for the decreased incretin effect. Rather, beta cells in patients with T2DM are resistant to GIP. GIP is rapidly degraded by DPP-4 into inactive peptides (half-life is minutes) (Figure 6). The characteristics of GLP-1 and GIP are shown in table 21.

Table 21. Characteristics of GLP-1 and GIP
	GLP-1	GIP
Post meal levels in patients with diabetes	Normal	Normal
Effect on insulin secretion	Stimulates	Stimulates
Effect on glucagon secretion	Inhibits	No effect or stimulates
Gastric emptying	Delays	No effect
Satiety	Induces	Induces
Degradation by DPP-4	Yes	Yes

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

Introduction

The currently available DPP-4 inhibitors in the US are sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). Vidigliptin (Galvus) is available in Europe (245). DPP-4 inhibitors can be used as monotherapy, dual therapy, triple drug therapy, or in combination with insulin (245). These drugs are very similar and the minor differences will be discussed below.

Administration

The recommended dose of sitagliptin is 100 mg once daily with or without food. In patients with moderate renal impairment (eGFR >30 mL/min/1.73 m² but < 45, the dose of sitagliptin is 50 mg once daily. In patients with severe renal impairment (eGFR <30) the dose of sitagliptin is 25 mg once daily.

The recommended dosage of saxagliptin is 2.5 mg or 5 mg once daily with or without food. In patients with a creatinine clearance CrCl ≤50 mL/min the dose of saxagliptin is 2.5 mg.

The recommended dose of linagliptin is 5 mg once daily with or without food. No dose adjustment is required for decreased renal function.

The recommended dose of alogliptin is 25 mg once daily with or without food. The dose of alogliptin is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min) and 6.25 mg with severe renal impairment (CrCl <30 mL/min).

Renal function should be checked prior to initiating treatment and periodically because dose adjustments are required for all DPP-4 inhibitors except linagliptin.

Mechanism of Action

DPP-4 inhibitors increase the concentration and activity of the endogenous incretins, GLP-1 and GIP, by inhibiting the proteolytic cleavage of these hormones by DPP-4, into inactive molecules (245). As discussed above, GLP-1 is secreted by L-cells in the intestines and stimulates insulin secretion and suppresses glucagon secretion in a glucose dependent manner. GIP is secreted by the K cells in the proximal intestine and stimulates insulin secretion in a glucose dependent manner.

An increase in active GLP-1 and GIP potentiates glucose induced insulin secretion and an increase in GLP-1 inhibits glucagon secretion (245). Together an increase in insulin and a decrease in glucagon will result in a decrease in blood glucose levels. Of note, DPP-4 inhibition results in a 2–3-fold increase in postprandial active GLP-1 levels, which is not at a level that delays gastric emptying or increases satiety and induces weight loss. This is in contrast to GLP-1 receptor agonist administration that results in marked elevations in active GLP1 activity that is equivalent to a >10-fold increase in GLP-1, which can delay gastric emptying and increase satiety.

Glycemic Efficacy

DPP-4 inhibitors typically reduce A1c levels by 0.5-1.0% and are less effective in lowering A1c compared to metformin, TZDs, SGLT2 inhibitors, and GLP-1 receptor agonists (Table 6) (13,20,245). With regards to sulfonylureas, studies have shown a greater decrease in A1c with sulfonylureas compared to DPP-4 inhibitors in short term studies but in studies greater than one year the effect of sulfonylureas and DPP-4 inhibitors on A1c were similar (20,245). The ability of DPP-4 inhibitors to lower A1c is similar in monotherapy and when DPP-4 inhibitors are used in combination with other drugs (20,245). The decrease in A1c is similar for the different DPP-4 inhibitors (13,20). DPP-4 inhibitors are effective in lowering postprandial glucose levels. Because of their mechanism of action, DPP-4 inhibitors do not cause hypoglycemia but can potentiate the hypoglycemia induced by insulin or sulfonylureas (20,245). An adjustment in the dose of sulfonylureas or insulin may be required to reduce the risk of hypoglycemia.

The results of the GRADE study, which compared glargine insulin, glimepiride, liraglutide, and sitagliptin added to metformin, are discussed in the section entitled “OVERVIEW OF DRUGS”. The GLP1 receptor agonist was better than the sulfonylurea which was better than DPP-4 inhibitor in glycemic control (15).

Other Effects

WEIGHT

DPP-4 inhibitors are weight neutral (20,245).

BLOOD PRESSURE

A meta-analysis of 15 trials involving 5,636 participants found that DPP-4 inhibitors compared to placebo reduced systolic BP (mean difference, -3.04 mmHg: P < 0.00001) and diastolic BP (mean difference, -1.47 mmHg; P < 0.00001) (246).

LIPIDS

DPP-4 inhibitors decrease postprandial triglycerides by reducing circulating chylomicrons by decreasing intestinal lipoprotein production while having minimal effects on fasting lipid levels (247).

CARDIOVASCULAR DISEASE

The effect of the DPP-4 inhibitors saxagliptin, alogliptin, sitagliptin, and linagliptin on cardiovascular endpoints has been reported. In the saxagliptin study (SAVOR‐TIMI 53 trial), 16,492 patients with T2DM who had a history of cardiovascular events or who were at high risk were randomized to saxagliptin or placebo for 2.1 years (248). Saxagliptin did not increase or decrease cardiovascular death, myocardial infarction, or ischemic stroke. Interestingly more patients treated with saxagliptin were admitted to the hospital for heart failure. The risk of heart failure with saxagliptin was greatest in patients at a high overall risk of heart failure (i.e., history of heart failure, impaired renal function, or elevated baseline levels of NT-proBNP) (249). Additionally, in the patients treated with saxagliptin the increase in heart failure was an early event with a 6-month rate of 1.1% vs. 0.6% in the placebo group (HR 1.80, p=0·001) and a 12-month rate of 1·9% vs. 1·3% (1.46; p=0.002) (249). In contrast, after 12 months no difference in the rate of heart failure was observed in the saxagliptin and placebo groups indicating that the development of heart failure is an early event (249)

In the alogliptin trial (EXAMINE), 5,380 patients with either an acute myocardial infarction or unstable angina within the previous 15-90 days were randomized to alogliptin or placebo and followed for a median of 18 months (250). As seen in the saxagliptin study the rates of cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke) were similar in the alogliptin and placebo groups. The risk of hospitalization for heart failure was not statistically increased in the entire subset of patients treated with alogliptin (251). However, the hazard ratio for the subgroup of patients without heart failure at baseline was 1.76, p=0.026) (251).

In the sitagliptin trial (TECOS), 14,671 patients with established cardiovascular disease were randomized to sitagliptin or placebo for 3 years (252). Sitagliptin did not decrease the risk of major adverse cardiovascular events or increase hospitalization for heart failure. Finally, in the linagliptin trial (CARMELINA), 6,979 patients at high risk for cardiovascular disease were randomized to linagliptin or placebo for a median follow-up of 2.2 years (253). As in the other DPP-4 inhibitor studies, linagliptin did not have a beneficial effect on cardiovascular events. Additionally, linagliptin did not increase the risk of hospitalization for heart failure (254).

Thus, these results indicate that DPP-4 inhibitors do not reduce cardiovascular disease. Whether specific DPP-4 inhibitors (saxagliptin, alogliptin) increase the risk of heart failure remains to be resolved. Of note, a meta-analysis of 30 randomized controlled trials involving 29,938 patients comparing the effects of saxagliptin vs. placebo or sulfonylureas did not observe an increase in heart failure (RR 0.99, 95% CI 0.89 to 1.10; p = 0.85) (255).

RENAL DISEASE

Changes in renal function were examined in the large cardiovascular outcome trials described above. In the SAVOR-TIMI 53 trial treatment with saxagliptin decreased albuminuria but had no effect on eGFR (256). Saxagliptin reduced the development of macroalbuminuria independent of changes in A1c levels (248,256). Doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar in the saxagliptin and placebo groups (256). In the TECOS trial treatment sitagliptin also reduced the urinary albumin to creatinine ratio with no effect on eGFR (257). In the CARMELINA trial many of the patents had pre-existing renal disease (74% of patients had prevalent diabetic kidney disease, 43% had an eGFR below 45 mL/min/1.73 m2, 15.2% had an eGFR below 30 mL/min/1.73 m² and 80% had a urinary albumin creatinine ratio >30 mg/g) (253). Treatment with linagliptin reduced the progression of albuminuria but had no effect on death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline (253).

Taken together these studies indicate that DPP-4 inhibitors decrease proteinuria but do not provide data suggesting an improvement or delay in worsening of renal function. However, using large data bases studies have suggested that DPP-4 inhibitors have favorable effects on renal function and decrease the development of end stage renal disease (258-260). Randomized trials of DPP4 specifically examining the effect of renal parameters would be helpful.

Side Effects

DPP-4 inhibitors have been safe drugs with minimal side effects and are well tolerated by patients. Very rarely hypersensitivity reactions including urticaria, facial edema, anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome have occurred (261). Bullous pemphigoid has also rarely been associated with DPP-4 inhibitor treatment (261).

ACUTE PANCREATITIS

The package insert of DPP-4 inhibitors indicates that acute pancreatitis is a complication of DPP-4 inhibitor treatment. The individual results of the SAVOR–TIMI, EXAMINE, and TECOS trials discussed above did not show an increased risk of pancreatitis or pancreatic cancer. However, two meta-analyses of these studies demonstrated an 80% increased risk of acute pancreatitis in patients using DPP-4 inhibitors compared with those receiving standard care (262,263). It should be noted that the absolute risk was small (0.13%), which would result in one to two additional cases of acute pancreatitis for every 1,000 patients treated for 2 years (263). Thus, pancreatitis appears to be a rare side effect of DPP-4 inhibitors. In patients on DPP-4 inhibitors who have GI symptoms suggestive of pancreatitis further evaluation is indicated. The diagnosis of acute pancreatitis requires the presence of two of the following three criteria: acute onset of persistent, severe, epigastric pain often radiating to the back, elevation in serum lipase or amylase to three times or greater than the upper limit of normal, and characteristic findings of acute pancreatitis on imaging (264).

ARTHRALGIA

Severe and disabling arthralgia in patients taking DPP-4 inhibitors has been reported (265). The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication and a subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. If a patient develops severe joint pain discontinue the DPP-4 inhibitor.

Contraindications and Drug Interactions

It is unknown whether patients with a history of pancreatitis or who are at increased risk for the development of pancreatitis should be started on DPP-4 inhibitors. Given the availability of other hypoglycemic drugs many clinicians avoid the use of DPP-4 inhibitors in these patients.

The dosage of saxagliptin is 2.5 mg once daily when co-administered with a strong cytochrome P450 3A4/5 inhibitor (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) (package insert).

Summary

DPP-4 inhibitors, while not the most potent drugs at lowering A1c, nevertheless are very attractive to use in the treatment of patients with T2DM as they are safe drugs that do not have many side effects. They do not cause hypoglycemia, weight gain, or cardiovascular disease. Unfortunately, they do not reduce the risk of cardiovascular disease or prevent loss of renal function.

Table 22. Advantages and Disadvantages of DPP-4 Inhibitors
Advantages	Disadvantages
No hypoglycemia	Pancreatic disease
Weight neutral	Heart failure (saxagliptin/alogliptin)?
Decreases postprandial glucose	Arthritis
Once a day	Bullous pemphigoid
Well tolerated	Relatively expensive
Decreases BP	Modest glycemic lowering

INJECTABLE GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS

Introduction

There are currently six GLP-1 RAs available in the US, three drugs administered daily and three drugs administered weekly (Figure 6). Albiglutide (Tanzeum) was withdrawn from the market for commercial reasons and is no longer available. GLP-1 RAs can be used in combination with multiple oral anti‐diabetic drugs or in combination with insulin (266). The circulating concentrations of GLP-1 RA activity are much higher than physiological levels of GLP-1 activity (20). The GLP-1 RAs that are similar to exendin-4 (Exenatide and Lixisenatide) are eliminated by the kidneys and therefore in patients with severe renal disease these drugs are contraindicated (20). In contrast, the drugs that are analogues of GLP-1 are degraded by peptidases (20).

Figure 6. Structure of GLP-1 Receptor Agonists.

SHORT ACTING GLP-1 RECEPTOR AGONISTS

Exenatide (Byetta) is a synthetic exendin-4 that is a peptide originally isolated from the saliva of the Gila monster that has a 53% homology with human GLP-1 and is resistant to degradation by DPP-4 (20,266). Lixisenatide (Adylyxin) is an exendin-4 analogue with six Lys residues added at the C terminus to confer resistance to DPP-4 (20,266).

LONG ACTING GLP-1 RECPTOR AGONISTS

Even though liraglutide (Victoza) is administered daily it is considered a long acting GLP-1 RA because its effects on fasting glucose levels are similar to weekly GLP-1 RAs and its effects on gastric emptying wane as seen with weekly GLP-1 RAs. Liraglutide is an analogue of GLP-1 with the addition of a 16-carbon fatty acid chain that masks the DPP-4 cleavage site preventing degradation (8,179). Once weekly exenatide (Bydureon and Bydueron BCise) is a sustained-release formulation that consists of exenatide embedded within biodegradable polymeric microspheres of poly (DL-lactic-co-glycolic acid) (20). Dulaglutide (Trulicity) has two copies of a GLP-1 analogue covalently linked to an Fc fragment of human IgG4 (20,266). Semaglutide (Ozempic) is an analogue of human GLP‐1 RA and is linked via a hydrophilic spacer and a fatty acid side chain to albumin (266).

For information on the use of GLP-1 RAs for the treatment of weight loss see the Endotext chapter entitled “Pharmacologic Treatment of Overweight and Obesity in Adults” (267).

Administration

SHORT ACTING GLP-1 RECEPTOR AGONISTS

Initiate exenatide at 5 ug twice daily; increase to 10 ug twice daily after 1 month based on clinical response. Inject subcutaneously within 60 minutes prior to morning and evening meals (or before the two main meals of the day).

The starting dose of lixisenatide is 10 ug subcutaneously once daily within one hour before the first meal of the day for 14 days and then increase the dose to the maintenance dose of 20 ug once daily.

LONG ACTING GLP-1 RECPTOR AGONISTS

Initiate liraglutide with a dose of 0.6 mg per day for one week. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. Inject subcutaneously once-daily at any time of day, independently of meals.

The recommended dose of long acting exenatide is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals.

The recommended initiating dose of dulaglutide is 0.75 mg subcutaneously with or without food once weekly. The dose may be increased to 1.5 mg once weekly to achieve glycemic control. If after 4 weeks glycemic control is not achieved the dose can be increased to 3.0 mg once weekly and then after another 4 weeks to 4.5 mg once weekly for additional glycemic control.

The recommended initiating dose of semaglutide is 0.25 mg subcutaneous injection with or without food once weekly for 4 weeks. The 0.25 mg dose is intended for treatment initiation and is not effective for glycemic control. After 4 weeks on the 0.25 mg dose, increase the dosage to 0.5 mg once weekly. If additional glycemic control is needed after at least 4 weeks on the 0.5 mg dose, the dosage may be increased to 2 mg once weekly (note the maximum dose for the treatment of obesity is 2.4mg).

Note that exenatide and lixisenatide are contraindicated in patients with renal dysfunction (for details see Contraindications section).

Information on the pen delivery systems for the GLP-1 RAs is shown in table 23.

Table 23. Characteristics of GLP-1 Receptor Agonist Pen Devices
Generic	Exenatide	Exenatide	Exenatide	Lixisenatide	Liraglutide	Dulaglutide	Semaglutide
Brand	Byetta	Bydureon	Bydureon BCise	Lyxumia	Victoza	Trulicity	Ozempic
Single or multiple use	Multiple	Single	Single	Multiple	Multiple	Single	Multiple
Dose*	5 or 10ug	2mg	2mg	10 or 20ug	0.6, 1.2, or 1.8mg	0.75 or 1.5mg	0.25, 0.5, 1.0 or 2mg
Preparation	None	Resuspend	Mix	None	None	None	None

*Only the liraglutide pen can deliver different doses.

Mechanism of Action

GLP-1 RAs potentiate glucose dependent insulin secretion increasing insulin levels and lowering glucose levels (20). In addition, GLP-1 RAs potentiate the glucose dependent inhibition of glucagon secretion, which will also lower glucose levels (20). Finally, because of the supraphysiological levels of GLP-1 activity, GLP-1 RAs may delay gastric emptying resulting in a decrease in postprandial glucose levels and induce satiety, which will decrease food intake (20).

Glycemic Efficacy

GLP-1 RAs typically lower A1c by 1-2% (20). The efficacy of GLP-1 RAs vary with semaglutide being the most potent and lixisenatide being the least potent (see table 6) (13). Note table 6 does not include the 3.0mg and 4.5mg of dulaglutide, which lower A1c by 1.6% and 1.8% respectively (268). In general, long acting GLP-1 RAs are better at lowering A1c levels compared to short acting agents (13,266). The efficacy in lowering A1c is similar in monotherapy and during combination therapy (20). The reduction in A1c is sustained over several years (164). Long acting GLP-1 RAs lower fasting glucose levels more effectively than short acting drugs (266). Conversely, short acting GLP-1 RAs lower postprandial glucose excursions to a greater extent than long acting agents (266). Short acting GLP-1 RAs induce a substantial retardation in gastric emptying, which likely contributes significantly to the lowering of postprandial glucose excursions after meals when they are administered (266). Notably, the ability of short acting GLP-1 RAs to prevent postprandial glucose excursions is greatly diminished for meals when they are not administered (266). In patients with diminished beta cell function the glycemic response to GLP-1 RAs therapy is reduced (269).

The GRADE trial compared treatment with liraglutide to treatment with a sulfonylurea or DPP4 inhibitor (15). As one would expect liraglutide was more effective in lowering A1c levels and more patients achieved an A1c level less than 7% than with either sulfonylurea or DPP4 inhibitor therapy.

Studies have compared adding a GLP-1 RA to basal insulin vs. adding rapid acting insulin to basal insulin (270). In a meta-analysis there were no differences in lowering A1c levels but treatment with basal insulin plus GLP-1 RA led to a significant reduction in body weight, whereas basal insulin plus rapid acting insulin treatment was associated with weight gain (difference -2.95 kg; p = 0.0001) (270). Additionally, patients treated with basal insulin plus GLP-1 RA were less likely to experience symptomatic hypoglycemia (OR: 0.52; p < 0.0001) and severe hypoglycemia (OR: 0.27; p = 0.07) than those treated with basal insulin plus rapid acting insulin. Thus, adding a GLP-1 RA to basal insulin instead of bolus insulin will result in similar improvements in glycemic control with fewer side effects.

Studies have also compared adding insulin therapy vs. adding a GLP-1 RA. In a meta-analysis of 19 studies GLP-1 RAs reduced A1c levels slightly more than insulin therapy (difference -0.12%, P < .0001) (271). As expected, hypoglycemia was less frequent in the patients treated with the GLP-1 RAs.

Because the effect of GLP‐1 RAs on insulin and glucagon secretion are glucose dependent they have a low potential to cause hypoglycemia (20,266). The risk of hypoglycemia increases when GLP-1 RAs are used in combination with insulin or insulin secretagogues (266).

Both GLP-1 RAs and SGLT-2 inhibitors have been shown to decrease cardiovascular disease (GLP-1 RAs primarily decrease atherosclerotic complications while SGLT-2 inhibitors primarily decrease heart failure). Therefore, the use of these drugs in combination to prevent cardiovascular disease has been proposed. In an analysis of four randomized trials adding a GLP-1 RA to a SGLT-2 inhibitor it was reported that the addition of a GLP-1 receptor agonist resulted in a greater reduction in HbA1c (-0.74%), body weight (-1.61 kg), and systolic blood pressure (-3.32 mmHg) demonstrating the benefits of using these drugs in combination (272).

Other Effects

WEIGHT LOSS

GLP-1 RAs induce weight loss (20,266). A comparison of the ability of the maximum dose of different GLP-1 RAs to induce weight loss are shown in table 24. It should be recognized that the weight loss shown in Table 24 represents averages. In clinical practice some patients lose a large amount of weight with GLP-1 RAs while other patients can actually gain weight. The author has personally seen patients’ loss more than 50 lbs. Higher doses of liraglutide and semaglutide are approved for the treatment of obesity, which is discussed in the Endotext chapter “Pharmacologic Treatment of Overweight and Obesity in Adults” (273). Studies have compared the effect of high doses of GLP-1 RAs used for weight loss and lower doses used for treating diabetes (table 25). In general, higher doses of GLP-1 RAs result in a modest further lowering of A1c and a more robust decrease in body weight.

Table 24. Effect of GLP-Receptor Agonists on Mean Weight Loss (13)
GLP-1 Receptor Agonist	Mean Weight Loss
Dulaglutide 1.5mg weekly	1.1Kg
Exenatide 10ug bid	1.2Kg
Exenatide 2mg weekly	1.1Kg
Liraglutide 1.8mg qd	1.5Kg
Lixisenatide 20ug qd	0.7Kg
Semaglutide 1mg weekly	3.8Kg

Based on a baseline weight of 90 kg after 26 weeks of treatment

Table 25. Comparison of Low and High Dose GLP-1 RA on A1c and Body Weight
	Change in A1c (%)	Change in Body Weight (% or kg)
SCALE Diabetes (274)
Placebo	-0.3%	-2.0%
Liraglutide 1.8mg qd	-1.1%	-4.7%
Liraglutide 3.0mg qd	-1.3%	-6.0%
STEP-2 (275)
Placebo	-0.4%	-3.4%
Semaglutide 1mg weekly	-1.5%	-7.0%
Semaglutide 2.4mg weekly	-1.6%	-9.6%
SUSTAIN FORTE (276)
Semaglutide 1mg weekly	-1.9%	-6.2%
Semaglutide 2.0mg weekly	-2.2%	-7.2%
AWARD-11 (268)
Dulaglutide 1.5mg weekly	-1.5%	-3.1kg
Dulaglutide 3.0mg weekly	-1.7%	-4.0kg
Dulaglutide 4.5mg weekly	-1.9%	-4.7kg

The exact mechanisms responsible for the decrease in weight are not yet fully understood but both central and peripheral mechanisms are thought to play a part in activating receptors in the central nervous system associated with weight loss (266). GLP‐1 RAs are thought to reduce body weight through decreased gastrointestinal motility and the promotion of satiety via the activation of GLP‐1 receptors in various regions of the brain (266).

BLOOD PRESSURE

GLP-1 RAs result in modest but significant reductions in systolic blood pressure (2-5 mmHg) (20).

HEART RATE

The effects of GLP-1 RAs on heart rate differ between drugs. Short-acting GLP-1 RAs result in a modest increase (1-3 beats per minute) while long-acting GLP-1 RAs are associated with a more pronounced and sustained increase (3-10 beats per minute) during the day and night (277).

LIPIDS

GLP-1 RAs can favorably affect the lipid profile by inducing weight loss (decreasing triglycerides and very modestly decreasing LDL-C levels) (82). In a review by Nauck and colleagues it was noted that GLP-1 RAs lowered TG levels by 18 to 62 mg/dl depending upon the specific GLP-1 RA while decreasing LDL-C by 3-8 mg/dl and increasing HDL-C by less than 1 mg/dl (247). Additionally, GLP-1 RAs reduce postprandial triglycerides by reducing circulating chylomicrons by decreasing intestinal lipoprotein production (82,247).

ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

The effect of six GLP-1 RAs on cardiovascular disease has been reported.

ELIXA

In the Elixa trial 6,068 patients with T2DM and who recently had a myocardial infarction or been hospitalized for unstable angina were randomized to placebo or lixisenatide, and followed for a median of 25 months (278). The primary end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina was similar in the placebo or lixisenatide groups.

LEADER Trial

In contrast, the LEADER trial has shown that liraglutide decreased cardiovascular events (279). In this trial 9,340 patients with T2DM at high cardiovascular risk (~ 81% with established cardiovascular disease) were randomly assigned to receive liraglutide or placebo. After a median time of 3.5 years, the primary outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke occurred in significantly fewer patients in the liraglutide group (13.0%) than in the placebo group (14.9%) (HR 0.87, P=0.01). Additionally, deaths from cardiovascular causes (HR 0.78, P=0.007) or any cause was lower in the liraglutide group than in the placebo group (HR 0.85; P=0.02). Interestingly patients with established cardiovascular disease or decreased renal function (eGFR < 60) appeared to derive the greatest benefit of liraglutide treatment (280,281). The decrease in cardiovascular events were similar in patients with and without a history of heart failure (282). Finally, a significant reduction in amputations with liraglutide vs. placebo was observed (HR 0.65; P = 0.03]) (283).

SUSTAIN 6 Trial

In support of the beneficial effects of some GLP1 receptor agonists to reduce cardiovascular events, semaglutide has also been shown to reduce cardiovascular events (284). In this trial, 3,297 patients with T2DM with established cardiovascular disease (83%), chronic heart failure, chronic kidney disease, or age >60 with at least one cardiovascular risk factor were randomized to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke occurred in 6.6% of the semaglutide group and 8.9% of the placebo group (HR 0.74; P = 0.02).

EXSCEL Trial

The effect of once weekly exenatide vs. placebo on cardiovascular outcomes was tested in 14,752 patients with T2DM, 73% who had cardiovascular disease (285). The primary outcome was the occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. After a median follow-up of 3.2 years (duration of drug exposure 2.4 years) the primary outcome was reduced in the exenatide treated group but this difference just missed achieving statistical significance (HR 0.91; 95% CI 0.83-1.00; p=0.06). While not statistically significant these results are consistent with the results observed with other GLP-1 receptor agonists. It should be recognized that a high percentage of patients discontinued exenatide therapy in this trial (>40%) and this could have adversely affected the ability of exenatide treatment to favorably effect cardiovascular outcomes.

HARMONY Outcomes Trial

The effect of once weekly albiglutide vs. placebo was tested in 9,463 patients with T2DM and cardiovascular disease (286). The primary outcome was first occurrence of cardiovascular death, myocardial infarction, or stroke. After a median follow-up of 1.6 years a 22% decrease in the primary endpoint was observed in the albiglutide group (HR 0.78, p<0·0001). It should be noted that albiglutide is no longer available as it was removed from the market due to commercial considerations by the manufacturer.

REWIND Trial

This was a randomized study of weekly dulaglutide (1.5 mg) or placebo in 9,901 patients with T2DM who had either a previous cardiovascular event or cardiovascular risk factors (approximately 70% of patients did not have prior cardiovascular disease) (287). During a median follow-up of 5.4 years the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes was decreased by 12% in the dulaglutide treated group (HR 0.88, p=0.026). The decrease in events was similar in participants with and without previous cardiovascular disease. In an analysis that focused on stroke it was noted that dulaglutide reduced ischemic stroke by 25% compared to placebo but had no effect on hemorrhagic stroke (288).

GRADE Trial

This trial compared the effect of adding 4 different hypoglycemic agents to metformin therapy in 5,047 patients with a relatively short duration of diabetes (mean 4.2 years) (16). The vast majority of participants had no history of cardiovascular disease (6% had positive history). The duration of this trial was approximately 5 years. The results are shown in table 26 and suggest that in this population treatment with liraglutide has beneficial effects on cardiovascular disease. One should note that this was predominantly a primary prevention trial. This trial supports the observations in the REWIND trial that patients without cardiovascular disease may benefit from GLP-1 agonist therapy. However, because of the complexity of this trial the authors note “These results should not be viewed as definitive proof that GLP-1 RAs reduce the incidence of cardiovascular disease in low-risk populations”. Clearly additional trials are required in low-risk populations.

Table 26. Cardiovascular Outcomes in the GRADE Trial
Outcome *Rate (95% CI)**	Glargine (N=1263)	Glimepiride (N=1254)	Liraglutide (N=1262)	Sitagliptin (N=1268)
Any cardiovascular disease	1.87 (1.54–2.25)	1.92 (1.59–2.31)	1.36 (1.08–1.69)	2.00 (1.66–2.39)
MACE**	1.05 (0.81–1.34)	0.96 (0.73–1.24)	0.78 (0.57–1.03)	1.12 (0.87–1.41)
Hospitalization for heart failure	0.42 (0.27–0.61)	0.48 (0.33–0.69)	0.22 (0.12–0.38)	0.48 (0.32–0.68)
Death from cardiovascular causes	0.33 (0.21–0.51)	0.26 (0.15–0.42)	0.14 (0.07–0.27)	0.33 (0.21–0.51)

Table 26. Cardiovascular Outcomes in the GRADE Trial

Outcome

Rate* (95% CI)

Glargine

(N=1263)

Glimepiride

(N=1254)

Liraglutide (N=1262)

Sitagliptin (N=1268)

Any cardiovascular disease

1.87

(1.54–2.25)

1.92

(1.59–2.31)

1.36

(1.08–1.69)

2.00

(1.66–2.39)

MACE**

1.05

(0.81–1.34)

0.96

(0.73–1.24)

0.78

(0.57–1.03)

1.12

(0.87–1.41)

Hospitalization for heart failure

0.42

(0.27–0.61)

0.48

(0.33–0.69)

0.22

(0.12–0.38)

0.48

(0.32–0.68)

Death from cardiovascular causes

0.33

(0.21–0.51)

0.26

(0.15–0.42)

0.14

(0.07–0.27)

0.33

(0.21–0.51)

*Rate is events per 100 participant years.

**MACE- death from cardiovascular disease or nonfatal myocardial infarction or stroke.

Summary

Thus, most studies have clearly demonstrated that treatment with GLP-1 RAs reduces cardiovascular events. Why there are differences in results between these studies is unknown but could be due to differential effects of the GLP-1 RAs, differences in the patient populations studied, or other unrecognized variables. A meta-analysis of 7 cardiovascular outcome studies using GLP-1 RAs (ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide) reported a 12% decrease in cardiovascular death, stroke, or myocardial infarction (p<0.0001), 12% decrease in cardiovascular deaths (p<0.003), 16% decrease in fatal or non-fatal strokes (p<0·0001), and 9% decrease in fatal or non-fatal myocardial infarctions (p=0.043) (289) (Table 27). It should be noted that in a large randomized trial (n= 17,604) in patients with obesity without diabetes semaglutide decreased a composite of endpoint consisting of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke by 20% compared to placebo (HR 0.80; 95%CI 0.72 to 0.90; P<0.001) (290). Thus, GLP-1 RAs reduce cardiovascular disease in patients with and without diabetes.

Table 27. Summary of GLP-1 Receptor Agonist Cardiovascular Outcome Trials
	Number	Prior CVD	HbA1c	Mean Follow-up (years)	*Hazard Ratio (95% CI)**	P value
ELIXA Lixisenatide	6068	100%	7.7%	2.1	1.02 (0.89-1.17)	0.78
LEADER Liraglutide	9340	81%	8.7%	3.8	0.87 (0.78-0.97)	0.015
SUSTAIN 6 Semaglutide	3297	83%	8.7%	2.1	0.74 (0.58-0.95)	0.016
EXSCEL Exenatide	14,752	73%	8.0%	3.2	0.91 (0.83-1.00)	0.061
HARMONY Albiglutide	9463	100%	8.7%	1.6	0.78 (0.68-0.90)	<0.001
REWIND Dulaglutide	9901	31%	7.3%	5.4	0>88 (0.79-0.99)	0.026
PIONEER 6** Semaglutide oral	3183	85%	8.2%	1.3	0.79 (0.57-1.11)	0.17
Overall (289)					0.88 (0.82-0.94)	<0.001

*CVD death, MI, Stroke. ** The Pioneer study is included in this table to provide information on all the studies examining the effect of GLP-1raon cardiovascular disease.

The mechanism accounting for this decrease in cardiovascular disease is uncertain but could be related to reductions in glycated hemoglobin, body weight, systolic blood pressure, postprandial triglyceride levels, inflammation, or the direct effect of activation of GLP-1 receptors on the atherosclerotic process such as improving endothelial function (291).

The effect of a GLP-1 receptor agonist (efpeglenatide- not available) in patients on an SGLT-2 inhibitor was determined in the AMPLITUDE-O trial (292). The effect of efpeglenatide vs. placebo on cardiovascular and renal outcomes (macroalbuminuria) was similar in the absence and presence of baseline SGLT-2 inhibitors. (see section below on combination therapy).

HEART FAILURE

Several of the large cardiovascular outcome trials described above have analyzed the effect of administration of GLP-1 RAs in the subgroup of patients with a history of heart failure. In the EXSCEL trial patients with heart failure at baseline had no decrease in all-cause mortality whereas mortality was reduced in the subgroup without HF (HR 0.79; CI 0.68–0.92) (293). Similarly, in the combined data from the SUSTAIN-6 and PIONEER-6, patients with prior heart failure were the only subgroup that did not have a decrease in cardiovascular events (294). In contrast, in the LEADER trial the decrease in cardiovascular events were similar in patients with and without a history of heart failure (282).

The large cardiovascular outcome studies have determined the effect of GLP-1 RAs on the occurrence of heart failure events. In a meta-analysis of the seven large cardiovascular outcome trials with a combined total of 56,004 participants, hospital admission for heart failure was decreased by 9% (HR 0.91, 0.83-0.99; p=0.028) (289) (Table 28). In the SELECT trial that determined the effect of semaglutide 2.4mg weekly in patients with obesity who were not diabetic a decrease in heart failure events was also observed (HR 0.82; 95%CI 0.71- 0.96) (290).

Table 28. Effect of GLP-1 RAs on Heart Failure
Cardiovascular Outcome Trial	Heart Failure Hospitalization Heart Failure (HR (CI))
ELIXA (lixisenatide)	0.96 (0.75–1.23)
LEADER (liraglutide)	0.87 (0.73–1.05)
SUSTAIN-6 (semaglutide)	1.11 (0.77–1.61)
EXSCEL (exenatide)	0.94 (0.78–1.13)
HARMONY (albiglutide)	0.71 (0.53–0.94)
PIONEER-6 (oral semaglutide)	0.86 (0.48–1.55)
REWIND (dulaglutide)	0.93 (0.77–1.12)
Meta-analysis (289)	0.91 (0.83–0.99)

HR= hazard ratio; CI= 95% confidence interval.

In patients with heart failure with preserved ejection fraction, a BMI> 30, and type 2 diabetes the effect of weekly semaglutide (2.4 mg) (n= 310) vs placebo (n= 306) for 52 weeks was determined (295). The Kansas City Cardiomyopathy Questionnaire clinical summary score, a measure of symptoms and physical limitations, was greatly improved in the semaglutide group and the 6-minute walk distance increased by 12.7 meters in the semaglutide group and decreased by 1.6 meters in the placebo group. Additionally, the NT-proBNP level decreased by 23% in the semaglutide vs. 4.6% the placebo group. Finally, hospitalization or urgent visit for heart failure was decreased in the semaglutide group (2.3% vs 5.9%). Similar beneficial effects of semaglutide on heart failure with preserved ejection fraction have been observed in patients without diabetes (296). The mechanisms accounting for this improvement is uncertain but could be related to reductions in glycated hemoglobin, body weight, systolic blood pressure, postprandial triglyceride levels, inflammation, or the direct effect of activation of GLP-1 receptors on the myocardium.

The results of these studies provide evidence that GLP-1 RAs have favorable effects on heart failure and additional studies are in progress to confirm and extend these findings.

RENAL DISEASE

The cardiovascular outcome studies described above also examined the effect of GLP-1 RAs on kidney disease.

ELIXA Trial

Lixisenatide treatment decreased urinary albumin-to-creatinine ratio in patients with pre-existing micro or macroalbuminuria (297). Additionally, lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo (297). However, no significant differences in eGFR decline or the number of patients doubling their serum creatinine levels were seen between the lixisenatide treated group vs. placebo group (297).

LEADER Trial

The renal outcome in this trial was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The renal outcome occurred in fewer patients in the liraglutide group than in the placebo group (HR 0.78; P=0.003) (298). This favorable outcome was driven primarily by a decrease in the development of macroalbuminuria. The renal benefits did not appear to be driven by changes in A1c, body weight, or decreases in systolic BP.

SUSTAIN 6 Trial

In this trial, new or worsening nephropathy, defined as persistent macroalbuminuria, persistent doubling of the serum creatinine, or a creatinine clearance < 45ml/min/1.73m2, occurred in 3.8% of the patients in the semaglutide group and 6.1% of the patients in the placebo group (HR 0.64; P=0.005) (284). As seen in the LEADER trial this favorable outcome was driven primarily by a decrease in the development of macroalbuminuria.

EXSCEL Trial

Exenatide treatment resulted in a reduction in new‐onset macroalbuminuria compared with placebo (2.2% vs 2.8%, P = 0.031), with no significant changes in either microalbuminuria (7.2% vs 7.5%) or ESKD requiring renal replacement therapy (0.7% vs 0.9%) (285).

REWIND Trial

The renal outcome included the occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy (299). During a median follow-up of 5.4 years the renal outcome developed in 17.1% of patients in the dulaglutide group and in 19.6% of patients in the placebo group (HR 0.85, p=0·0004). This beneficial effect was driven by a reduction in the development of macroalbuminuria (HR 0.77; p<0.0001)

AWARD 7 Trial

While the large studies described above demonstrated that GLP-1 RAs primarily decrease albuminuria the AWARD 7 trial provides data on eGFR. The Award 7 was a multicenter randomized trial of dulaglutide 0.75mg weekly (n= 190), 1.5mg weekly (n= 193), or daily insulin glargine (n= 194) in patients with T2DM and Stage 3 and 4 chronic kidney disease (300). At 52 weeks, eGFR was higher with dulaglutide 1.5 mg (eGFR 34.0; p=0.005 vs insulin glargine) and dulaglutide 0.75 mg (eGFR 33.8; p=0·009 vs insulin glargine) than with insulin glargine (31.3mL/min per 1·73 m²). In contrast to the cardiovascular studies described above at 52 weeks dulaglutide 1.5 mg and 0.75 mg did not affect albuminuria.

FLOW Trial

In this trial patients with T2DM and chronic kidney disease (defined by an eGFR of 50 to 75 and a urinary albumin-to-creatinine ratio of >300 and <5000 or an eGFR of 25 to <50 and a urinary albumin-to-creatinine ratio of >100 and <5000) were randomized to receive semaglutide 1.0 mg weekly (n= 1767) or placebo (n= 1766) and followed for a median of 3.4 years (301). The primary outcome was a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes and was decreased by 24% in the semaglutide group (HR 0.76; 95% CI 0.66 to 0.88; P = 0.0003). Notably, the composite of the kidney-specific components of the primary outcome was reduced by 21% (HR 0.79; 95% CI, 0.66 to 0.94) while cardiovascular death was reduced by 29% (HR 0.71; 95% CI, 0.56 to 0.89). Additionally, the decrease in eGFR was slower in the semaglutide group. These beneficial effects were seen regardless of glycemic control, eGFR, or albumin‐to‐creatinine ratio. Interestingly, in patients taking an SGLT2 inhibitor no benefit was observed but the number of events in this subgroup was very small and therefore larger studies are required to address this important issue.

Summary

The Flow trial in combination with the other trials demonstrates that GLP-1 RAs have beneficial effects on kidney function decreasing albuminuria and slowing the decrease in eGFR. A pooled analysis of the LEADER (liraglutide) and SUSTAIN 6 trials found a preservation in eGFR with GLP-1 RAs, particularly in patients with a reduced baseline eGFR (302). Moreover, the FLOW trial demonstrated a decrease in clinically important kidney outcomes including kidney failure (dialysis, transplantation, or an eGFR of <15 ml), a 50% reduction in the eGFR, or death from kidney-related causes. Similar beneficial effects on renal function have been observed in patients with obesity treated with semaglutide (303). Specifically, there was a 22% decrease in the development of the composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent eGFR) < 15, persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria), primarily due to a reduction in persistent macroalbuminuria, in the semaglutide group compared to placebo.

METABOLIC DYSFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH)

Studies have suggested that GLP-1 RAs have beneficial effects on MASLD and MASH (101). A meta-analysis of liraglutide studies and a separate meta-analysis of lixisenatide studies have reported that these drugs decrease liver enzymes (304,305). A 12-week randomized trial in 60 patients with MASLD of exenatide + basal insulin vs. rapid acting insulin + basal insulin demonstrated lower liver enzymes in the exenatide treated group (306). Moreover, the reversal rate of fatty liver was greater in the group treated with exenatide (93.3%) than the intensive insulin group (66.7%) (p < 0.01). Similarly, liraglutide and dulaglutide has also been shown to decrease intrahepatic fat (307-309).

In the LEAN Trial 52 patients with MASH were randomized to liraglutide 1.8 mg daily or placebo and followed for 48 weeks (310). Resolution of MASH occurred in 39% of patients treated with liraglutide and only 9% of patients in the placebo group (RR 4.3; p=0.019). Progression of fibrosis occurred in 9% of patients in the liraglutide group versus 36% of patients in the placebo group (p=0.04).

A recent trial of semaglutide subcutaneously given daily (0.1, 0.2, and 0.4 mg) demonstrated an improvement in MASH without a beneficial effect on fibrosis (311). Whether weekly semaglutide or daily oral semaglutide would have similar effects is unknown.

While these data are suggestive larger and longer studies on the effect of GLP-1 RAs on MASLD and MASH are required.

EFFECT OF GLP1 RECEPTOR AGONISTS IN PATIENTS ON SGLT2 INHIBITOR THERAPY

As discussed earlier, the effect of a GLP-1 RA (efpeglenatide- not available) in patients on an SGLT-2 inhibitor was determined in the AMPLITUDE-O trial (292). The effect of efpeglenatide vs. placebo on cardiovascular and renal outcomes (macroalbuminuria) was similar in the absence and presence of baseline SGLT-2 inhibitors. In the HARMONY trial the effect of albiglutide in patients on an SGLT-2 inhibitor on cardiovascular death, myocardial infarction, or stroke was similar.

In patients with T2DM and chronic kidney disease treated with semaglutide (FLOW trial), a small number of patients were taking a SGLT2 inhibitor at baseline (N = 550) (312). The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death, or cardiovascular death. In patients not taking an SGLT2 inhibitor (N = 2,983) the primary endpoint was reduced by 27% (HR 0.73; 95% CI 0.63-0.85; P < 0.001) and the kidney specific endpoint by 25% (HR 0.75; 95%CI 0.61-0.90; P = 0.003). In patients on a SGLT2 inhibitor at baseline the primary endpoint and kidney specific endpoint were not decreased (Primary endpoint- HR 1.07; 95% CI 0.69-1.67; P = 0.755; Kidney endpoints- HR 1.18; 95%CI 0.71-1.98; P = 0.532). In contrast, cardiovascular death, all cause death, and non-fatal MI were decreased in the sitagliptin group to a similar degree with or without SGLT2 inhibitor use at baseline. Thus, the results of this analysis do not provide strong evidence that adding a GLP1 RA to a SGLT2 inhibitor will provide additional benefits on renal outcomes.

Thus, treatment with a GLP-1 RA reduces cardiovascular events to a similar degree in patients regardless of whether they are taking an SGLT2 inhibitor at baseline. The effect of a GLP-1 RA on renal outcomes in patients on a SGLT2 inhibitor is not clear. It should be recognized that there were only a small number of patients on combination therapy in the studies described above, which limits the ability to make firm conclusions and larger studies of combination therapy are required.

Side Effects

GASTROINTESTINAL

The most common adverse effects are GI and include nausea, vomiting, constipation, and diarrhea (266). These symptoms are usually transient, resolving overtime (20). The GI side effects can be reduced by slowly increasing the dose (20). GI side effects tend to be more pronounced with short acting GLP-1 RAs (266). Dehydration can occur secondary to GI side effects and can result in acute kidney failure (package insert).

GALL BLADDER DISEASE

Observational studies have shown an association of treatment with GLP-1 RAs and bile duct and gallbladder disease (313). Additionally, a meta-analysis of randomized trials using GLP-1 RAs reported an association with an increased risk of cholelithiasis (314). Higher doses and a longer duration of treatment increased the risk of gallbladder disease (315). Finally, large cardiovascular trials with liraglutide (LEADER Trial), exenatide (EXSCEL Trial), and lixisenatide (ELIXA Trial) also reported an increased risk of gall bladder or biliary tract disease (278,285,316), however the large cardiovascular trial with semaglutide (SUSTAIN 6) did not observe an increase (284). It has been hypothesized that weight loss and/or decreased gallbladder motility induced by GLP-1 RAs could contribute to this increase in gall bladder disease.

INJECTION-SITE REACTIONS

Injection-site reactions (rash, erythema) are also common with GLP-1 RAs (20). Subcutaneous injection-site nodules may occur with the use of weekly exenatide (package insert), an abnormality that is due to the formulation.

MEDULLARY THYROID CANCER

Thyroid C-cell hyperplasia and medullary cell carcinoma has also been raised as possible concerns based on preclinical studies in rodents, but clinical studies in humans have not shown any indication of thyroid disorders (20). A meta-analysis of the four large cardiovascular outcome studies described above did not demonstrate an increased risk of medullary thyroid cancer with GLP-1 RA treatment (317)

PANCREATITIS

Subclinical increases in pancreatic enzyme levels are commonly observed with all GLP‐1 RAs and pancreatitis has been reported (266). Importantly increases in lipase and amylase were not predictive of subsequent pancreatitis (318). A meta-analysis of four large cardiovascular outcome studies described above did not demonstrate an increased risk of pancreatitis or pancreatic cancer with GLP-1 RA treatment (317,319). A meta-analysis of all seven cardiovascular outcome studies also did not demonstrate an increase in pancreatitis with GLP-1 RA treatment (320).

RETINOPATHY

In the SUSTAIN 6 trial described above the rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher in the semaglutide group compared to the placebo group (hazard ratio, 1.76; P=0.02) (284). This increased risk of retinopathy complications has been attributed to the magnitude and rapidity of A1c reduction during the first 16 weeks of treatment in patients who had pre-existing retinopathy and poor glycemic control at baseline (“early worsening”) (321). A meta-analysis of GLP-1 RA cardiovascular trials found an association between retinopathy and the magnitude of A1c reduction supporting the hypothesis that the increase in retinopathy in SUSTAIN 6 was due to lowering of A1c (322).

Of note, other trials using semaglutide did not observe an increased risk of retinopathy (321). Additionally, an increase in diabetic retinopathy was not observed in the other cardiovascular outcome trials (278,279,285,286). In a meta-analysis of 60 studies with 60,077 patients, treatment with GLP-1RAs did not increase the incidence of diabetic retinopathy, macular edema, retinal detachment, or retinal hemorrhage (323). However, the incidence of vitreous hemorrhage was higher in subjects treated with GLP-1 RAs compared with placebo (odds ratios 1.93; 95% CI 1.09 to 3.42). Thus, it is possible that GLP-1 RA treatment results in an increase in diabetic eye disease. A 5 years eye safety study for semaglutide, the FOCUS trial (NCT03811561), is currently underway and should provide a definitive answer.

As discussed above GLP-1 RAs slow gastric emptying and the retention of gastric contents could increase the risk of aspiration during surgical procedures. The American Society of Anesthesiologists recommended “For patients on daily dosing consider holding GLP-1 agonists on the day of the procedure/surgery. For patients on weekly dosing consider holding GLP-1 agonists a week prior to the procedure/surgery. This suggestion is irrespective of the indication (type 2 diabetes mellitus or weight loss), dose, or the type of procedure/surgery. If the patient has no GI symptoms, but the GLP-1 agonists were not held as advised, proceed with ‘full stomach’ precautions…” (324). A clinical practice update by the American Gastroenterological Association (AGA) pointed out the lack of meaningful data and that well-designed studies investigating patients on GLP-1 RAs are needed (324). In the absence of definitive data they advised that patients on GLP-1 RAs who have followed standard perioperative procedures and who do not have symptoms of nausea, vomiting, dyspepsia, or abdominal distention, to proceed with upper and/or lower endoscopy. In patients with symptoms suggesting possible retained gastric contents, transabdominal ultrasonography can be used to assess the presence of stomach contents but evidence to support this is lacking. Rapid-sequence intubation can be considered if there is uncertainty. “Lastly, when possible, placing patients on a liquid diet the day before sedated procedures may be a more acceptable strategy, in lieu of stopping GLP-1 RAs, and more consistent with the holistic preprocedural management of other similar conditions.” Clearly this is an area that requires additional studies and health care providers will need to use their judgement in deciding how to manage anesthesia in patients taking GLP-1 RAs.

SUICIDE

Concerns have been raised that GLP-1 RAs increase the risk of suicide and self-harm. A large cohort study compared 124,517 patients started on a GLP-1 RA and 174,036 patients started on an SGLT2 inhibitor and did not find an association between use of GLP-1 RAs and an increased risk of suicide death, self-harm, or incident depression and anxiety-related disorders (325). Other studies have reported similar results (326-328).

Contraindications and Drug Interactions

RENAL

Care needs to be exercised in patients with severe renal disease as they are more susceptible to the side effects of GLP-1 RAs and more likely to have serious side effects (package inserts). There is limited data in patients with end stage renal disease.

Exenatide should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (package insert). Caution should be applied when initiating or escalating doses of exenatide from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) (package insert).

Weekly exenatide is not recommended for use in patients with eGFR below 45 mL/min/1.73m2 or end stage renal disease (package insert).

Lixisenatide is not recommended in patients with end stage renal disease (eGFR <15 mL/min/1.73 m2) (package insert).

No dose adjustments for liraglutide, semaglutide, or dulaglutide are recommended for patients with renal impairment (package insert).

OTHER

Exenatide is not recommended in patients with gastroparesis or severe gastrointestinal disease (package insert).

In patients with a history of pancreatitis or at high risk for pancreatitis many clinicians avoid GLP-1 RAs.

GLP-1 RAs are contraindicated in patients with a personal or family history of Medullary Thyroid Cancer and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) (package insert).

Summary

The ability of GLP-1 RAs to effectively decrease A1c levels, reduce atherosclerotic cardiovascular disease, renal disease, and induce significant weight loss make these drugs very attractive in the treatment of patients with T2DM.Additionally, once weekly administration for certain drugs in this class can improve compliance.

Table 29. Advantages and Disadvantages of GLP- 1 Receptor Agonists
Advantages	Disadvantages
Weight Loss	GI side effects
No Hypoglycemia	Requires Injection
Reduce CVD (liraglutide, semaglutide, dulaglutide)	Pancreatitis?
Improve NAFLD	Thyroid cancer?
Once a week therapy possible	Gall bladder disease
Decrease renal disease	Expensive
Decrease postprandial glucose
Improve heart failure

ORAL GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS

Introduction

In 2019 an oral form of semaglutide (Rybelsus) became available. To facilitate absorption of semaglutide, which is a 31 amino acid peptide, the tablet contains a permeation enhancer N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC, Eligen® Technology, Emisphere Technologies), which is a small fatty acid derivative that accelerates the absorption of semaglutide across the gastric epithelium avoiding the activation of proteolytic enzymes and pH-induced degradation in the stomach (329). This allows for the absorption of an intact peptide. One should note that the bioavailability of oral semaglutide is very low as the dose of oral semaglutide is 7-14 mg per day vs 0.5-2.0 mg once a week with the injectable dose.

Administration

The oral form of semaglutide must be taken at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water (package insert). Waiting less than 30 minutes, or taking with food, beverages (other than plain water), or other oral medications will adversely affect the absorption of semaglutide. Waiting more than 30 minutes to eat may increase the absorption. The starting dose is 3 mg once daily for 30 days. After 30 days on the 3 mg dose, increase the dose to 7 mg once daily. The dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dose (package insert). Patients treated with once weekly semaglutide 0.5 mg injections can be transitioned to oral semaglutide 7 mg or 14 mg a day. No dose adjustment is recommended for patients with renal or hepatic impairment (package insert).

Mechanism of Action

The mechanism of action is identical to injected GLP-1 RAs described above.

Glycemic Efficacy

In a meta-analysis of five trials of oral semaglutide vs. placebo, treatment with oral semaglutide reduced HbA1c by 0.89% (330). In the Pioneer 1 study 703 patients were randomized (mean baseline HbA1c 8.0%) to placebo vs. various doses of oral semaglutide (331). After 26 weeks of treatment A1c decreased by -0.6% in the 3 mg group, -0.9% in the 7 mg group, and -1.1% in the 14 mg group compared to placebo (P < 0.001 for all results). If the decrease in A1c was adjusted for premature drug discontinuation or initiation of rescue medication the estimated decreases in A1c were -0.7% in the 3 mg group, -1.2% in the 7 mg group, and -1.4% in the 14 mg group (P < 0.001 for all).

Studies have also examined the ability of oral semaglutide to lower A1c vs. other drugs. Compared to sitagliptin, oral semaglutide 7mg per day reduced A1c by -0.3% while 14mg per day reduced A1c by 0.5% (P < .001 for both) (332). In a similar trial with flexible dose adjustment of semaglutide, treatment with semaglutide (60% on 14mg per day) resulted in a 1.4% decrease in A1c while 100mg sitagliptin decreased A1c by 0.7% (333). In a randomized trial comparing switching to oral semaglutide vs. DPP-4 inhibitor continuation A1c was decreased by 0.7% in the semaglutide group compared to continuing the DPP4 inhibitor (334). In a trial comparing empagliflozin vs. oral semaglutide, treatment with semaglutide resulted in a greater decrease in A1c compared to empagliflozin (-1.3% vs. -0.9%; P < 0.0001) (335). In a comparison of liraglutide 1.8mg per day vs. oral semaglutide 14mg per day the change from baseline in A1c was -1.2% (SE 0·1) with oral semaglutide and -1.1% with subcutaneous liraglutide (336). If the decrease in A1c was adjusted for premature drug discontinuation or initiation of rescue medication then oral semaglutide treatment resulted in a slightly greater decreases in A1c than subcutaneous liraglutide (estimated treatment difference -0·2%). Finally, early in the development of oral semaglutide various doses of oral semaglutide were compared to weekly injected semaglutide (337). Compared to placebo 10mg per day of oral semaglutide reduced A1c by –1.2%, 20mg by –1.4%, while 1mg per week of injected semaglutide decreased A1c by 1.9% (not significantly different than the 20mg oral dose). Thus, oral semaglutide is more effective in lowering A1c levels than DPP-4 inhibitors or SGLT2 inhibitors and similar to liraglutide and perhaps slightly less potent than injected semaglutide.

While not approved studies have shown that higher doses of oral semaglutide are more effective in lowering A1c levels (14mg- 1.5% decrease, 25mg- 1.8% decrease, 50mg- 2.0% decrease) (338).

Other Effects

WEIGHT LOSS

In a meta-analysis of weight loss, treatment with oral semaglutide reduced body weight by 2.99 kg compared to placebo (330). In a 26-week study comparing sitagliptin vs. oral semaglutide the 7mg dose resulted in a 1.6kg decrease and the 14mg dose a 2.5kg decrease in weight compared to sitagliptin (332). In contrast, oral semaglutide 14mg and empagliflozin 25mg resulted in a similar decrease in body weight at 26-weeks (-3.8 vs. -3.7kg) and 52-weeks (-3.8 vs. -3.6kg) (335). Finally, in a 26-week trial oral semaglutide resulted in greater weight loss (-4.4 kg than liraglutide (-3·1 kg) (336).

While not approved higher doses of oral semaglutide are more effective in decreasing body weight ((14mg- 4.7% decrease, 25mg- 7.3% decrease, and 50mg- 8.5% decrease) (338).

BLOOD PRESSURE AND PULSE RATE

In a meta-analysis of blood pressure, treatment with oral semaglutide reduced systolic blood pressure by 3.16 mmHg and increased pulse rate by 1.90 beats per minute compared with placebo (330).

CARDIOVASCULAR DISEASE

In the PIONEER 6 study 3,183 patients with T2DM at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors) were randomly assigned to receive oral semaglutide or placebo (339). After a median time of 15.9 months, major adverse cardiovascular events, the primary outcome, occurred in 3.8% of the subjects treated with oral semaglutide and 4.8% of the placebo group (HR 0.79; 95% CI 0.57 to 1.11). Deaths from cardiovascular causes were 0.9% in the oral semaglutide group and 1.9% in the placebo group (HR 0.49; 95% CI, 0.27 to 0.92) while death from any cause occurred in 1.4% in the oral semaglutide group and 2.8% in the placebo group (HR 0.51; 95% CI, 0.31 to 0.84). It should be noted that the primary outcome was not statistically decreased in this study, which may be due to the relatively small number of subjects studied and the short duration of the study that together resulted in a small number of events. Additionally, more patients in the placebo group received treatment with an SGLT2 inhibitor than in the oral semaglutide group and SGLT2 inhibitors are well recognized to reduce cardiovascular disease events (see section on SGLT2 inhibitors), which could also have diminished the ability to observe a decrease in events in the oral semaglutide group. Because the glucose lowering, weight loss, and many other effects of oral semaglutide are very similar to injected semaglutide many experts consider the effects on cardiovascular and renal disease to also be similar.

Side Effects

The most common adverse effects are GI and include nausea, vomiting, constipation, and diarrhea (329). Transient mild or moderate nausea was the most common adverse event occurring in 5-21% of subjects treated with oral semaglutide (329).

Severe hypoglycemia is uncommon in patients treated with oral semaglutide (329). The risk of hypoglycemia is increased when oral semaglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia when used in combination with oral semaglutide.

The safety profile of oral semaglutide is similar to other GLP-1 RAs (see side effect section for GLP1 receptor agonists).

Contraindications and Drug Interactions

Similar to other GLP1 RAs oral semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

No notable drug interactions have been described (package insert).

Summary

The delivery of a GLP1 RA via the oral route is advantageous and make oral semaglutide an attractive choice in the treatment of patients with T2DM who do want to inject medications given its ability to decrease A1c, body weight, and blood pressure with few serious side effects. Some patients may have difficulty following the relatively complex instructions for taking this medication. It should be noted that weight loss is less with oral semaglutide and studies using higher doses for weight loss are underway. It is likely that the other beneficial effects of GLP1 receptor agonists (e.g., reducing cardiovascular disease and renal disease) will also occur with the oral formulation.

DUEL GLP-1 RECEPTOR AND GIP RECEPTOR AGONIST

Introduction

Tirzepatide (Mounjaro) is a 39 amino acid peptide that was engineered from the native GIP sequence and has agonist activity at both the GIP and GLP-1 receptors (340,341). A C20 fatty diacid moiety is conjugated at the position 20 lysine residue, which facilitates binding to albumin thereby resulting in a half-life after administration of approximately 5 days allowing for weekly administration (340,341).

For information on the use of tirzepatide for the treatment of weight loss see the Endotext chapter entitled “Pharmacologic Treatment of Overweight and Obesity in Adults” (267).

Administration

Tirzepatide is administered weekly at any time of day, with or without meals. The starting dose is 2.5mg subcutaneously and after 4 weeks the dose is increased to 5 mg (341). Depending upon the response one may increase the dosage in 2.5 mg increments every 4 weeks to a maximum dose of 15 mg per week (341). No dosage adjustment is recommended for renal or hepatic disease (package insert).

Mechanism of Action

Both GLP-1 and GIP stimulate insulin secretion in a glucose dependent fashion (342). The higher the glucose the greater the effect with no effect when glucose levels are in the normal to low range (342). As one would expect tirzepatide stimulates both first- and second-phase insulin secretion (341,343). GLP-1 inhibits glucagon secretion when glucose levels are increased while GIP will stimulate glucagon secretion, particularly when glucose levels are in the normal to low range (342). Tirzepatide reduces fasting and postprandial glucagon concentrations (343). These effects on insulin and glucagon secretion lead to decreases in glucose levels with a low risk of hypoglycemia as the increase in insulin secretion and decrease in glucagon secretion are dependent on elevated glucose levels. In addition, tirzepatide improves insulin sensitivity (343,344). While this increase in insulin sensitivity may be due to weight loss studies suggest that there may be additional factors contributing to the improved insulin sensitivity (344). GIP may have peripheral effects that could enhance insulin sensitivity.

Pharmacologic levels of GLP-1 slow gastric emptying and induce satiety by activating receptors in the hypothalamus thereby leading to decreased food intake and weight loss (342). GIP also appears to have central effects leading to decreased food intake in rodents but the effect in humans is not well defined (342).

Glycemic Efficacy

A number of different studies (SURPASS trials) have examined the effect of 5mg, 10mg, and 15mg of tirzepatide on glycemic control under a variety of clinical situations (Table 30). SURPASS 1 compared tirzepatide vs. placebo in patients on no medications (345), SURPASS 2 compared tirzepatide vs. semaglutide at a dose of 1 mg in patients on metformin (346), SURPASS 3 compared tirzepatide vs. degludec insulin in patients on metformin alone or in combination with an SGLT2 inhibitor (347). SURPASS 4 compared tirzepatide vs glargine insulin in patients treated with any combination of metformin, sulfonylurea, or SGLT-2 inhibitor (348), and SURPASS 5 compared tirzepatide vs. placebo in patients treated with glargine insulin with or without metformin (349). The treatment duration was 40 weeks in SURPASS 1, 2, and 5 and 52 weeks in SURPASS 3 and 4. Baseline A1c levels were between 7.9% and 8.5% in the SURPASS studies.

Table 30. Decrease in HbA1c with Tirzepatide Treatment
	SURPASS 1	SURPASS 2	SURPASS 3	SURPASS 4	SURPASS 5
	Tirzepatide vs. Placebo	Tirzepatide vs. Semaglutide	Tirzepatide vs. Degludec	Tirzepatide vs. Glargine	Tirzepatide vs. Placebo
Baseline A1c	7.9%	8.3%	8.2%	8.5%	8.3%
Tirzepatide 5mg	-1.8	-2.0	-1.9	-2.1	-2.1
Tirzepatide 10mg	-1.7	-2.2	-2.0	-2.3	-2.4
Tirzepatide 15mg	-1.7	-2.3	-2.1	-2.4	-2.3
Comparator	-0.1	-1.9	-1.3	-1.4	-0.9

It should be noted that the reduction in A1c induced by tirzepatide is quite impressive and results in an A1c level in an “intensive” control range. For example, in the SURPASS 2 trial 80% of patients had an A1c < 6.5% and 46% < 5.7% on 15mg tirzepatide. Additionally, comparison with semaglutide (SURPASS 2) demonstrated a modestly greater lowering of A1c with tirzepatide. A greater difference in the ability to decrease A1c was seen in an earlier study comparing tirzepatide vs. dulaglutide (tirzepatide 5mg- 1.6%, 10mg- 2.0%,15 mg- 2.4%; duluglutide 1.5mg- 1.1%) (350). Note the comparisons with semaglutide and dulaglutide used doses in these studies that were not the maximal dose. Comparisons with insulin therapy (SURPASS 3 and 4) show better glycemic control with tirzepatide, which is likely due to an increased risk of hypoglycemia with insulin therapy that limits treatment. In SURPASS 3, 48% of patients on insulin therapy had a blood glucose < 70mg/dL while on tirzepatide treatment 8-14% of patients had a blood glucose < 70mg/dL. The SURPASS 6 trial compared the addition of tirzepatide vs. insulin lispro three times per day (351). Tirzepatide decreased A1c by -2.1% vs -1.1% with insulin lispro with less severe hypoglycemia and greater weight loss. Severe hypoglycemia is not frequently observed with tirzepatide in the absence of concomitant insulin or sulfonylurea therapy. Finally, it is worth noting that the additional A1c reduction with an increased dose of tirzepatide is very modest. This is important to recognize that in patients that have side effects with higher doses of tirzepatide treatment it is not necessary to achieve maximal doses of tirzepatide to robustly improve glycemic control.

Other Effects

WEIGHT LOSS

Significant weight loss has been observed with tirzepatide administration. Table 31 shows the weight loss observed in the SURPASS trials. In contrast to the modest effects of increased doses of tirzepatide on A1c levels increased doses of tirzepatide have a greater effect on weight loss. At the 15mg dose over a 10% loss in weight is observed. It should be noted that in SURPASS 2 tirzepatide is compared to semaglutide 1.0mg, which is not the dose that is recommended for weight loss (the recommended dose is 2.4mg) and therefore one cannot be certain that tirzepatide is more efficacious than higher doses of semaglutide. In a comparison of tirzepatide vs. dulaglutide, tirzepatide resulted in greater weight loss (tirzepatide 5mg- 4.8kg, 10mg- 8.7kg, 15mg-11.3kg; dulaglutide 1.5mg- 2.7kg) (350). In a large 72-week trial focused on weight loss (SURMONT-2) in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg (n=312) and 15 mg (n=311) resulted in a 9.6% and 11.6% loss in weight compared to the placebo group (n=315) (352).

Table 31. Decrease in Weight with Tirzepatide Treatment
	SURPASS 1	SURPASS 2	SURPASS 3	SURPASS 4	SURPASS 5
	Tirzepatide vs. Placebo	Tirzepatide vs. Semaglutide	Tirzepatide vs. Degludec	Tirzepatide vs. Glargine	Tirzepatide vs. Placebo
Tirzepatide 5mg	-6.3kg/ -7.9%	-7.6kg/ -8.5%	-7.0kg/ -8.1%	-6.4kg/ -8.1%	-5.4kg/ -6.6%
Tirzepatide 10mg	-7.0kg/ -9.3%	-9.3kg/ -11.0%	-9.6kg/ -11.4%	-8.9kg/ -10.7%	-7.5kg/ -8.9%
Tirzepatide 15mg	-7.8kg/ -11.0%	-11.2kg/ -13.1%	-11.3kg/ -13.9%	-10.6kg/ -13.0%	-8.8kg/ -11.6%
Comparator	-1.0kg/ -0.9%	-5.7kg/ -6.7%	+1.9kg/ +2.7%	+1.7kg/ +2.2%	+1.6kg/ +1.7%

BLOOD PRESSURE AND PULSE

In the SURPASS studies described above tirzepatide treatment decreased systolic BP by 2.8 to 12.6 mm Hg and diastolic BP by 0.8 to 4.5 mm Hg (340). Tirzepatide treatment increased heart rate by approximately 2 to 4 beats per minute.

LIPIDS

In the SURPASS studies described above plasma triglyceride levels were consistently decreased by 13-25% (table 32). In most studies with the exception of SURPASS 5, HDL cholesterol levels increased by 3-11%. Total cholesterol and LDL cholesterol levels are modestly decreased in most studies. Not unexpectedly given the decrease in triglyceride levels small LDL particles were decreased (353). The decrease in triglycerides could be related to weight loss, which is well known to affect triglycerides (354). Additionally, GIP and tirzepatide increase lipoprotein lipase activity, which could increase the clearance of triglyceride rich lipoproteins (342,353). Finally, tirzepatide lowered Apo-CIII levels, which could also play a role in the decrease in triglyceride levels (353).

Table 32. Effect of Tirzapetide 15mg on Lipid Levels
	SURPASS 1	SURPASS 2	SURPASS 3	SURPASS 4	SURPASS 5
	Tirzepatide vs. Placebo	Tirzepatide vs. Semaglutide	Tirzepatide vs. Degludec	Tirzepatide vs. Glargine	Tirzepatide vs. Placebo
Total Cholesterol	-7.6%	-1.5%	-3.0%	-5.6%	-12.6%
Triglycerides	-25.7%	-13.3%	-13.0%	-16.1%	-19.4%
LDLc	-10.8%	+1.2%	-3.8%	-9.3%	-17.3%
HDLc	+11.3%	+2.7%	+9.2%	+7.9%	-0.8%

Results are percent change in tirzepatide group minus percent change in comparator group.

CARDIOVASCULAR DISEASE

A meta-analysis of seven randomized controlled trials with 4,887 participants treated with tirzepatide and 2,328 control participants found that MACE 4 (cardiovascular death, myocardial infarction, stroke, and hospitalized unstable angina) was decreased but not statistically significant (HR 0.80; 95% CI, 0.57–1.11) (355). One should note that the number of events in this meta-analysis was small because the duration of these studies was relatively short (approximately 1 year) and the population of patients included in these studies were not at high risk for cardiovascular events (only 1/3 with pre-existing cardiovascular disease). A long-term trial dedicated to determining the effect of tirzepatide on cardiovascular disease is ongoing (SURPASS-CVOT trial NCT04255433) (356).

RENAL DISEASE

A post-hoc analysis of the SURPASS-4 compared the effect of tirzepatide and glargine insulin on kidney function with a median treatment duration of treatment 85 weeks (357). The mean rate of eGFR decline was -1.4 per year in the combined tirzepatide groups and -3.6 per year in the insulin group (between-group difference 2.2 [95% CI 1.6 to 2.8]) with a greater benefit in participants with eGFR < 60 (i.e., patients with pre-existing kidney disease). It should be noted that tirzepatide treatment resulted in an early decrease in eGFR, however, after 12 weeks eGFR values were higher in the tirzepatide group than in the glargine insulin group. Additionally, urine albumin to creatinine ratio in the glargine insulin group increased but in the tirzepatide treated group there was very little change. The UACR stabilizing effect of tirzepatide was similar in SGLT2 inhibitor users vs. non-users suggesting that these drugs will have additive beneficial effects on kidney function. The SURPASS 1, 3, and 5 trials similarly showed beneficial effects on urine albumin to creatinine ratio. The SURPASS 2 trial compared tirzepatide and semaglutide and there was no difference in the urine albumin to creatinine ratio. The effect of tirzepatide on urine albumin to creatinine ratio and eGFR did not appear to be mediated by changes in HbA1c or bodyweight. Most importantly, tirzepatide reduced the risk of the composite kidney endpoint of new-onset macroalbuminuria, eGFR decline of at least 40%, end-stage kidney disease, or death due to kidney failure by 42% (HR 0.58; 95% CI 0.43–0.80), mainly due to a reduction in new-onset macroalbuminuria (357).

These results strongly suggest that tirzepatide has beneficial on kidney function but further studies dedicated to determining the benefits of tirzepatide on renal function are indicated.

LIVER DISEASE

Liver fat content was decreased to a greater degree with tirzepatide treatment compared to treatment with insulin degludec (358). Additionally, tirzepatide decreased alanine aminotransferase and aspartate aminotransferase levels (359).

A recent randomized trial compared the response to tirzepatide 5, 10, or 15mg vs. placebo in patients with metabolic dysfunction-associated steatohepatitis (MASH) with moderate or severe fibrosis after 52 weeks of treatment (360). Resolution of MASH without worsening of fibrosis was seen in 10% of the patients in the placebo group, 44% of the patients in the 5-mg tirzepatide group, 56% of the patients in the 10-mg tirzepatide group, and 62% of the patients in the 15-mg tirzepatide group (P<0.001 for all three comparisons with placebo group). Improvement of at least one fibrosis stage without worsening of MASH occurred in 30% of the placebo group, 55% of the 5-mg tirzepatide group, 51% of the 10-mg tirzepatide group, and 51% of the 15-mg tirzepatide group. As seen in other studies alanine aminotransferase and aspartate aminotransferase decreased by approximately 50% and liver fat by 40-50% in patients treated with tirzepatide compared to placebo.

These studies suggest that tirzepatide will have beneficial effects in patients with metabolic dysfunction associated steatotic liver disease (MASLD) and MASH.

OBSTRUCTIVE SLEEP APNEA

In individuals who were not diabetic but were obese with moderate-to-severe obstructive sleep apnea, treatment with tirzepatide resulted in “a clinically meaningful change in sleep-disordered breathing and alleviation of perceived sleep disturbance and sleep-related impairment, as well as reductions in common obstructive sleep apnea-related cardiovascular risk factors” (361). Hopefully future studies will determine if similar beneficial effects with tirzepatide treatment occur in patients with diabetes and obstructive sleep apnea.

Side Effects

The side effects described in the section on GLP-1 RAs also are of concern with tirzepatide.

Patients treated with tirzepatide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia may be decreased by a reduction in sulfonylurea or insulin dose.

The incidence of pancreatitis was increased in patients treated with tirzepatide compared to comparator treatment ((0.23 patients per 100 years of exposure vs. 0.11 patients per 100 years of exposure) (package insert). Additionally, acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was increased with tirzepatide treatment (0.6% of tirzepatide-treated patients and 0% of placebo-treated patients) (package insert).

As with other GLP-1 RAs nausea, diarrhea, vomiting, dyspepsia, constipation, and decreased appetite are common side effects.

Contraindications and Drug Interactions

Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with MEN2. Tirzepatide has not been studied in patients with a prior history of pancreatitis and it is unknown if patients with a history of pancreatitis are at higher risk for developing pancreatitis.

Tirzepatide delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. The delay is largest after the first dose and diminishes over time.

Summary

The major advantage of tirzepatide compared to GLP-1 RAs is the greater decrease in weight and A1c levels.

INSULIN-GLP-1 RECEPTOR AGONIST COMBINATIONS

Introduction

There are currently two insulin-GLP-1 RA combinations available for use; glargine insulin/lixisenatide (iGlarLixi) (Soliqua) and degludec insulin/liraglutide (iDegLira) (Xultophy). Both combine a basal insulin with a once-a-day GLP-1 RA. iGlarLixi contains 100U glargine and 33 ug lixisenatide per ml. iDegLira contains 100U degludec insulin and 3.6 mg liraglutide per ml.

Administration

In patients naive to basal insulin or to a GLP-1 RA, currently on a GLP-1 RA, or currently on less than 30 units of basal insulin daily the recommended starting dosage of iGlarLixi 100/33 is 15 units (15 units insulin glargine/5 ug lixisenatide) given subcutaneously once daily. In patients currently on 30 to 60 units of basal insulin daily, with or without a GLP-1 RA the recommended starting dosage of iGalLixi 100/33 is 30 units (30 units insulin glargine/10 ug lixisenatide) given subcutaneously once daily. After starting with the recommended dose, titrate the dosage upwards or downwards by two to four units weekly based on the patient’s glycemic control until the desired fasting plasma glucose is achieved. Administer iGlarLixi 100/33 subcutaneously once a day within an hour prior to the first meal of the day. The maximum dose of iGlarLixi 100/33 is 60 units daily (60 units insulin glargine/20 ug lixisenatide).

The recommended starting dose of iDegLira 100/3.6 is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) given subcutaneously once-daily. After starting the recommended starting dose, titrate the dosage upwards or downwards by two units every three to four days based on the patient’s blood glucose monitoring results and glycemic control goal until the desired fasting plasma glucose is achieved. Administer iDegLira 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food. The maximum dose of iDegLira 100/3.6 is 50 units daily (50 units of insulin degludec and 1.8 mg of liraglutide).

Mechanism of Action

Basal insulin regulates fasting blood glucose levels between meals and overnight while a GLP-1 RA lowers postprandial glucose levels (362). Together this drug combination results in 24-hour glycemic control.

Glycemic Efficacy

A number of studies have compared the ability of the combination of insulin-GLP RA to lower A1c levels compared to either insulin alone or GLP-1 RA alone (362). Table 33 shows the results of two large studies. As shown in Table 33 combination therapy was better at lowering A1c levels compared to the individual components (362). Additionally, the risk of hypoglycemia was similar with combination therapy compared to basal insulin alone. In a study of patients poorly controlled on glargine insulin adding rapid acting insulin (basal/bolus therapy) vs. switching to iDegLira was found to result in a similar reduction in A1c levels but the risk of hypoglycemia was greater with basal/bolus insulin (363). Not unexpectedly basal/bolus insulin resulted in greater weight gain (difference 3.6 kg) (363). Indirect comparisons suggest that iDegLira reduces A1C slightly more (< 0.5%) than iGlarLixi but this could be due to different study design, different patient populations, or other differences between the trials (362). A meta-analysis of 8 studies concluded that iDegLira and iGlarLixi demonstrated no significant differences in absolute HbA1c changes, fasting plasma glucose levels, or body weight changes relative to baseline (364). Moreover, a small head-to-head comparison of iDegLira and iGlarLixi did not demonstrate differences in glycemic control (365).

Table 33. Effect of Combination Therapy vs Individual Components on Key Outcomes
Study	Treatment	A1c Reduction	% Subjects with Hypoglycemia	Change in Body Weight (Kg)
Rosenstock et al (366)	iGlarLixi	1.6%	26	-0.3
	Glar	1.3%	24	+1.1
	Lixi	0.9%	6	-2.3
Gough et al (367)	iDegLira	1.9%	32	-0.5
	Deg	1.4%	39	+1.6
	Lira	1.3%	7	-3.0

Other Effects

As shown in Table 33 the typical weight gain seen with insulin therapy alone is blunted with combination therapy.

Side Effects

Studies have noted that the typical GI side effects seen with GLP-1 RA therapy is blunted with combination therapy (148). The likely explanation is that the titration of the GLP-1 RA is slower with combination therapy (148).

Contraindications

The maximum daily insulin dose of 60 units for iGlarLixi and 50 units for iDegLira, may not be sufficient in patients requiring higher daily basal insulin doses (e.g., patients with severe insulin resistance). The maximum dose is determined by the GLP-1 RA (the max dose of iDegLira delivers 1.8 mg of liraglutide while the max dose of iGlarLixa delivers 20 ug of lixisenatide). Conversely, there may be some patients who require only a low dose of basal insulin and thus because of the fixed ratio of basal insulin to GLP-1 RA the dose of the GLP-1 RA may be too low. These examples are a limitation of fixed ratio delivery systems. In these patients one can use basal insulin and a GLP-1 RA independently. It should be noted that for the majority of patients the fixed ratio will be acceptable.

Summary

The effects of combination therapy are predictable based on studies of basal insulin and GLP-1 RAs but providing them in a single injection provides convenience and makes it easier for patients to comply. Additionally, these combination drugs are titrated based on fasting glucose values and therefore frequent home blood glucose monitoring is not required, which also makes compliance easier. In patients who do not have adequate control on basal insulin alone or a GLP-1 RA alone combination therapy can be a useful therapeutic option.

BILE ACID SEQUESTRANTS

Introduction

Colesevelam (Welchol) is a non-absorbed, polymeric, LDL cholesterol lowering and glucose lowering agent that is a high-capacity bile acid-binding molecule (368). This drug was developed primarily to lower LDL cholesterol levels and was later noted to have favorable effects on blood glucose levels and was approved for improving glycemic control in patients with T2DM (20,368). It should be noted that other bile acid sequestrants (cholestyramine) also have favorable effects on glycemic control (369).

Administration

The recommended dose of colesevelam is 6 tablets once daily or 3 tablets twice daily with meals (tabs 625 mg). Alternatively, one can take one 3.75-gram packet once daily mixed with water, fruit juice, or diet soft drinks and taken with meals or one flavored chewable bar (80 calories per bar) with meals. For patients with difficulty swallowing tablets the use of packets or chewable bars is recommended.

Mechanism of Action

The mechanism by which bile acid sequestrants improve glucose metabolism is not well understood and the literature on this topic is often contradictory (370,371). Colesevelam does not alter hepatic or peripheral insulin sensitivity or decrease glucose GI absorption (371,372). Neither acute nor chronic treatment affect post oral glucose tolerance test blood glucose levels (372). Additionally, colesevelam treatment did not alter endogenous glucose production, gluconeogenesis, or glycogenolysis (371,372). Thus, the mechanisms accounting for the decrease in glucose effect of bile acid sequestrants remain unclear.

A leading hypothesis is that bile acid sequestrants improve glucose metabolism by stimulating the incretin pathway. Colesevelam increases GLP-1 and GIP concentrations suggesting that an increase in incretins contributes to the improvement in glycemic control (372-374). There are two pathways by which colesevelam increases GLP-1 secretion; (1) TGR5-mediated GLP-1 secretion in L cells and (2) intestinal proglucagon expression.

TGR5 is a G protein–coupled receptor expressed in many organs and tissues including the intestine (372,374). Bile acids activate TGR5 on the surface of intestinal L cells promoting GLP-1 secretion (372,374,375). Bile acid sequestrants appear to augment TGR5 activation and GLP-1 release, which occurs primarily in the distal intestine and colon (372,375,376).

FXR is a nuclear hormone receptor that complexes with RXR to alter the expression of a large number of genes (374). Bile acids are a ligand for FXR and activate FXR thereby regulating gene expression (374). FXR activation in intestinal L cells decreases proglucagon expression resulting in a decrease in GLP-1 production (377). Conversely, a decrease in bile acids due to binding to colesevelam increases GLP-1 gene expression and secretion in response to glucose improving glucose metabolism (377).

It is likely that there are both incretin dependent and independent mechanisms that account for the improvement in glycemic control with colesevelam treatment. The exact mechanisms by which bile acid sequestrants lower A1c levels remain to be elucidated.

Glycemic Efficacy

Colesevelam has modest effects on glycemic control, lowering A1c levels by approximately 0.5% when added to metformin, sulfonylureas, pioglitazone, or insulin (20,368,378). Colesevelam does not lead to an increase in weight (368). In combination with metformin hypoglycemia is not a problem but when used in combination with insulin or sulfonylureas hypoglycemia may occur (368).

Other Effects

LIPIDS

Colesevelam lowers LDL cholesterol levels by 15-20% and has only a modest effect on HDL cholesterol levels (368,379). The effect of bile acid sequestrants on triglyceride levels varies (379). In patients with normal triglyceride levels, bile acid sequestrants increase triglyceride levels by a small amount. However, as baseline triglyceride levels increase, the effect of bile acid sequestrants on plasma triglyceride levels becomes greater, and can result in substantial increases in triglyceride levels (379). In patients with triglycerides > 500mg/dl the use of bile acid sequestrants is contraindicated (379).

CARDIOVASCULAR DISEASE

There have been no randomized studies that have examined the effect of bile acid sequestrants on cardiovascular end points in subjects with diabetes. In non-diabetic-subjects bile acid sequestrants have reduced cardiovascular events(380,381). Since bile acid sequestrants have a similar beneficial impact on serum lipid levels in diabetic and non-diabetic subjects one would anticipate that these drugs would also result in a reduction in events in the diabetic population.

Side Effects

Colesevelam does not have major systemic side effects as it is not absorbed and remains in the intestinal tract (379). However, it does cause gastrointestinal (GI) side effects (379). Constipation is a common side effect and can be severe. In addition, patients will often complain of bloating, dyspepsia, abdominal discomfort, and aggravation of hemorrhoids. Because of GI distress, a small number of patients will discontinue therapy with colesevelam. One can reduce or ameliorate these GI side effects by increasing hydration, adding fiber to the diet (psyllium), and using stool softeners.

Contraindications and Drug Interactions

Colesevelam treatment is contraindicated in patients with a history of bowel obstruction and is cautioned in those with a history of gastrointestinal motility disorders (i.e., gastroparesis) or gastrointestinal surgery (368,379). Colesevelam is contraindicated in patients with plasma triglyceride levels > 500 mg/dL or a history of hypertriglyceridemia-induced pancreatitis (package insert).

In the intestine bile acid sequestrants can impede the absorption of many other drugs (379). Colesevelam, which requires a much lower quantity of drug because of its high affinity and binding capacity for bile salts, has less of an effect on the absorption of other drugs than other bile acid sequestrants but can still adversely affect the absorption of certain drugs (Table 34) (379). Administration of these drugs, as well as vitamin supplements, 4 hours prior to administration of colesevelam minimizes pharmacokinetic interactions (379). This is particularly important with drugs that have a narrow toxic/therapeutic window, such as thyroid hormone, digoxin, or warfarin. It can be difficult for some patients, particularly those on multiple medications, to take colesevelam given the need to separate pill ingestion.

Table 34. Drugs Affected by Colesevelam
L-thyroxine	Cyclosporine	Glimepiride	Glipizide
Glyburide	Phenytoin	Olmesartan	Warfarin
Oral contraceptives	Repaglinide	Fenofibrate	Vitamin Supplements

Colesevelam may also decrease the absorption of fat-soluble vitamins A, D, E, and K (package insert).

Summary

Colesevelam has the advantage of lowering both A1c and LDL cholesterol levels. However, the efficacy of lowering A1c and LDL cholesterol levels is modest compared to other drugs. Additionally, in our patients with diabetes who are often on multiple medications it can be difficult to coordinate taking colesevelam with these other medications.

Table 35. Advantages and Disadvantages of Colesevelam
Advantages	Disadvantages
Lowers LDL cholesterol	Increases triglyceride levels particularly if already high
Minimal systemic effects	GI side effects
Once a day administration possible	Inhibits the absorption of other drugs
No hypoglycemia	Modest effect on A1c
Weight neutral	Relatively Expensive

PRAMLINTIDE (SYMLIN)

Introduction

Pramlintide is a soluble synthetic analog of human amylin (382). Amylin is co-sequestered and co-secreted with insulin by the pancreatic beta cells in response to nutrient stimuli (382). Amylin secretion in response to nutrients is absent in type 1 diabetes and in patients with T2DM there is impaired beta-cell secretion of amylin in response to nutrients (382). Amylin suppresses post-prandial arginine-stimulated glucagon secretion, suppresses appetite, and slows gastric emptying time through effects on the brain (382).

Administration

In patients with T2DM initiate pramlintide at 60 ug subcutaneously immediately prior to each major meal. Increase the dose from 60 to 120 ug prior to each major meal when no clinically significant nausea has occurred for at least 3 days. Note the dose used to treat patients with Type 1 diabetes differs from the dose used in patients with T2DM.

Mechanism of Action

Pramlintide attenuates post-prandial glucagon secretion, enhances satiety, and reduces food intake, which together improve glycemic control (382). These effects are mediated centrally (382)

Glycemic Efficacy

In a review of three randomized trials in patients with T2DM comparing pramlintide vs. placebo the A1c level was decreased by approximately 0.3-0.6% in the pramlintide group (383). Postprandial glucose excursions are significantly blunted with the addition of pramlintide (382). Pramlintide has only minimal effects on fasting glucose levels (383).

In a study comparing rapid acting insulin vs. pramlintide with meals a similar reduction in A1c was observed (384). In contrast to rapid acting insulin, patients treated with pramlintide did not gain weight (384). Additionally, the frequency of hypoglycemia was less with pramlintide compared with rapid acting insulin (384).

Other Effects

Pramlintide treatment decreases weight (approximately 1-3 kg), which is likely due to decreased food intake (382,383). In a comparison of food intake during an ad libitum buffet meal, treatment with pramlintide resulted in an approximately 200 calorie decrease in food intake compared to placebo administration (385). Pramlintide also decreases gastric emptying (382).

Side Effects

A major side effect of pramlintide is nausea which can lead to patients discontinuing this drug (383).

Although pramlintide alone does not cause hypoglycemia, in combination with rapid acting meal time insulin the two drugs synergistically increase the risk of severe hypoglycemia (382). Therefore, rapid acting meal time insulin needs to be reduced upon initiation of pramlintide treatment to decrease the risk of hypoglycemia (382). Reducing rapid acting meal time insulin by 30-50% is recommended during the initial dose titration period (382).

Contraindications and Drug Interactions

Pramlintide is contraindicated in patients with hypoglycemia unawareness and confirmed gastroparesis (package insert).

Summary

Pramlintide is currently seldom used. Its modest effect on A1c levels coupled with the difficulties of administration (extra injections) and side effects has led to minimal use of this agent. Additionally, its major advantage of weight loss is now superseded by the use of GLP-1 RAs.

Table 36. Advantages and Disadvantages of Pramlintide
Advantages	Disadvantages
Weight loss	Hypoglycemia
Decrease postprandial glucose	Frequent dosing
	GI side effects
	Expensive
	Modest reduction in A1c

SUMMARY

A large number of drugs are now available for lowering glucose levels. For information on the management of T2DM and selecting amongst the available pharmacological agents see the chapter by Schroeder (5). For information on the use of these drugs to treat diabetes during pregnancy, in children and adolescents, and for the prevention of diabetes see other Endotext chapters (2-4).

ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

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Cushing’s Syndrome

ABSTRACT

Cushing’s syndrome results from chronic exposure to excessive circulating levels of glucocorticoids. Cushing’s disease, pituitary-dependent Cushing’s syndrome, is the most common cause of endogenous hypercortisolism. The recommended screening tests include the 1mg overnight dexamethasone suppression test, late-night salivary cortisol (at least 2 samples), and 24-hour urinary free cortisol (at least two 24-hour collections). If the initial test is positive on 2 occasions the patient should be evaluated by an endocrinologist for further assessment. Plasma 09:00h ACTH measurement guides imaging and further investigations. If ACTH is elevated/inappropriately normal, MRI scanning of the pituitary should be performed, but if ACTH is suppressed imaging of the adrenals should follow. The corticotrophin releasing hormone (CRH) or desmopressin tests helps distinguishing pituitary from ectopic ACTH-dependent Cushing's syndrome, while bilateral petrosal sinus sampling remains the gold standard test and should be considered, if available, with the exception of the presence of a pituitary macroadenoma. It is prudent to perform a CT of the thorax, abdomen and pelvis in all patients. Transsphenoidal surgery is the first line treatment for Cushing’s disease, followed by radiotherapy as a second-line option. Adrenalectomy is the first-choice treatment for adrenal ACTH-independent Cushing’s syndrome and resection of the ACTH source should be performed for the ectopic ACTH-dependent Cushing’s syndrome, where possible. Bilateral adrenalectomy can always be considered as an option. Steroidogenesis inhibitors remain the most effective medical agents and are useful when surgery or the effects of radiotherapy are awaited or are unsuccessful.

INTRODUCTION

Cushing’s syndrome results from chronic exposure to excessive circulating levels of glucocorticoids. It is now more than one hundred years since Harvey Cushing reported the classical clinical syndrome that bears his name. Even now, its investigation and management can vex the most experienced endocrinologist. It may be difficult to miss the diagnosis in its most florid form but, given the high prevalence of many of its non-specific symptoms such as obesity, muscle weakness, and depression, clinicians are now required to consider the diagnosis in its earlier manifestations. The plethora of investigations often needed for the diagnosis and differential diagnosis has grown over the intervening century, and require careful interpretation. In its severe form and when untreated, the metabolic upset of Cushing's syndrome is associated with a high mortality. However, more subtle excesses of cortisol may also have significant effects on glycemic control and blood pressure, and may therefore be an important cause of morbidity. Treatment is often complex and may require all the modalities of surgery, radiotherapy. and medical management.

PATHOPHYSIOLOGY, ETIOLOGY, AND EPIDEMIOLOGY OF CUSHING’S SYNDROME

In normal physiology the final product of the hypothalamo-pituitary-adrenal (HPA) axis is the glucocorticoid cortisol, secreted from the zona fasciculata of the adrenal gland under the stimulus of adrenocorticotrophin (ACTH) from the pituitary gland. ACTH is secreted in response to corticotrophin-releasing hormone (CRH) and vasopressin from the hypothalamus. Cortisol exerts negative feedback control on both CRH and vasopressin in the hypothalamus, and ACTH in the pituitary. In normal individuals, cortisol is secreted in a circadian rhythm; levels fall during the day from a peak at 07.00h-08.00h to a nadir at around midnight: they then begin to rise again at 02.00h.

It is the loss of this circadian rhythm, together with loss of the normal feedback mechanism of the hypothalamo-pituitary-adrenal (HPA) axis, which results in chronic exposure to excessive circulating cortisol levels and that gives rise to the clinical state of endogenous Cushing's syndrome (1, 2). Any of the numerous synthetic steroids that have glucocorticoid activity, if administered in excessive quantities, can give rise to exogenous Cushing's syndrome. This is the commonest cause of Cushing's syndrome seen in general clinical practice, usually due to treatment for chronic conditions such as asthma or rheumatological disease. The clinician needs to carefully search for exogenous exposure to topical, inhaled, or injected forms of corticosteroids.

The etiology of Cushing's syndrome can broadly be divided into two categories, ACTH-dependent and ACTH-independent (Table 1).

ACTH-dependent forms are characterized by excessive ACTH production, which stimulates all three layers of adrenal cortex and results in bilateral adrenocortical hyperplasia and hypertrophy of adrenal gland. This results in increased weight of the adrenals, which often show micronodular or sometimes macronodular changes. Circulating glucocorticoids are increased and often, to a lesser extent, are accompanied by a rise in serum androgens.

ACTH-independent forms constitute a heterogeneous group characterized by low levels of plasma ACTH, either because of adrenal glucocorticoid hypersecretion or secondary to the exogenous administration of glucocorticoids. Except for adrenal adenomas, which usually secrete only glucocorticoids, among the other endogenous adrenal entities there is usually also a rise in androgens and sometimes steroid precursors. The microscopic and macroscopic appearance of non-affected adrenal tissue mainly depends on the etiology of the disorder.

Table 1. Etiology of Cushing's Syndrome
ACTH-dependent
Pituitary-dependent Cushing's syndrome (Cushing's disease)
Ectopic ACTH syndrome
Ectopic CRH syndrome (very rare)
Exogenous ACTH administration
ACTH-independent
Adrenocortical adenoma
Adrenocortical carcinoma
ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) – now known as bilateral macronodular adrenocortical disease (BMAD)(3)
Idiopathic micronodular adrenocortical disease (i-MAD)
Primary pigmented (micro)nodular adrenocortical disease (PPNAD, <1cm nodules), associated with Carney complex (c-PPNAD) or idiopathic (i-PPNAD)
McCune-Albright syndrome
Exogenous glucocorticoid administration

ACTH-Dependent Cushing's Syndrome

CUSHING’S DISEASE

Pituitary-dependent Cushing's syndrome, better known as Cushing's disease, is the most common cause of endogenous Cushing’s syndrome, accounting for 60-80% of all cases. Epidemiologic studies from Europe suggest an incidence of between 0.7 and 2.4 per million per year (4, 5). It presents much more commonly in women, usually between 25 and 40 years of age.

It is almost always due to a corticotroph adenoma (6, 7). Although apparent nodular corticotroph hyperplasia (in the absence of an CRH-producing tumor) has been described, it is rare in large surgical series (8, 9), and its existence is still debated. The majority of tumors are intrasellar microadenomas (<1 cm in diameter), although macroadenomas account for approximately 5-10% of tumors, and extrasellar extension or invasion may occur. True pituitary corticotroph carcinomas with extra-pituitary metastases causing Cushing's syndrome have also rarely been described (10, 11).

Despite much research, the molecular pathogenesis of corticotroph adenomas remains unknown, but the evidence supports the concept of primary pituitary rather than a hypothalamic disorder (12). However, recent data suggest that around one-third are due to a somatic mutation causing constitutive activation of USP8, a deubiquitinase which leads to increased expression of the EGF receptor on corticotrophs (13). Corticotroph adenomas could rarely be associated with familial syndromes such as MEN1, MEN2, Carney Complex, or familial isolated pituitary adenoma syndrome. Those are secondary to mutations in the menin gene (MEN1), the RET oncogene, PRKR1A and the AIP (gene coding for aryl hydrocarbon receptor-interacting protein) respectively (14). Very rarely, Cushing’s disease has been described in individuals with McCune-Albright and Beckwick-Wiedemann syndromes, where ACTH-independent CS is more common.

Up to 40 percent of older patients with long-existing Cushing’s disease develop ACTH-dependent macronodular adrenocortical hyperplasia. The adrenals tend to be enlarged, with occasional prominent nodules, but invariably with internodular hyperplasia (15, 16); the level of ACTH may be lower than anticipated, and recovery of the hypercortisolemia delayed after apparent removal of the pituitary tumor.

ECTOPIC ACTH SYNDROME AND ECTOPIC CRH TUMORS

Most other cases of endogenous ACTH-dependent Cushing’s syndrome, after excluding Cushing’ disease, are associated with non-pituitary tumors secreting ACTH, referred to as the ectopic ACTH syndrome. Ectopic sources of ACTH derive from a diverse group of tumor types, which can broadly be divided into the group of highly malignant carcinomas and the more indolent group of neuroendocrine tumors, although this may be thought of as a continuum rather than as a binary separation. This may not be evident from series at endocrine centers where often more occult tumors are investigated (Table 2), but bronchial neuroendocrine tumors tend to predominate and account for up to 25% of ectopic ACTH-dependent Cushing’s syndrome cases. The next in frequency is small-cell lung carcinoma, causing around 19% of ectopic Cushing's syndrome (17-19). Around 16% patients with an ectopic source of ACTH remain occult and require repeat imaging. The ectopic ACTH syndrome is more common in men, and usually presents after the age of 40 years, but should always be considered, even in children.

Table 2. Etiology of the Ectopic ACTH Syndrome in Patients (17-19)
Tumor type	Percentage of total Ectopic Cushing's syndrome cases reported in selected literature (n=398)
Lung carcinoma	18.8
Bronchial neuroendocrine tumor	25.4
Thymic neuroendocrine tumor	7.3
Medullary cell carcinoma	4.5
Pancreatic or gastrointestinal NET	11.8
Phaeochromocytoma/paraganglioma	3.8
NET of unknown primary	6.0
Occult tumor	16.1
Miscellaneous malignant tumors	6.3

NET - neuroendocrine tumor

The ACTH precursor molecule, pro-opiomelanocortin (POMC) is expressed not only in normal pituitary but also in several normal extra-pituitary tissues, as well as in some tumors (lung, testis) (20). The mechanism by which these non-corticotroph tumors express the POMC gene is not fully understood, but may be related to hypomethylation of the POMC promoter (21, 22). In general, such tumors tend to produce higher amounts of POMC compared to ACTH, in contrast to the situation in Cushing’s disease. As well as producing ACTH and POMC, these tumors may also produce other pre-ACTH precursor peptides, so-called "big" ACTH (23, 24), which may potentially be helpful in the differential diagnosis of these tumors (25). However, assays for these are not routinely available in clinical practice. Isolated ectopic CRH production is difficult to diagnose and exceedingly rare, with few confirmed cases described in the literature (26). In general, patients secreting CRH ectopically usually also secrete ACTH, rendering the distinction of little practical value.

ACTH-Independent Cushing’s Syndrome

ACTH-independent causes of Cushing’s syndrome, apart from exogenous glucocorticoids, encompass a heterogeneous group of diseases. The most common pathology is an adrenal adenoma or carcinoma. The latter may lack some of the classic histological features of malignancy, but can usually be differentiated on the basis of weight (more than 100g), nuclear pleomorphism, necrosis, mitotic figures, and vascular or lymphatic invasion. These features are incorporated in the Weiss score for the distinction between adenomas and carcinomas.

Adrenal adenomas occur most often around 35 years of age and are significantly more common in women, with an incidence of approximately 0.6 per million per year (5). The incidence of adrenal cancer is approximately 0.2 per million per year (5). It is one and a half times more common in women, and has a bimodal age distribution, with peaks in childhood and adolescence, and 40-50 years (1, 27). Approximately 50-60% of adrenocortical carcinomas secrete adrenal hormones of which the most common are glucocorticoids and adrenal androgens (28).

Bilateral macronodular adrenocortical disease (BMAD, previously known as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH)) is a rare form of Cushing’s syndrome with sometimes huge nodular (>5cm) adrenal glands with more than 1cm nodules on imaging. Most cases are sporadic, but a few familial cases have been reported (29). In most the etiology is unknown, but in a few cases the nodules have been shown to express increased numbers of receptors normally found on the adrenal gland, or ectopic receptors that then can stimulate cortisol production. Most present as subclinical CS. The best described example is food-dependent Cushing’s syndrome, in which ectopic glucose-dependent insulinotropic polypeptide (GIP) receptors on the adrenal glands respond to GIP released after a meal causing hypercortisolemia (30). Treatment with octreotide may ameliorate the syndrome (31); however, the effect decreases after few months due to down-regulation of somatostatin receptors in the intestine (32). Abnormal expression of vasopressin, b-adrenergic, luteinizing hormone/human chorionic gonadotrophin, serotonin, angiotensin, leptin, glucagon, IL-1, and TSH have also been described and functionally linked to cortisol production (32). BMAD tissue may express more than one of these aberrant receptors (33). Around one-third of patients with BMAD have been found to show inactivating germline mutations of the tumor suppressor gene ARMC5 (armadillo repeat containing protein 5), with each of the nodules demonstrating second independent hits in the same gene: familial forms of BMAD have been described (34). Heterozygous germline pathogenic variants in KDM1A gene encoding lysine-specific demethylase 1 have been reported in GIP-dependent Cushing’s syndrome in BMAD (35). In some individuals with BMAD, germline mutations in MEN1, FH (fumarate hydratase gene), and ACP (familial polyposis coli gene) have been found (36, 37)

Cushing’s syndrome due to bilateral nodular adrenal disease can also be a feature of McCune-Albright syndrome (38). The characteristic features are fibrous dysplasia of bone, café-au-lait skin pigmentation, and endocrine dysfunction: pituitary, thyroid, adrenal, or most commonly gonadal hyperfunction (precocious puberty). This condition is caused by an activating mutation in the GNAS gene encoding for the a-subunit of the G protein stimulating cyclic adenosine monophosphate (cAMP) formation. This occurs in a mosaic pattern in early embryogenesis (39). However, if this affects some adrenal cells the constitutive activation of adenylate cyclase leads to nodule formation and glucocorticoid excess. The normal adrenal cortex, where the mutation is not present, becomes atrophic (40, 41).

Primary pigmented nodular adrenal disease (PPNAD), otherwise known as micronodular adrenal disease, is another rare form of Cushing’s syndrome. It is characterized by small or normal-size adrenal glands with cortical micronodules (average 2–3 mm) that may be dark or black in color. The internodular cortex is usually atrophic, unlike in ACTH-dependent macronodular hyperplasia (42). Cases of PPNAD have been reported without Cushing’s syndrome. Bilateral adrenalectomy is curative. 70% of PPNAD occur as part of the Carney complex in association with a variety of other abnormalities, including myxomas of the heart, skin or breast, hyperpigmentation of the skin, and other endocrine disorders (sexual precocity; Sertoli cell, Leydig cell, or adrenal rest tumors; and acromegaly). Cushing’s syndrome occurs in approximately 30% of cases of Carney complex. The tumor suppressor gene PRKAR1A (type 1A regulatory subunit of protein kinase A) has been shown to be mutated in over 70% of patients with Carney complex. A few cases of pituitary corticotrophinoma have been identified in patients with Carney complex, one of them having both adrenal and pituitary Cushing’s syndrome (43, 44). In isolated PPNAD, mutations in PRKAR1A and also the phosphodiesterase 11A (PDE11A) gene have been demonstrated (45, 46).

A missense mutation of the ACTH receptor resulting in its constitutive activation and ACTH-independent Cushing’s syndrome has also been reported (47).

Other very rare causes of Cushing's syndrome have been reported: adrenal rest tissue in the liver, in the adrenal beds, or in association with the gonads which may produce hypercortisolemia, usually in the context of ACTH-dependent disease after adrenalectomy (48, 49). Ectopic cortisol production by an ovarian carcinoma has also been noted (50).

Exogenous Cushing’s Syndrome

The basis for iatrogenic Cushing’s syndrome was discussed earlier. The development of the features of Cushing’s syndrome depends on the dose, duration, and potency of the corticosteroids used in clinical practice. ACTH is rarely prescribed nowadays, but it will also result in Cushingoid features if administered long-term. Some features, such as an increase in intraocular pressure, cataracts, benign intracranial hypertension, aseptic necrosis of the femoral head, osteoporosis, and pancreatitis, are reported as more common in iatrogenic than endogenous Cushing’s syndrome, whereas other features, notably hypertension, hirsutism, and oligomenorrhoea/amenorrhea, are less prevalent. However, it is unclear as to whether these are true differences (51).

Pseudo-Cushing's Syndrome

Pseudo-Cushing's states are conditions in which a patient presents with clinical features suggestive of true Cushing's syndrome and with some biochemical evidence of hypercortisolemia. Both resolve after resolution of the predisposing condition. The pathophysiology has not clearly been established. Depression and alcohol abuse are the two most common such states (1).

CLINICAL MANIFESTATIONS OF CUSHING’S SYNDROME

The clinical manifestations in Cushing’s syndrome result from a chronic exposure to excess glucocorticoids and show a wide spectrum of abnormalities, from mild, subclinical disease to florid manifestations.

The classical impression of the disease in its most obvious form, as the association of gross obesity of the trunk with wasting of the limbs, facial rounding and plethora, hirsutism with frontal balding, muscle weakness, spontaneous bruising, vertebral fractures, hypertension and diabetes mellitus, is less commonly seen nowadays (Table 3) (52-54). More frequently, the clinical diagnosis may be equivocal because many symptoms common in Cushing's syndrome, including lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularity, are also very common in the general population. Therefore, it is useful to have an investigation strategy exploring the more specific features considering the diagnosis, most helpfully relating to the catabolic features of glucocorticoid excess. It is very helpful to notice the presence of several signs and symptoms, accompanied by a progressive course. Sequential photographs of the patient over many years can be extremely helpful in demonstrating progression to a Cushingoid state.

The clinical manifestations are usually determined by the duration and amplitude of glucocorticoid exposure, but in some aggressive cases of ectopic ACTH secretion, such as small cell carcinoma, symptoms of hypercortisolism are hard to detect because of the predominant malignant signs and symptoms such as weight loss and anorexia. The mean time to diagnosis of Cushing’s syndrome is reported as 34 months, and depends on the cause of glucocorticoid excess with shortest time to diagnosis in the ectopic Cushing’s syndrome (14 months), ACTH-independent CS (30months) and the longest with Cushing’s disease (38 months)(55).

The type of steroid excess is determined by the underlying condition. Adrenal adenomas generally secrete glucocorticoids, but in ACTH-dependent disease or a carcinoma hyperandrogenism is common.

Table 3. Presenting features of patients with Cushing’s syndrome (43-45)
Presenting features	Prevalence (% of patients)
Weight gain/obesity	81-97
Muscle weakness/tiredness	46-67
Round face	88-92
Skin thinning	84
Easy bruising	21-62
Edema	48-50
Purple wide striae	35-84
Hirsutism	56-81
Acne	19-64
Female balding	13-51
Dysmenorrhea	35-84
Reduced libido	33-100 (higher in men)
Hypertension	68-90
Mental health disorders	26-62
Recurrent infections	14-25
Diabetes/impaired glucose tolerance	43-50
Fractures	21-56

It is important to observe that combinations of Cushingoid features very much depend on the natural course of its underlying cause.

Patients with the ectopic ACTH syndrome usually present with severe and rapidly developing metabolic signs, most prominently anorexia, myopathy, and glucose intolerance. Because of severe hypercortisolemia and additional mineralocorticoid effect, hypokalemic alkalosis is found with peripheral edema on clinical examination. The combination of rapid clinical deterioration, hyperpigmentation, hypokalemic alkalosis, and clinical signs of mineralocorticoid excess should be indicative for suspicion of a small cell lung carcinoma secreting ACTH, or a high-grade bronchial carcinoid or pancreatic neuroendocrine tumor. In contrast, most patients with ACTH-producing low-grade bronchial carcinoids, because of the long duration of hypercortisolemia before clinical presentation, tend to develop all of the typical Cushingoid features, complicating its differentiation from Cushing’s disease.

Patients with adrenal carcinomas have a rapid onset of symptoms, and may complain of abdominal pain accompanied with a palpable tumor mass. In addition to hypercortisolism, they often secrete mineralocorticoids and androgens, therefore distinguishing them from benign adenomas which usually secrete cortisol alone (56). In women with androgen secreting ACC acne and hirsutism is usually readily apparent. However, increasingly, these tumors are discovered incidentally after routine scanning for other reasons.

In 10 percent of patients with adrenal incidentalomas, “subclinical” Cushing’s syndrome (currently called mild autonomous cortisol secretion, MACS) can be found; this is characterized by mild hypercortisolism without very obvious clinical manifestations of Cushing’s syndrome (57).

Unlike in men, where the main source of androgens is the testes, in women a substantial proportion of circulating androgens are adrenal in origin, such that the signs and symptoms of adrenal hyperandrogenism are readily diagnosed by symptoms of hirsutism and acne, and signs of virilization.

Obesity and weight gain are among the most common signs in Cushing’s syndrome. The distribution of fat can be useful, as typically in Cushing's syndrome there is increased visceral adiposity giving rise to truncal obesity, fat deposition in the cheeks and temporal fossae ("moon face"), dorsocervical area ("buffalo hump"), and supraclavicular fat pads (52, 58). Rarely, fat deposition in the epidural space can be manifest as a neurological deficit (59), while retroorbital deposition is noticeable as exophthalmos (60). In children, more generalized weight gain associated with growth retardation should highlight the possibility of the diagnosis (2). Other signs that are more discriminatory are proximal myopathy, wide purple striae, osteoporosis, thin skin, and easy bruising. Based on the screening study of 369 individuals with obesity, or weight in the overweight range, there were no reported cases of Cushing’s syndrome (61). Therefore, screening patients with generalized obesity and no specific features of Cushing’s syndrome is generally not recommended.

Myopathy of the proximal muscles of the lower limb and shoulder results from a catabolic glucocorticoid effect and is reported in 40-70% of patients with active Cushing’s syndrome. When assessing for myopathy it is useful to ask questions about function, typically affected by proximal muscle weakness, such as climbing stairs or getting up from a chair. Formal testing can be of leg extension whilst sitting, or rising unaided from a squatting position. Muscle weakness can be exacerbated by hypokalemia, as a result of concomitant mineralocorticoid activity; it is uncommon in pseudo-Cushing’s states (1). The myopathy may not fully recover after cure of hypercortisolism has been achieved (62).

Osteoporosis occurs in approximately 50% of adult patients with Cushing’s syndrome (63) and can be assessed by formal bone densitometry, or from a history of fractures, typically vertebral due to the preferential loss of trabecular bone induced by glucocorticoids. Glucocorticoids inhibit osteoblast function (64). Vertebral compression fractures lead to height loss. Rib fractures are often painless, with typical radiographic appearance of exuberant callus. Also, osteonecrosis (aseptic necrosis) of the femoral head has been described, usually in relation to iatrogenic Cushing’s syndrome following chronic high-dose glucocorticoid therapy (65). After successful treatment of the cause, bone density improves to a large extent (66-68).

There are many changes in the skin and subcutaneous tissue, which are rarely seen in the general population, suggesting the possibility of Cushing’s syndrome (1, 52). The result of hypercortisolemia is thinning of the skin, which is best tested over the dorsum of the hand, visible as “cigarette paper” (Liddle’s sign), but it is helpful to consider the age and gender of the patient as natural atrophy increases with age. In addition, skin thickness may be preserved in women with hyperandrogenemia related to Cushing's syndrome. The classic plethora (facial redness) is not only a consequence of skin thinning but also of a loss of a facial subcutaneous fat. Because subcutaneous fat and elastic tissue is also diminished, patients suffer easy bruising, which often can be misinterpreted as senile purpura or even a coagulation disorder. Purple-colored "violaceous" striae greater than 1 cm in diameter are almost pathognomonic of Cushing's syndrome (Figure 1). Typically seen on the abdomen, they can also occur in other areas, such as the thighs, breasts and arms. Narrow and colored striae are more commonly present, and should be differentiated from the typical healed ‘pearl’ striae seen most commonly post-partum.

Figure 1. The wide purple striae on the abdominal wall due to Cushing’s syndrome (patient permission obtained).

Increased fine non-pigmented vellus hair on the upper cheeks or forehead may be seen in Cushing’s syndrome, as well as more typical terminal hair hirsutism on the face and body, reflecting increased androgens. Cutaneous fungal infections as truncal tinea versicolor and onychomycosis are often found.

Skin hyperpigmentation is much more common in ectopic Cushing’s syndrome (most often from small cell lung carcinoma) than Cushing’s disease. It is also associated with the rapid onset of profound weakness, often with little or no weight gain, and an absence of a gross Cushingoid appearance. However, as noted above, other forms of the ectopic ACTH syndrome, particularly associated with neuroendocrine tumors, may be clinically indistinguishable from patients with other forms of hypercortisolism (69).

Severe hirsutism and virilization strongly suggest an adrenal carcinoma (70).

Hypercortisolism may suppress other pituitary hormones. In both men and women, hypogonadotrophic hypogonadism is common and correlates with the degree of hypercortisolemia (71). Glucocorticoids inhibit gonadotrophin–releasing hormone pulsatility and the release of luteinizing (LH) and follicle-stimulating hormone (FSH). Women experience menstrual irregularity, while both sexes have decreased libido. Gonadal dysfunction is reversible after correction of the hypercortisolemia (72). In addition, the coexistence of polycystic ovarian syndrome in Cushing’s syndrome is common (73). There is reduced GH secretion during sleep and blunted GH responses to dynamic stimulation tests (74). Thyrotrophin-releasing hormone and thyroid-stimulating hormone release has been shown to be disturbed, and in particular the nocturnal surge of thyroid-stimulating hormone is lost (75). This may not have a significant effect on free thyroid hormone levels during active hypercortisolemia, but there is a significantly increased prevalence of autoimmune thyroid disease in patients successfully treated for Cushing’s syndrome, and it is therefore important to follow them with serial thyroid function tests (76, 77).

Hypokalemic metabolic alkalosis is related to the degree of hypercortisolemia and represents a mineralocorticoid action of cortisol at the renal tubule due to saturation of the enzyme 11b-hydroxysteroid dehydrogenase type 2, which inactivates cortisol to cortisone and allows selective binding of aldosterone to the mineralocorticoid receptor (78). When this occurs, cortisol can now access the mineralocorticoid receptor and act as a mineralocorticoid. This hypersaturation occurs when urine free cortisol excretion is greater than about 4100 nmol per day (79). Therefore, although a more common feature of ectopic ACTH secretion, it may also occur in approximately 10% of patients with Cushing’s disease.

Cushing’s syndrome is characterized by insulin resistance and hyperinsulinemia. Glucose intolerance is evident in 20-64%, and overt diabetes mellitus in 30-47% of patients (80-83). Glucocorticoids stimulate glycogen deposition, promote gluconeogenesis, inhibit glucose uptake in peripheral tissues, activate lipolysis, and have a permissive effect on the counter-regulatory hormones, glucagon and catecholamines. An excess of cortisol also stimulates serum and glucocorticoids-inducible kinase-1 which raises the phosphorylation of the forkhead box protein O1 (FOXO1) in adipocytes, increasing insulin resistance (84). It has been suggested that 2-3% of overweight, poorly-controlled patients with diabetes may have occult Cushing’s syndrome (85, 86). However, in the absence of clinical suspicion the percentage is lower (87, 88), and therefore it is probably not justified to screen for Cushing’s in poorly-controlled diabetic patients unless other suggestive features are present (89). Hyperglycemia becomes easier to control after treatment of hypercortisolism and diabetes remits with cure of Cushing’s syndrome in the majority of patients (90). .

There is an increase in total cholesterol and triglyceride levels, and a variable effect on high-density lipoprotein (HDL). These changes are multifactorial, including cortisol effects on increased hepatic synthesis of very low density lipoprotein (VLDL), lipolysis, and free fatty acid metabolism (91, 92).

The major cause of mortality in Cushing’s disease are cardiovascular events, and patients exhibit direct markers of accelerated cardiovascular disease, including increased carotid artery intima-media thickness and atherosclerotic plaques (93) as well as hypertension, glucose intolerance, overt diabetes mellitus, dyslipidemia, and visceral obesity. Overall, hypertension is common in patients with Cushing’s syndrome (82). Severe hypertension with additional hypokalemia is more prevalent in ectopic Cushing’s syndrome, usually best controlled with spironolactone or related drug (94). Cardiovascular risk markers continue to be present long after cure of the hypercortisolemia (95) and the cardiovascular risk remains increased (96, 97). Sympathetic autonomic function is also abnormal in patients with Cushing's syndrome (98), and the ECG abnormalities of a prolonged QTc dispersion and left ventricular hypertrophy have been identified as characteristic features in patients with Cushing's disease (99).

Hypercortisolemia increases clotting factors including factor VIII, fibrinogen, and von Willebrand factor, and reduces fibrinolytic activity by elevated plasminogen activator inhibitor-1 and antiplasmin. This along with other risk factors such as obesity, surgery, and invasive investigative procedures, results in a significantly increased risk of thrombotic events in patients with Cushing's syndrome (100). Rates of thromboembolic events, either postoperatively or unrelated to surgery, are 18-fold higher in patients with Cushing’s syndrome than the estimated incidence in an age and sex matched control population (101, 102). Venous thromboembolism (VTE) has been reported in 20% of patients with Cushing’s syndrome who did not receive thromboprophylaxis, at a mean follow-up of 6-9 years (103). In contrast, VTE occurred in only 6% of patients who received a therapeutic dose of unfractionated heparin at least for 2 weeks after any surgery. The hypercoagulable state may persist even up to 12 months of Cushing’s syndrome remission, and some experts recommend thromboprophylaxis from 24 hours following surgery; however, there is no clear evidence substantiating the duration of thromboprophylaxis (104). The recent Pituitary Society guidelines recommended use of thromboprophylaxis with low molecular weight heparin in patients undergoing surgery for Cushing’s syndrome and having an additional risk for VTE such us previous VTE, use of estrogens, reduced mobility, and severe hypercortisolism; however, there is no consensus on the duration of VTE prophylaxis (105). This ranged from 2-14 days before surgery to 2 days - 3months after surgery.

Ophthalmic complications include glaucoma and exophthalmos due to retroorbital fat deposition (106). Cataract is rare, mostly a complication of diabetes.

Psychiatric symptoms such as insomnia, depression, anxiety, easy irritability, paranoid episodes, and attempted suicide or panic attacks are present in more than half of patients having any cause of Cushing’s syndrome (107, 108). Cognitive defects as learning, cognition, and impairment of short-term memory may be prominent (109, 110). These changes are not always reversible with treatment.

In patients with Cushing's syndrome there is a greater frequency of infections because of inhibition of immune function by glucocorticoids by decreasing the number of CD4 cells and NK cells and inhibition in cytokine synthesis (111), with predominant effects on cell-mediated immunity (Th1 responses). The most common infections are bacterial, and special attention should be pointed to the possibility of opportunistic pathogens, especially in cases of severe hypercortisolism (112).

Some cases of ACTH-dependent Cushing's syndrome occur in a periodic or cyclical form, with intermittent and variable cortisol secretion, the symptoms and signs waxing and waning according to the active periods of the disease. These patients can cause particular diagnostic difficulty, as it is imperative that the diagnostic tests are performed in the presence of hypercortisolemia to allow accurate interpretation. Patients may 'cycle in' or 'cycle out' over periods of months or years; if at presentation they are eucortisolemic, they will need regular re-evaluation usually with urinary free cortisol or late-night salivary cortisol to allow full investigation at the appropriate time. Cyclicity can in fact occur with all causes of Cushing’s syndrome (113).

BIOCHEMICAL CONFIRMATION OF CUSHING’S SYNDROME

As stated above, there are many clinical features in various combinations in Cushing’s syndrome, but a small number of relatively pathognomonic ones, such as myopathy, wide purple striae, skin thinning and bruising, usually suggest the need for biochemical investigation. The basis for establishing the diagnosis of Cushing’s syndrome is biochemical confirmation of hypercortisolism, prior to any test of the differential diagnosis in terms of a specific cause.

Hypercortisolemia together with the loss of the normal circadian rhythm of cortisol secretion, and disturbed feedback of the HPA axis, are the cardinal biochemical features of Cushing's syndrome. Almost all tests to confirm the diagnosis are based upon these principles. Furthermore, to screen for Cushing's syndrome, tests of high sensitivity should be used initially so as to avoid missing milder cases. Tests of high specificity can then be employed to exclude false positives. In moderate to high clinical probability of Cushing’s syndrome, 2-3 different screening tests should be used, while if the probability of CS is low 1 negative test such as an overnight dexamethasone suppression test is generally sufficient (105).

It is important to realize that the validation of the published test criteria employed have been on specific assays, and thus test responses should ideally be validated on the local assay used before the results can be interpreted in particular patients. This is aided by supra-regional and nationwide inter-assay quality control assurance programs (1).

Cortisol is normally secreted in a circadian rhythm, with the highest levels early in the morning (07.00-08.00h) and reaching their nadir levels at about midnight (<50 nmol/L or 1.8 μg/dL). In patients with Cushing’s syndrome the circadian rhythm is lost. However, many patients still maintain their morning values within the normal range, but have raised nocturnal levels, rendering midnight levels most useful diagnostically. The measurement of free serum cortisol is very challenging, so either levels of salivary cortisol or total serum cortisol are used. However, exogenous oral estrogens and some medical conditions (see below) will increase cortisol-binding globulin and therefore total cortisol levels. Hence, in all investigations relying on a serum cortisol assay that measures total cortisol, hormone replacement therapy or the oral contraceptive pill should be stopped 4-6 weeks prior to investigation, although it is likely that a shorter time off treatment may still be effective.

Late Night Salivary Cortisol

Late-night salivary cortisol measurement accurately reflects the plasma free cortisol concentration, because cortisol-binding globulin (CBG) is absent from saliva. Loss of the circadian rhythm of cortisol secretion by measuring late night-time salivary cortisol (best taken at bedtime as nadir salivary cortisol level is detected at the time of falling asleep) can be utilized as a sensitive screening test for Cushing’s syndrome. Due to the simple non-invasive collection procedure which can conveniently be performed at home, and the fact that salivary cortisol is stable for days at room temperature, it offers a number of attractive advantages over blood collection, particularly in children or in cyclical Cushing’s syndrome. Due to variability, taking at least 2 samples on different days is recommended and patients should be advised not to eat, drink, smoke or brush teeth at least 15 minutes before saliva collection. Understandably, this test should not be used in the night-shift workers and individuals with a variable work pattern. Assays using a modification of the plasma cortisol radioimmunoassay, enzyme-linked immunosorbent assay, or liquid chromatography tandem mass spectrometry are now widely available.

Over the past decade there has been considerable increasing interest in this test and it was used in 28% of patients with Cushing’s syndrome from a European registry of 1341 patients diagnosed in 2000-2016 and included in the ERCUSYN registry (114). It has been evaluated at a large number of centers worldwide. In a meta-analysis of multiple studies, in adult patients the sensitivity and specificity of the late-night salivary cortisol appears to be relatively consistent in different centers, and overall is 92% and 96% respectively (115). However, it should be noted that the diagnostic value cut-off varies between studies because of different assays and the comparison groups studied. Late-night salivary cortisol used as a screening test had a somewhat lower sensitivity of 88-89% in subjects from the ERCUSYN registry. Normal values also differ between adults and pediatric populations, and may be affected by other comorbidities such as diabetes (116), and the method by which the saliva is collected (117). Not surprisingly, this test performs less well in patients with ‘subclinical Cushing's syndrome’ (118). Salivary cortisol has also been evaluated as the endpoint for the overnight dexamethasone suppression test. This has the potential benefit in terms of convenience but requires further evaluation (119). Salivary cortisol has also been advocated as a sensitive tool to detect recurrence or treatment failure in patient’s post-pituitary surgery for Cushing's disease (120, 121).

In summary, late-night salivary cortisol appears to be a useful and convenient screening test for Cushing's syndrome, particularly in the outpatient setting. However, local normal ranges need to be validated based on the assay used and population studied.

Urinary Free Cortisol

Measurement of urinary free cortisol (UFC) is a non-invasive test that is most commonly used in the screening of Cushing's syndrome (performed in 78% of individuals in the ERCUSYN registry) (114). Under normal conditions, 5-10% of plasma cortisol is 'free' or unbound and physiologically active. Unbound cortisol is filtered by the kidney, with the majority being reabsorbed in the tubules, and the remainder excreted unchanged. As serum cortisol increases in Cushing’s syndrome, the binding capacity of CBG is exceeded and a disproportionate rise in UFC is seen. Thus, 24-hour UFC collection produces an integrated measure of serum cortisol, smoothing out the variations in cortisol during the day and night. In a series of 146 patients with Cushing's syndrome, UFC measurement was shown to have a sensitivity of 95% for the diagnosis (122). However, within this series 11% had at least one of four UFC collections within the normal range, which confirmed the need for multiple collections (at least 2-3 collections are recommended). Furthermore, this sensitivity figure is based on the more florid cases, and is likely to be much less for the more common subtle cases now being seen (123). In the ERCUSYN registry UFC was reported to show 86% sensitivity in adrenal and ectopic Cushing's syndrome and 95% in Cushing’s disease (114).

The major drawback of the test is the potential for an inadequate 24-hour urine collection, and written instructions must be given to the patient. Also, multiple collections reduce the possibility of overlooking episodic cortisol secretion. In addition, simultaneous creatinine excretion in the collection should be measured to assess completeness, and should equal approximately 1g/24 hours in a 70kg patient (variations depend on muscle mass). This should not vary by more than 10% between collections in the same individual (70). The cortisol to creatinine ratio in the first urine specimen can be used as a screening test, especially when cyclic secretion is suspected (124), with a cortisol to creatinine ratio over 25 nmol/mmol being suggestive of Cushing’s syndrome.

The 24-hour UFC is of little value in the differentiation from pseudo-Cushing's states (125, 126).

High-performance liquid chromatography or tandem mass spectrometry are now used to measure UFC, which overcomes the previous problem with conventional radioimmunoassays of cross-reactivity of some exogenous glucocorticoids and other structurally similar steroids (127). Drugs such as carbamazepine, digoxin, and fenofibrate may co-elute with cortisol during high-performance liquid chromatography and cause falsely elevated results (128).

In summary, UFC measurements have a high sensitivity if collected correctly, and several completely normal collections make the diagnosis of Cushing's syndrome very unlikely. Values greater than four-fold normal are rare except in Cushing's syndrome. For intermediate values the specificity is somewhat lower, and thus patients with marginally elevated levels require further biochemical assessment (1, 123). It is our opinion that the test is of little use for screening, and in general we rarely utilize it as a 1^st line screening test nowadays.

Low-Dose Dexamethasone Suppression Test (LDDST)

This test works on the principle that in normal individual’s administration of an exogenous glucocorticoid results in suppression of the HPA axis, whilst patients with Cushing's syndrome are resistant, at least partially, to negative feedback. Dexamethasone is a synthetic glucocorticoid that is 30 times more potent than cortisol, and with a long duration of action. It does not cross-react with most cortisol assays. The original low-dose dexamethasone test (LDDST) described by Liddle in 1960 measured urinary 17-hydroxy-corticosteroid after 48 hours of dexamethasone 0.5mg 6 hourly (129). However, the simpler measurement of a single plasma or serum cortisol at 09.00h has been validated in various series, and gives the test a sensitivity of between 95% and 100% (123, 130).

The overnight dexamethasone suppression test (ONDST) was first proposed by Nugent et al. in 1965; this measures a 09.00h plasma cortisol after a single dose of 1mg dexamethasone taken at midnight (131), and is thus considerably easier to perform. Since then, various doses have been suggested for the overnight test, between 0.5 and 2mg, and various diagnostic cut-offs have been used (132, 133). There appears to be no advantage in discrimination between 1mg and 1.5mg or 2mg (134). Although higher doses have been tried, the increased suppression in some patients with Cushing's syndrome significantly decreases the sensitivity of the test (135). The 1mg ONDST was used in 60% of the subjects in the European registry of Cushing's syndrome (n=1341) and had the best performance among screening tests, with a sensitivity of 98-99% (114).

In a comprehensive review of the LDDST, both the original 2-day test and the overnight protocol appear to have comparable sensitivities (98-100%) using the criteria of a post-dexamethasone serum cortisol of <50nmol/L (1.8μg/dl) (136). However, the specificity is greater for the 2-day test (95-100%) compared to the overnight test (88%) (136).

If the ONDST test is used, we suggest that a dose of dexamethasone 1mg to be given at midnight and a threshold of cortisol <50nmol/L (1.8 μg/dl) at 09.00h will rarely lead to the diagnosis being missed, but false positives remain significant. In general, the overnight test is an excellent screening test, and we use the 48 hours LDDST as a confirmation test.

It may be useful to measure the dexamethasone level when ONDST is positive to exclude interference of other medications acting as CYP3A4 inducers causing fast metabolism of dexamethasone and subsequent false positive results (see below), although such measurements are not readily available. Another reason for the false positive results on LDDST is increasing cortisol-binding globulin (seen in pregnancy, estrogens users or chronic active hepatitis).

It should be noted that patients with PPNAD may show a paradoxical rise in cortisol levels to dexamethasone (137).

Second Line Tests

In some patients with equivocal results, other tests may be needed. The most useful of these are a midnight serum cortisol, LDDST as described above, and the dexamethasone-CRH test. Less reliable tests include the insulin tolerance test and the loperamide test (138). The desmopressin test is discussed below.

MIDNIGHT SERUM CORTISOL

Before the introduction of salivary cortisol, measurement of a midnight serum cortisol was the only reliable method used to determine loss of the circadian rhythm of cortisol secretion. It is still useful as a second-line test in cases of diagnostic difficulty. However, it is a burdensome test that requires that the patient should have been an in-patient for at least 48 hours to allow acclimatization to the hospital environment. The patient should not be forewarned of the test, and should be asleep prior to venipuncture, which must be performed within 5-10 minutes of waking the patient. A single sleeping midnight plasma cortisol <50nmol/L (1.8 μg/dL) effectively excludes Cushing's syndrome (139), but false positive results do occur, particularly in the critically ill, in acute infection, heart failure, and in the pseudo-Cushing's state associated with depression (140).

An awake midnight cortisol of greater than 207 nmol/L (7.5 mg/dL) was reported to show 94% sensitivity and 100% specificity for the differentiation of Cushing's syndrome from pseudo-Cushing's states (141). In the ERCUSYN cohort, 62% individuals with Cushing's syndrome had this test performed with a reported sensitivity of 96-99% (114).

This test has been currently replaced by LNSC and in most hospitals with high demand for the in-patient medical beds, investigations for CS are done mainly on an out-patient environment.

DEXAMETHASONE-CRH TEST

In 1993 the combined dexamethasone-CRH (Dex-CRH) test was introduced for the difficult scenario of the differentiation of pseudo-Cushing’s states (currently known as non-neoplastic hypercortisolism) from true Cushing’s syndrome in patients with only mild hypercortisolemia and equivocal physical findings (125). The theory is that a small number of patients with Cushing's disease as well as normal individuals will show suppression to dexamethasone, but those with Cushing's disease should still respond to CRH with a rise in ACTH and cortisol afterwards. In the original description of the test, dexamethasone 0.5 mg every 6 hours was given for eight doses, ending 2 hours before administration of ovine CRH (1 µg/kg intravenously) to 58 adults with UFC less than 1000 nmol/day (360 µg/day). Subsequent evaluation proved 39 to have Cushing’s syndrome and 19 to have a pseudo-Cushing’s state. The plasma cortisol value 15 minutes after CRH was less than 38 nmol/L (<1.4 µg/dL) in all patients with pseudo-Cushing’s states and greater in all patients with Cushing’s syndrome. A prospective follow-up study by the same group in 98 patients continued to show the test to have an impressive sensitivity and specificity of 99% and 96%, respectively (125). Importantly, in these two studies although eight of 59 patients with proven Cushing's disease showed suppression to dexamethasone, all were correctly characterized after CRH. However, the results from a number of other smaller studies have challenged the diagnostic utility of this test over the standard LDDST. Overall, in these reports the specificity of the LDDST in 92 patients without Cushing's syndrome was 79%, versus 70% for the Dex-CRH. The sensitivity in 59 patients with Cushing's syndrome was 96% for the LDDST versus 98% for the Dex-CRH (142). It is perhaps not surprising that the diagnostic utility of the Dex-CRH has altered with further studies at more centers. There are a number of reasons why there might be the case: variable dexamethasone metabolism in individuals; different definitions of patients with pseudo-Cushing's; different protocols and assays; and variable diagnostic thresholds. It is recommended that if this test is used, a dexamethasone level is measured at the time of CRH administration and the serum cortisol assay is accurate down to these low levels (89). We would not recommend its use, and indeed with the lack of availability of CRH currently, it is generally impossible to perform.

DESMOPRESSIN TEST

ACTH-secreting adenomas express V3 receptors therefore desmopressin increases ACTH and subsequently cortisol in patients with Cushing’s disease. The test involves intravenous injection of 10mcg of desmopressin and ACTH measurement every 15 minutes from -15minutes to 90minutes. The study of 173 subjects including 76 with Cushing’s disease, 30 with non-neoplastic hypercortisolism, 36 with obesity and 31 of controls proposed cut-off criteria for positive desmopressin test as ACTH increment of >6pmol/L (30ng/L) (143). Subsequently, another study of 52 patients with Cushing’s syndrome and 28 controls suggested new criteria with ACTH increment of 4pmol/L and basal cortisol above 331nmol/L providing sensitivity of 90.3% and specificity of 91.5% (144). The meta-analysis of 3 studies described use of desmopressin test in differentiation of Cushing’s disease and non-neoplastic hypercortisolism with cut-off for ACTH increment by 6 pmol/L in 2 studies and ACTH increment of 4 pmol/L and basal cortisol more than 331nmol/L gave pooled sensitivity of 88% and specificity of 94% (143-145). However, there was high patient selection bias and low certainty of evidence in that meta-analysis (145).

DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROME

Once Cushing's syndrome has been diagnosed, the next step is to differentiate between ACTH-dependent and ACTH-independent causes by measurement of plasma ACTH. Modern two-site immunoradiometric assays are more sensitive than the older radioimmunoassays and therefore provide the best discrimination. Rapid collection and processing of the sample is essential as ACTH is susceptible to degradation by peptidases so that the sample must be kept in an ice water bath and centrifuged, aliquoted, and frozen within 2 hours to avoid a spuriously low result. Measurements are usually taken on two different days to avoid misinterpretation because of the episodic secretion of ACTH. The circadian rhythm of ACTH in patients having Cushing’s syndrome is lost, as it is for cortisol measurement, and the optimal sample should be taken at 08.00-09.00h (146).

It is useful to repeat this test because patients with ACTH-dependent Cushing’s disease have been shown to have on occasion ACTH levels less than 10 ng/L (2 pmol/L) on conventional radioimmunoassay (147). The ACTH immunoassays can interfere with heterophilic antibodies or ACTH fragments and cases of falsely elevated ACTH have been reported using the Immulite ACTH assay (148). Therefore, if results are inconsistent or not in keeping with the clinical or imaging features, ACTH should be remeasured using an alternative immunoassay.

Consistent ACTH measurements of <10 ng/L (2 pmol/L) essentially confirm ACTH-independent Cushing's syndrome, and radiologic evaluation of adrenals is the next step in diagnosis. Conversely, if levels are consistently greater than 20-30 ng/L (4-6 pmol/L), Cushing's syndrome is ACTH-dependent, due to pituitary disease or ectopic ACTH secretion.

Intermediate levels are less discriminatory, but a lack of ACTH response to the CRH test or the desmopressin test (see below) may be particularly helpful in these intermediate cases.

Investigating ACTH-Independent Cushing's Syndrome

Imaging of the adrenal glands is the mainstay in differentiating between the various types of ACTH-independent Cushing's syndrome. High-resolution computed tomography (CT) scanning of the adrenal glands is the investigation of choice, is accurate for masses greater than 1 cm, and allows evaluation of the contralateral gland (149). MRI may be useful for the differential diagnosis of adrenal masses; the T2-weighted signal is progressively less intense in phaeochromocytoma, carcinoma, adenoma, and finally normal tissue (150).

Adrenal tumors typically appear as a unilateral mass with an atrophic contralateral gland (151). If the lesion is greater than 5 cm in diameter it should be considered to be potentially malignant until proven otherwise, and discussed in the local adrenal Multidisciplinary Team meeting (MDT). In comparison to carcinomas, adrenal adenomas are usually smaller and have a lower unenhanced CT attenuation value (usually <20HU) (152). Adrenal adenomas are homogeneous and hypointense on MRI T1-weighted images and iso- or hyperintense comparing to the liver on T2 images. Adrenal adenomas also demonstrate signal drop on out-of-phase MR imaging consistent with lipid-rich tissue. Signs of necrosis, hemorrhage and calcification are characteristics of both carcinoma and phaeochromocytomas, which can also co-secrete ACTH (153). Additional laboratory diagnostics reveal solely raised cortisol levels in adenomas, unlike additionally raised androgen levels in adrenocortical carcinomas. Bilateral adenomas can be present (154).

In PPNAD the adrenal glands appear normal or slightly lumpy from multiple small nodules, but are not generally enlarged (150, 155).

Exogenous administration of glucocorticoids results in adrenal atrophy and very small glands may be a clue as to this entity.

BMAD is characterized by bilaterally large (>5 cm) adrenals with a nodular configuration (15, 156).

Confusion can arise as the CT appearance of the adrenals in BMAD may be similar to the appearance seen in ACTH-dependent forms of Cushing's syndrome, where adrenal enlargement is present in 70% of cases (157), but the two can usually be distinguished by the ACTH level and the degree of adrenal enlargement. Some patients with Cushing's disease can also develop a degree of adrenal autonomy which can cause biochemical confusion (16).

Identifying the Source in ACTH-Dependent Cushing's Syndrome

This has been one of the most significant challenges in the investigation of Cushing's syndrome in the past, although advances over the last 15 years have greatly improved our diagnostic capability. Cushing's disease accounts for by far the majority of cases of ACTH-dependent Cushing's syndrome, between 85% and 90% in most series. In the European registry of Cushing’s syndrome (n=1341), 67% of cases were due to pituitary disease and, of ACTH-dependent Cushing's syndrome , 92% were of pituitary origin (54).This depends on gender, and in the series of 115 patients with ACTH-dependent Cushing's syndrome, of the 85 women, 92% had Cushing's disease; this percentage was 77% in the 30 men (158). Therefore, even before one starts investigation, the pretest probability that the patient with ACTH-dependent Cushing’s syndrome has Cushing's disease is very high, and any investigation must improve on this pretest likelihood. However, as transsphenoidal pituitary surgery is widely accepted as the primary treatment of Cushing's disease, testing should be designed to avoid inappropriate pituitary surgery in patients with ectopic ACTH production. Thus, any test should ideally be set with 100% specificity for the diagnosis of Cushing's disease.

Levels of serum cortisol and ACTH tend to be higher in the ectopic ACTH syndrome, but there is considerable overlap of values, producing poor discrimination (158, 159). Hypokalemia is more common in ectopic ACTH-dependent Cushing's syndrome than in patients with Cushing’s disease.

INVASIVE TESTING

Bilateral Inferior Petrosal Sinus Sampling

This is the "gold standard" test for distinguishing between Cushing's disease and an ectopic source of ACTH. However, most experts agree that if a pituitary macroadenoma (tumor of ³ 10mm) is visualized on MRI and dynamic tests (hCRH/desmopressin) are consistent with Cushing’s disease, Bilateral inferior petrosal sinus sampling (BIPSS) is not necessary (105).The procedure involves placement of sampling catheters in the inferior petrosal sinuses that drain the pituitary. Blood for measurement of ACTH is obtained simultaneously from each sinus and a peripheral vein at two time points before and at 3-5 minutes and possibly also 10 minutes after the administration of 100mcg of human CRH if available, or nowadays 10mg desmopressin. A central (inferior petrosal) to peripheral plasma ACTH gradient of 2:1 or greater pre-desmopressin, or a gradient of 3:1 post-desmopressin (previously post-CRH), is consistent with Cushing's disease. The results from early series show these criteria to be 100% sensitive and specific for Cushing’s disease when CRH stimulation was used (160, 161). However, it is now clear that false negative tests and to a smaller degree false positive test results do occur (162-164). A meta-analysis including 23 studies and 1642 patients with ACTH-dependent Cushing's syndrome reported that IPSS had sensitivity of 94% and specificity of 89% with area under the ROC curve of 97% to diagnose Cushing’s disease again all with CRH stimulation (165).

In order to minimize these inaccuracies it is important to ensure the patient is actively hypercortisolemic (as above) at the time of the study (166), and that catheter position is confirmed as bilateral and any anomalous venous drainage noted by venography before sampling (167). There appears to be no discriminatory difference between ovine or human sequence CRH; however, as CRH is no longer available, desmopressin 10 μg shows similar efficacy (168). The study with 226 patients with Cushing’s disease and 24 patients with ectopic ACTH-dependent CS who underwent BIPSS with desmopressin stimulation achieved sensitivity of 97.8% and specificity of 100% when ACTH ration >2.8 was applied (169). However, it has been noted that for all with >6mm pituitary microadenoma on MRI baseline ACTH ratio of >1.4 distinguished all with Cushing’s disease without need for desmopressin stimulation. The meta-analysis of 11 studies including 611 patients compared BIPPS with CRH versus DDAVP stimulation and found no statistical difference in the results with pooled sensitivity of 96 % for desmopressin and 98% for CRH with 100% specificity (170). None of the studies using desmopressin reported subsequent hyponatremia when fluid restriction in the next 24hs has been followed.

It should be noted that the procedure is technically difficult, and should only be performed by radiologists experienced in the technique. The most common complications are transient ear discomfort or pain, and local groin hematomas. More serious transient and permanent neurological sequelae have been reported, including brainstem infarction, although these are rare (<1%), and most have been related to a particular type of catheter used (171, 172); if there are any early warning signs of such events the procedure should be immediately halted. Patients should be given heparin during sampling to prevent thrombotic events (82). There appears to be no advantage in trying to sample the cavernous sinus. Sampling of the internal jugular veins is a simpler procedure but is not as sensitive as BIPSS (173).

A baseline inferior petrosal sinus (IPS) to peripheral prolactin ratio of >1.8 has been suggested as a confirmation of a successful catheterization (174). A multicenter study including 156 individuals with ACTH-dependent Cushing’s disease who underwent IPSS reported that IPS to peripheral ACTH to prolactin ratio of ³1.4 improved further BIPSS performance in differentiating Cushing’s disease from ectopic ACTH-dependent CS with sensitivity of 96% and specificity of 100% (175), but not all are agreed that this extra level of analysis is worthwhile.

BIPSS has also been suggested to help to lateralize microadenomas within the pituitary using the inferior petrosal sinus ACTH gradient (IPSG), with a basal or post-stimulus inter-sinus ratio of at least 1.4 being the criteria for lateralization used in all large studies (161, 162, 176, 177). In these studies, the diagnostic accuracy of localization as assessed by operative outcome varied between 59% and 83%. This is improved if venous drainage is assessed to be symmetric (178). A study of 501 cases of Cushing’s disease showed that an interpetrosal ACTH ratio of ≥1.4 was achieved in 98% of patients but lateralized the lesion correctly in only 69% of subjects. A pituitary lesion was identified on the pre-operative MRI in 42% of patients in that study and, if seen, had a positive predictive value of 86% (179). Hence, the interpetrosal ratio can guide pituitary exploration in cases of a normal pre-surgery MRI scan. In this study, MRI was falsely positive in 12% of individuals.

An enhanced dynamic MRI has a better detection rate of pituitary microadenomas than conventional MRI and was reported to identify a pituitary lesion in 81% (83 out of 102) of patients with Cushing’s disease and lateralized correctly the pituitary adenoma in 62 out of 71 patients with histologically-proven Cushing's disease (180).

The accuracy of lateralization appears to be higher in children (90%), a situation where imaging is often negative (181). There is some discrepancy between studies as to whether CRH or desmopressin improve the predictive value of the test (182). If a reversal of lateralization is seen pre- and post-stimulus, the test cannot be relied upon (183).

NON-INVASIVE TESTS

High Dose Dexamethasone Suppression Test

As with the LDDST, the high dose dexamethasone suppression test (HDDST) was originally proposed by Liddle to differentiate between cortisol-secreting adrenal tumors and Cushing's disease (129). The HDDST’s role in the differential diagnosis of ACTH-dependent Cushing’s syndrome is based on the premise that most pituitary corticotroph tumors retain some albeit reduced responsiveness to negative glucocorticoid feedback, whereas ectopic ACTH-secreting tumors, like adrenal tumors, typically do not, with the exception of some neuroendocrine tumors, mainly bronchial (184, 185).

The test is performed according to the same protocol as the LDDST, either as 2mg 6 hourly for 2 days, or as an overnight using a single dose of 8mg of dexamethasone at 23.00h. The latter is more convenient for a patient because a single blood specimen is being tested on the next day at 08.00h. In most patients with pituitary-dependent Cushing’s syndrome, the final serum cortisol level is less than 5 mcg/dL (140 nmol/L). In normal subjects the level is usually undetectable (186).

Overall, only about 80% of patients with Cushing's disease will show a positive response to the test, defined by suppression of cortisol to less than 50% of the basal value. There are a high number of false positive tests (~10-30%) seen in ectopic Cushing’s syndrome (186-189). Shifting the criteria can only increase sensitivity with a loss of specificity, and vice-versa. Therefore, the test achieves worse discrimination than the pretest probability of Cushing's disease. In addition, one study has shown that suppression to HDDST can be inferred by a >30% suppression of serum cortisol to the 2-day LDDST (190). Therefore, we no longer recommend the routine use of the HDDST except when bilateral inferior petrosal sinus sampling is not available, and then only as part of a combined testing strategy with other tests. (see below).

The HDDST was performed in 30% of subjects (n=402) from the European registry of patients with Cushing's syndrome, with a cortisol reduction supporting the diagnosis of pituitary Cushing's syndrome in 92% and ectopic Cushing's syndrome in 93% of patients (specificity not given) (114). When used in individuals with negative IPSS, HDDST supported the diagnosis of pituitary disease in 100% and ectopic Cushing's syndrome in 82%.

The combined use of the HDDST and enhanced dynamic MRI of the pituitary was compared to BIPSS in 71 patients with histologically-proven Cushing's disease (180). The combination had a 98.6% positive predictive value (PPV) for Cushing's disease but a sensitivity of only 69.6%. In that study BIPSS alone had a similar PPV of 97%.

The CRH Test

Both ovine and human-sequence CRH are currently unavailable in most countries, and the test has been superseded by desmopressin. However, as it may become available in the future, the following section may be useful.

The use of the CRH (corticotrophin-releasing hormone) test for the differential diagnosis of ACTH-dependent Cushing's syndrome is based on the premise that pituitary corticotroph adenomas retain responsivity to CRH, while ectopic ACTH tumors lack CRH receptors and therefore do not respond to the agent. 100 µg of human sequence CRH (hCRH) is given as a bolus injection and the change in ACTH and cortisol measured. Human-sequence CRH has qualitatively similar properties to oCRH, although it is shorter-acting with a slightly smaller rise in plasma cortisol and ACTH in obese patients, and in those with Cushing's disease (191). This may be related to the more rapid clearance of the human sequence by endogenous CRH-binding protein (192).

Different centers have used differing protocols, including type of CRH and sampling time-points, and thus there is little consensus on a universal criterion for interpreting the test. In one of the largest published series of the use of oCRH, an increase in ACTH by at least 35% from a mean basal (-5 and -1 minutes) to a mean of 15 and 30 minutes after oCRH in 100 patients with Cushing's disease and 16 patients with the ectopic ACTH syndrome gave the test a sensitivity of 93% for diagnosing Cushing’s disease, and was 100% specific (193). Conversely, in the large series of the use of hCRH in 101 patients with Cushing's disease and 14 with the ectopic ACTH syndrome, the best criterion to differentiate Cushing's disease from ectopic ACTH syndrome was a rise in cortisol of at least 14% from a mean basal (-15 and 0 minutes) to a mean of 15 and 30 minutes, giving a sensitivity of 85% with 100% specificity. The best ACTH response was a maximal rise of at least 105%, giving 70% sensitivity and 100% specificity (158). In a multicentered analysis from Italy, both hCRH and oCRH were used in 148 patients with Cushing's disease and 12 with the ectopic ACTH syndrome. A maximal 50% increase in ACTH and cortisol levels were considered as consistent with Cushing's disease, excluding all patients with the ectopic ACTH syndrome and thus giving 100% specificity. The sensitivity and specificity for the ACTH response were comparable for the two types of CRH (sensitivity: 85% vs 87% for oCRH and hCRH respectively).

A CRH test was performed in 351 patients with ACTH-dependent Cushing's syndrome from the European registry of Cushing's syndrome, with a peak ACTH supporting the diagnosis of Cushing's disease in 90% of cases and ectopic Cushing's syndrome in 84% of patients (114). However, the sensitivity for the cortisol response was significantly greater with oCRH than with hCRH (sensitivity: 67% vs 50% for oCRH and hCRH respectively) (194). The authors do not report in this paper or an associated publication (27) whether time-point combinations other than the maximal were analyzed for the rise in cortisol. Indeed, our data showed that if the maximal rise in cortisol is used the sensitivity falls to 71% (158). These results again demonstrate that specific criteria need to be developed for each test, and cannot readily be extrapolated from other similar but non-identical agents.

In summary, the CRH test has been a useful discriminator between causes of ACTH-dependent Cushing's syndrome, particularly in a combined testing strategy with the HDDST or LDDST when diagnostic accuracy is greater than that of either test alone, yielding 98% to 100% sensitivity, and an 88% to 100% specificity (187, 190, 195). Which cut-off to use should be evaluated at individual centers, and caution should be exercised as there will undoubtedly be patients with the ectopic ACTH syndrome who respond outside these cut-offs. However, it should be remembered that responses to both CRH and high-dose dexamethasone are more frequently discordant in Cushing's disease due to a macroadenoma (196). Nevertheless, where BIPSS is unavailable, a response to both CRH (a rise) and the LDDST (a fall) renders an ectopic source extremely unlikely.

Desmopressin Test

Both vasopressin and desmopressin (a synthetic long-acting vasopressin analogue without the V1-mediated pressor effects) stimulate ACTH release in Cushing’s disease, probably through the corticotroph-specific V3 (or V1b) receptor. The study of 170 patients including 149 with Cushing’s disease reported that an ACTH increase after desmopressin by more than 32.4% provided sensitivity of 83% but specificity of 62%, which was inferior to HDDST (197). The meta-analysis of 11 studies using DDAVP in the differential diagnosis of ACTH-dependent Cushing’s syndrome reported that combination of an ACTH increase of >35% and a cortisol increase of >20% including 511 individuals had a pooled sensitivity of 88% and specificity of 74% to correctly diagnose Cushing’s disease (145).

Hexarelin, a growth hormone secretagogue, stimulates ACTH release probably occurs through stimulation of vasopressin release in normal subjects (198), and by stimulation of aberrant growth hormone secretagogue receptors in corticotroph tumors (199).

These peptides have been utilized in a similar manner to CRH to try and improve the differentiation of ACTH-dependent Cushing’s syndrome, but have unfortunately proved inferior (200-202).

A combined desmopressin and hCRH stimulation test initially looked promising (203), but further study of this combined test showed significant overlap in the responses (204). The inferior discriminatory value of these stimulants is most likely due to the expression of both vasopressin and growth hormone secretagogue receptors by some ectopic ACTH-secreting tumors (82, 205).

A retrospective study including 167 patients with Cushing’s disease and 27 patients with ectopic ACTH-dependent CS reported 100% positive predictive value for diagnosing Cushing’s disease when both CRH-stimulation test and DDAVP stimulation test were positive when the pituitary MRI scan and CT scan for ectopic source were negative. The positive test was defined as an ACTH increment of >33% and cortisol increment of >18% after administration of desmopressin and ACTH increment of 37% and cortisol >18% after administration of CRH (206). The negative predictive value was 100% when both tests were negative and pituitary MRI was negative but CT for ectopic source of ACTH positive. The authors concluded that this strategy would avoid IPSS in 47% of the patients.

IMAGING

Pituitary

Imaging of the pituitary is an important part of the investigation of ACTH-dependent Cushing's syndrome to identify a possible pituitary lesion and to aid the surgeon during exploration. However, the results must be used in conjunction with the biochemical assessment as approximately 10% of normal subjects may have pituitary incidentalomas on MRI (207). Modern MRI techniques using T1-weighted spin echo and/or spoiled gradient recalled acquisition (SPGR, 1mm slice thickness) techniques will identify an adenoma in up to 80% of patients with Cushing’s disease (208). They provide greater sensitivity than conventional MRI but with more false positive results (208, 209). On MRI, 95% of microadenomas exhibit a hypointense signal with no post-gadolinium enhancement (Figure 2); however, as the remaining 5% have an isointense signal post-gadolinium, pre-gadolinium images are essential (210). The delayed pituitary microadenoma contrast washout was detected on FLAIR MRI as hyperintensity in 80% of patients with Cushing's disease and negative dynamic MRI (n=5) (211, 212).

If corticotroph microadenoma has not been clearly identified with modern MRI techniques, ¹¹C-methionine PET co-registered with 3D gradient echo MRI may help in selected cases (213). The main limitation of this technique is short half-life of isotope of around 20min and it requires cyclotron on the site.

CT has a sensitivity of only approximately 40-50% for identifying microadenomas, and is thus significantly inferior to MRI (sensitivity 50-60%) (27, 214), and it should therefore be reserved for patients in whom MRI is contraindicated or unavailable. CT imaging typically shows a hypodense lesion that fails to enhance post-contrast.

Preoperative localization to one side of the pituitary gland by MRI had been advocated as better than BIPSS with a positive predictive value of 93% (163, 215). Other groups have found MRI less effective (162, 216). In addition, as noted above, we have found MRI often to be unhelpful in the pediatric age group, and BIPSS to be of significant value in these patients (181).

Figure 2. Magnetic resonance scan of the head with gadolinium showing left-sided pituitary hypointense microadenoma (white arrows) in 2 different patients (T1 image post-contrast).

Ectopic Tumors

Visualizing an ectopic ACTH source can be a challenge, but in general patients should begin with imaging of the chest and abdomen with CT and/or MRI, bearing in mind likely sites (Table 2). The most common site of the secretory lesion is the chest, and although small cell lung carcinomas are generally easily visualized, small bronchial carcinoid tumors that can be less than 1cm in diameter often prove more difficult. Fine-cut high-resolution CT scanning with both supine and prone images can help differentiate between tumors and vascular shadows (1). MRI can identify chest lesions that are not evident on CT scanning, and characteristically show a high signal on T2-weighted and short-inversion-time inversion-recovery images (STIR) (217).

The majority of ectopic ACTH secreting tumors are of neuroendocrine origin and therefore may express somatostatin receptor subtypes. Therefore, the radiolabeled somatostatin analogue (¹¹¹In-pentetreotide) scintigraphy may be useful to show either functionality of identified tumors, or to try and localize radiologically unidentified tumors (218). Undoubtedly this is a useful technique, but to date there are only sporadic reports that it identifies lesions not apparent using conventional imaging (219, 220). However, a lesion of uncertain pathology is more likely to represent a neuroendocrine tumor, and hence an ectopic source of ACTH, if somatostatin scintigraphy is positive. Unless the tumors are metabolically active, which is not usually the case, ¹⁸F-deoxyglucose positron-emission tomography (FDG-PET) does not generally offer any advantage over conventional CT or MRI (221, 222). However, ⁶⁸Ga-DOTA-conjugated peptides (octreotide, lanreotide or octreotide) PET scanning, targeting SST receptors 1-5, is more sensitive than conventional octreotide scintigraphy and is indicated in the detection of primary occult neuroendocrine tumors (NETs) when conventional imaging modalities have failed (223). In a systematic review of small studies including a total of 77 patients with ectopic Cushing’s syndrome, the detection rate of the tumor was 70% for ⁶⁸Ga-labelled peptide PET and 61% for ¹⁸F-FDG PET (224). Subsequent systematic review of ⁶⁸Gallium-DOTATATE, DOTATOC, and DOTANOC positron emission tomography/computed tomography (⁶⁸Ga-SSTR PET/CT) in detecting ectopic ACTH-secreting tumors had a pooled sensitivity of 64%, increasing to 76% in histologically confirmed lesions (225). ⁶⁸Ga-somatostatin receptor analogues had better sensitivity in the diagnosis of bronchial carcinoids causing Cushing’s syndrome, while ¹⁸F-FDG PET appeared superior for small-cell lung cancers and other aggressive tumors (226).

STRATEGY FOR THE DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF CUSHING’S SYNDROME

There have been a number of international consensus statements published for the diagnosis and differential diagnosis of Cushing's syndrome, the latest on the diagnosis in 2021 (82, 89, 105). It is recommended that UFC (at least two measurements), the LDDST, or late-night salivary cortisol (two measurements) are used as the first line screening test. A second test should confirm abnormal results on one test (Figure 3).

Figure 3. Investigations algorithm for suspected Cushing’s syndrome; CS – Cushing’s syndrome, ONDST – overnight dexamethasone suppression test, UFC – urinary free cortisol, LDDST – low dose dexamethasone suppression test, HDDST – high dose dexamethasone suppression test, BIPSS – bilateral inferior petrosal sinus sampling, PPNAD – primary pigmented nodular adrenocortical disease, BMAD - bilateral multinodular adrenocortical disease.

In patients with discordant results second-line tests should be used as necessary for confirmation. Once the diagnosis of Cushing’s syndrome is unequivocal, ACTH levels, the desmopressin test (combined with the results of the LDDST), together with appropriate imaging, are the most useful non-invasive investigations to determine the etiology. BIPSS is recommended in cases of ACTH-dependent Cushing’s syndrome where the clinical, biochemical, or radiological results are discordant or equivocal. However, in many centers where BIPSS is available and validated, the practice is to use this test in almost all cases of ACTH-dependent Cushing’s syndrome with the exception of corticotroph macroadenomas, although the Bordeaux group have indicated that the use of dynamic testing plus high-quality imaging can reduce the necessity for BIPSS to some 50% of cases (206).

TREATMENT OF CUSHING’S SYNDROME

Treatment should be directed toward resolving the primary cause of Cushing’s syndrome, presuming accurate differential diagnosis. Hypercortisolism, accompanied with fatal consequences if left untreated, should be controlled by all means. Whenever possible, surgery, regardless of etiology, presents a first-line treatment option aiming for a permanent cure and resolving the hypercortisolism together with its clinical consequences. However, the approach to the patient with Cushing’s syndrome is individual, so radiation therapy or even medical therapy as first-line treatment could be appropriate depending on etiology, clinical state, and the personal choice of a patient.

Following treatment, all of the signs and symptoms of adrenal deficiency should be promptly corrected with steroid replacement therapy. Associated medical disorders of Cushing’s syndrome such as diabetes mellitus, hyperlipidemia, osteoporosis, and hypertension should be treated, aiming to avoid permanent dependence on therapy after resolving the primary cause of Cushing’s syndrome.

It should also be emphasized that in severely-unwell patients the metabolic complications should be vigorously treated as a matter of priority, including hypokalemia, hypertension, and hyperglycemia. Any infections should be sought and treated, and some would advise prophylactic antibiotics (especially against pneumocystis infections) if the serum cortisol is especially high (>1000-1200 nmol/L). Most importantly, most centers would now advise immediate anti-coagulation with prophylactic low molecular weight heparin peri-operatively in all but the mildest cases or unless there are contraindications (227).

Treatment of Cushing’s Disease

First-line therapy almost always comprises transsphenoidal surgery (Figure 4). Patients with persistent Cushing’s post-operatively can be re-operated with a lower success rate than primary surgery and with higher rates of other pituitary hormonal deficiencies. Prior to repeated surgery it is wise to repeat diagnostic testing, especially if corticotrophinoma has not been found on pathologic examination, to exclude the possibility of missed ectopic ACTH syndrome. Besides re-operation, patients can be treated either by radiotherapy, medical therapy, or as a definitive solution to the hypercortisolism, bilateral adrenalectomy.

TRANSSPHENOIDAL SURGERY

According to the relevant 2021 consensus statement on the treatment of ACTH-dependent Cushing's syndrome (105, 228, 229), transsphenoidal surgery is widely regarded as the treatment of choice for Cushing’s disease (229). Besides the traditional microscopic approach there is an endoscopic approach which appears useful in patients with persistent or recurrent disease (230, 231) and is associated with a shorter hospital stay (232), and is now most often utilized. It is recommended to limit the number of surgeons performing transsphenoidal surgery to increase the number of operations performed per surgeon per year and have one dedicated surgeon per center for treatment of Cushing’s disease. The surgeons who have performed 200 transsphenoidal operations have the best outcomes and the lowest complication rates (233). The Pituitary Society consensus recommends that surgery for Cushing’s disease should be performed in the Pituitary Tumor Centers of Excellence when possible (105). The remission rate of Cushing’s disease due to pituitary microadenoma is similar for both techniques (around 80%, total n=6695), with better results in pituitary macroadenomas when using endoscopic approach (59.9% vs 76.3%) (234).

The procedure is not without risks, and in the European Cushing’s disease survey group of 668 patients, the perioperative mortality was 1.9%, with other major complications occurring in 14.5% (235). The frequency of reported adverse events varies widely: diabetes insipidus (AVP-deficiency, either temporary or permanent) (3-46%); hypogonadism (14-53%); hypothyroidism (14-40%); cerebrospinal fluid rhinorrhea (4.6-27.9%); severe growth hormone deficiency (13%); bleeding (1.3-5%); and meningitis (0-2.8%) (235-237).

Where an adenoma is apparent at transsphenoidal exploration, a selective microadenomectomy of tumor tissue is performed, and the surgeon may be guided by pre-operative imaging. However, where no tumor is obvious, and there is no concern regarding fertility, subtotal resection of 85-90% of the anterior pituitary gland should be considered, leaving a small part near the pituitary stalk. However, there is still a substantial and unpredictable risk of panhypopituitarism.

The overall remission rate combined for microadenomas and macroadenomas in various large series is in the order of 70-79%, although higher rates of approximately 90% can be achieved with microadenomas (8, 234-236, 238-242) (241). Remission rates are based on post-operative pathologic and biochemical results, although both can be equivocal. Half of all tumors cannot be pre-operatively visualized (243), and therefore parts of the tumor can be overlooked intra-operatively and left behind, affecting the surgical success rate (244). Adenomas can occur near or within the pituitary stalk, rarely in ectopic locations (245, 246), and may show signs of microscopic invasion (247).

Prognostic markers of long-term remission are patient age over 25 years, a microadenoma detected by MRI, lack of invasion of the dura or cavernous sinus, histological confirmation of an ACTH-secreting tumor, low post-operative cortisol levels, and long-lasting adrenal insufficiency (228, 241). (242, 248).

Figure 4. Management algorithm of Cushing’s disease; TSA, Transsphenoidal adenomectomy; CD, Cushing’s disease.

Of patients achieving remission, some 10-15% of these will have a recurrence by 10 years and 20% by 20 years (249), this emphasizing the need for long-term annual follow-up based on the same diagnostic criteria as with initial diagnostics in the following order; salivary late-night cortisol, an overnight 1 mg dexamethasone suppression test, and lastly 24hours UFC (105). Special attention should be paid to patients with intermittent hypercortisolism (250). Transsphenoidal surgery is also a useful procedure in patients with Nelson’s syndrome to reduce tumor size, and ameliorate hyperpigmentation (251).

Thromboprophylaxis with low molecular weight heparin should be considered peri-operatively in all surgical procedures for Cushing's syndrome (100, 101, 105). The recent Pituitary Society guidelines recommended use of thromboprophylaxis with low molecular weight heparin in patients undergoing surgery for Cushing’s syndrome and especially having an additional risk for VTE such us previous VTE, use of estrogens, reduced mobility and severe hypercortisolism; however, there is no consensus on duration of VTE prophylaxis (105). Our practice is generally to consider LMW heparin prophylaxis in all patients, and to continue for some 2-3 months post-operatively.

POST-OPERATIVE EVALUATION AND MANAGEMENT

Many use glucocorticoid coverage for transsphenoidal surgery, tapering off within 1 to 3 days. Morning (09.00h) serum cortisol measurements are then obtained on day 4 or 5 post-operatively starting 20 hours after the last glucocorticoid administration, during which time the patient should be closely observed for the development of signs of adrenal insufficiency (252). However, where there is close post-operative supervision, it may be possible to assess early cortisol results in the absence of corticosteroid cover.

In the immediate post-operative period, there is a wide range of possible biochemical results. Post-operative hypocortisolemia (<50 nmol/L [1.8 µg/dL] at 09.00h) is probably the best indicator of the likelihood of long-term remission (253-255). However, detectable cortisol levels of less than 140 nmol/L (<5µg/dL) are also compatible with sustained remission (256-258). In cases of a mild or cyclic Cushing’s disease the normal corticotrophs may not be suppressed and sustain a normal cortisol level with a normal diurnal rhythm.

Higher post-operative cortisol levels are more likely to be associated with failed surgery; however, cortisol levels may sometimes gradually decline over 1-2 months reflecting gradual infarction of remnant tumor or a gradual loss of autonomy of the adrenal, reported in some 5% of patients (256, 259). Regardless of the possibility of this late remission, the approach should be individualized and additional testing done prior to 3 months if there is reason to believe in residual disease. Persistent cortisol levels greater than 140 nmol/L (>5 µg/dL) 3 months after surgery require further investigation. Persistent hypercortisolemia after transsphenoidal exploration should prompt reevaluation of the diagnosis of Cushing’s disease, especially if previous diagnostic test results were indeterminate or conflicting, or if no tumor was found on pathological examination.

The treatment options for patients with persistent Cushing’s disease include: repeat surgery, radiation therapy, and bilateral adrenalectomy. If immediate surgical remission is not achieved at the first exploration, early repeat transsphenoidal surgery including the endoscopic technique may be worthwhile in a significant proportion of patients (approximately 50%), at the expense of an increased likelihood of hypopituitarism (231, 260, 261). Repeat sellar exploration is less likely to be helpful in patients with empty sella syndrome or very little pituitary tissue on MRI scans. Patients with cavernous sinus or dural invasion identified at the initial procedure are not candidates for repeat surgery to treat hypercortisolism and should receive alternative therapy.

Patients who are hypocortisolemic should be started on glucocorticoid replacement. Eventually, hydrocortisone 15-20 mg total daily dose in three divided doses is the preferred choice by most. The largest dose (10 mg) should be taken before getting out of bed, and the last 5mg dose should be taken in early afternoon and no later than 18.00h because later administration of glucocorticoids may result in disordered sleep. This low dose of hydrocortisone should be used to avoid long-term suppression of the HPA axis. All patients receiving chronic glucocorticoid replacement therapy should be instructed that they are “dependent” on taking glucocorticoids as prescribed, and that failure to take or absorb the medication could lead to adrenal crisis and possibly death. They should be prescribed a 100mg hydrocortisone (or other high-dose glucocorticoid) intramuscular injection pack for emergency use. They should also obtain a medical information bracelet or necklace that identifies this requirement (Medic-Alert Foundation or similar). Education should stress the need for compliance with the daily dose of glucocorticoid; the need to double the oral dose for nausea, diarrhea, and fever; and the need for parenteral administration and medical evaluation during emesis, trauma, or severe medical stress.

The patient should be told to expect desquamation of the skin, and flu-like symptoms (malaise, joint aching, anorexia, and nausea) during the early post-operative months, and that these are signs that indicate remission. Symptoms can be especially prominent in patients with long-standing, severe Cushing’s syndrome. Some of these symptoms have been related to high levels of circulating interleukin-6 (262). Most patients tolerate these symptoms of glucocorticoid withdrawal much better if they are forewarned and alerted to their ‘positive’ nature. Signs of adrenal insufficiency, such as vomiting, electrolyte abnormalities, and postural hypotension, should be excluded (263). However, if patients develop severe symptoms of glucocorticoids withdrawal significantly affecting their quality of life, an initial higher dose of hydrocortisone replacement can be prescribed e.g. starting with double dose and tapering down to the total 20mg daily over 2-3 months (264).

Recovery of the HPA axis can be monitored by measurement of 09.00h serum cortisol after omission of hydrocortisone replacement for 20 hours. Because recovery after transsphenoidal surgery rarely occurs before 3-6 months and is common at 1 year, initial testing at 3-4 to 9 months is reasonable (122). If the cortisol is undetectable on 2 consecutive days, then recovery of the axis has not occurred and glucocorticoid replacement can be restarted. If the cortisol is >100nmol/L, adequate reserve of the HPA axis can be assessed using the insulin tolerance test (231), with a peak cortisol value of greater than 500 nmol/L (>18 µg/dL), indicating adequate reserve (265), although this value may need to be revised downwards with more recent assays. Many centers use the cortisol response to 250 µg synthetic (1-24) ACTH (Short Synacthen Test) as an alternative means of assessing HPA reserve (266, 267), but there is some controversy as to its reliability in this situation (267, 268) and it is certainly not recommended in the first 6 weeks post-surgery. If it is used instead of the insulin tolerance test, a 30-minute cortisol is most reliable (265), but the cut-off value for a ‘passed’ SST can vary between laboratories and assays (430-550nmol/L). Glucocorticoid replacement can be discontinued abruptly if the cortisol response is shown to be normal. Where recovery of the HPA axis is only partial on dynamic testing, but the 09.00h cortisol levels are above the lower limit of the normal range (200 nmol/L [7 µg/dL]), it is reasonable to slightly lower the hydrocortisone dose and repeat SST in 3-6 months unless symptoms of adrenal insufficiency occur. Patients need to continue to be aware of the continuing need for additional glucocorticoids at times of stress or illness and should be given a supply of oral hydrocortisone and an intramuscular injection pack. Assessment of adequate replacement of hydrocortisone dosing by measuring serum cortisol at various points throughout the day, ensuring that levels are always sufficient (>50 nmol/L [>1.8 µg/dL]) before each dose, is useful. This may mean that the peak levels after each dose appear to be unphysiological, but there is a trade-off between mirroring a normal physiologic rhythm as far as possible and the inconvenience of multiple dosing. Modified release hydrocortisone may provide more physiological replacement (269).

Two further conundrums may arise: the questions of recurrence and permanent lack of recovery of the axis. Life-long monitoring for recurrence of hypercortisolism is required (270). The evaluation of recurrence should start after the recovery of HPA axis has been confirmed and continue annually along clinical assessment. Patients who articulate that the Cushing’s syndrome has returned are often correct, even before physical and biochemical evidence are unequivocal. Investigation is warranted in a patient with these complaints or with recurrent physical signs characteristic of hypercortisolemia. Measurement of late-night salivary cortisol (at least 2 samples on different days) is most sensitive for detecting recurrence (105, 271), followed by 1mg dexamethasone suppression test and 24hours UFC (again at least 2-3 collections).

If recurrent Cushing’s disease is diagnosed, the therapeutic options are the same as for persistent disease. Repeat transsphenoidal surgery should be offered for recurrence of Cushing’s disease if tumor is visible on MRI, ACTH-staining from 1^st operation confirmed a corticotroph adenoma or the initial IPSS was consistent with Cushing’s disease (272, 273). The remission rates from re-operation are reported between 37% and 88% with increasing risk of complications (241). Predictors of remission were post-operative cortisol of <55nmol/L (<2ng/dL), and operation for recurrence rather than persistent disease. It should be remembered when investigating recurrence that long-standing ACTH stimulation by a pituitary adenoma causing macronodular adrenal hyperplasia may subsequently involve semi-autonomous cortisol production (274).

The patient who has a subnormal cortisol response to ACTH 3 years after transsphenoidal surgery (in the absence of over-replacement) is likely to proceed to life-long ACTH deficiency, but this is also highly indicative of a lack of recurrence long-term.

Post-operatively, assessment for deficiencies of other pituitary hormones should also be sought, and the appropriate replacement regimen initiated as necessary, especially growth hormone deficiency in children.

Diuresis is common after transsphenoidal surgery and may result from intraoperative or glucocorticoid-induced fluid overload or may be due to AVP deficiency. For these reasons, assessment of paired serum and urine osmolality and the serum sodium concentration is essential. It is advisable to withhold specific therapy unless the serum osmolality is greater than 295 mOsm/kg, the serum sodium is greater than 145 mmol/L, and the urine output is greater than 200 mL/hour with an inappropriately low urine osmolality. Desmopressin (DDAVP, Ferring) 0.5-1 µg given subcutaneously will provide adequate vasopressin replacement for 12 hours or more.

Hyponatremia may occur in as many as 20% of patients within 10 days of surgery. This may be due to injudicious fluid replacement or the syndrome of inappropriate antidiuretic hormone secretion (SIAD) as is frequently seen after extensive gland exploration, and fluid intake should be restricted (275).

While transient central diabetes insipidus is common, in about 20% of operations (276), a small minority of patients proceed to permanent AVP deficiency, requiring long-term treatment with a vasopressin analogue. The state of permanent diabetes insipidus is usually accompanied by other anterior pituitary hormone deficiencies (277).

Many glucocorticoid-induced abnormalities, including hypokalemia, hypertension, and glucose intolerance, may be normalized during the post-operative period so that preoperative treatments for these need to be reassessed.

BILATERAL ADRENALECTOMY

Bilateral adrenalectomy is also an important therapeutic option in patients with ACTH-dependent Cushing’s syndrome not cured by other techniques, particularly in young patients desiring fertility where there are concerns over radiotherapy-induced hypopituitarism. However, it has the disadvantages of life-long glucocorticoid and mineralocorticoid replacement therapy, and increased peri-operative morbidity and mortality (although these complications should be extremely low following laparoscopic adrenalectomy in experienced centers). The incidence of adrenal crisis following bilateral adrenalectomy throughout life is reported higher than in patients with Addison’s disease or ACTH deficiency (9.3 events per 100 patients versus 3-6 events/100 patients) (278). In the post-operative period after bilateral adrenalectomy, the hydrocortisone dose should be maintained at 50mg of hydrocortisone four times a day by intravenous/intramuscular injection or 200mg per 24 hours in continuous intravenous infusion (279). When no complications are seen after 48 hours post-operatively, the dose of hydrocortisone is reduced to the double replacement dose (40 mg total/day). At this stage, fludrocortisone 100-200mcg daily orally should be introduced.

In addition, the development of Nelson’s syndrome in patients with ACTH-secreting pituitary adenomas occurs in between 28% and 53% of cases (280-283) at a mean time of 5.3 years following surgery. The chance of developing Nelson’s syndrome (later renamed as “corticotroph tumor progression after bilateral adrenalectomy”) appears to be greater if adrenalectomy is performed at a younger age, and if a pituitary adenoma is confirmed at previous pituitary surgery (280, 284). Prophylactic pituitary radiotherapy probably reduces the risk of developing Nelson’s syndrome (280). However, it may be best to hold radiotherapy in reserve and undertake regular MRI scanning of the pituitary, especially when imaging has originally not shown any clear tumor (285). The expert consensus recommends MRI scanning at 3 months then 12-monthly for 3 years after bilateral adrenalectomy and every 2-4 years afterwards (283). New or worsening skin hyperpigmentation should prompt ACTH measurement and pituitary MRI. The ACTH threshold proposed as a cut-off for diagnosis of Nelson’s syndrome is not agreed and varies between 200 and 700pg/mL (44-154pmol/L, taken before the morning dose of hydrocortisone) with progressive increase of ACTH being more indicative (283). Others have advocated unilateral adrenalectomy plus pituitary irradiation as an alternative to bilateral adrenalectomy, as it gives similar remission rates to primary transsphenoidal surgery (286), but this should be reserved for selected cases. Transsphenoidal surgery for corticotroph tumor progression should be considered as first-line treatment before extrasellar expansion occurs with radiotherapy as second-line treatment if appropriate following multi-disciplinary team discussion (283). There is no established medical treatment in Nelson’s syndrome, and single case reports of aggressive tumors suggest some response to temozolomide (287, 288). A recurrence of hypercortisolism following bilateral adrenalectomy due to growth of rest adrenal tissue with persistent ACTH stimulation is reported in <10% of cases (105).

PITUITARY RADIOTHERAPY

For patients in whom fertility does not represent an important issue and with uncertain preoperative localization, radiotherapy may be used as primary treatment, while in patients showing no signs of remission after transsphenoidal resection of a tumor, pituitary irradiation is one of the next treatment options. It may also be considered as primary therapy for children under age 18 years, because results are comparable to surgery (289, 290). Pituitary irradiation may also decrease the occurrence of Nelson's syndrome (“corticotroph tumor progression after bilateral adrenalectomy”) after medical or surgical adrenalectomy, but this has not been tested in a prospective randomized trial (291).

Primary pituitary radiotherapy for the treatment of Cushing’s disease in adults has been shown to produce rather poor long-term remission rates of around 50% (249, 292). In contrast, as a second-line therapy to failed pituitary surgery, better results are achieved with around 80% showing long-term remission as defined by the normalization of the clinical state and biochemical parameters (293, 294). In children, however, not only primary therapy shows better results with cure rate of 80%, but also they respond more rapidly, usually within 12 months (290), while remission in adults usually occurs by two years although it can take considerably longer. Medical therapy to control hypercortisolemia is usually utilized in the interim, and patients should be reassessed at least yearly (295). In order to evaluate results of pituitary irradiation, urinary free cortisol or several serum cortisol levels throughout the day are measured and medical therapy should be stopped for several consecutive days, followed upon patient education of early recognition signs and symptoms of adrenal insufficiency in outpatient conditions.

Conventional pituitary radiotherapy using a linear accelerator is delivered at a total dose of 45 to 50 Gy in 25 fractional doses over 35 days using a 3-or 5-field (opposed lateral fields and vertex field) technique. Side effects when given as primary therapy are rare, but there is significant risk of growth hormone deficiency occurring early in 36-68% of treated adults, while other anterior pituitary deficiencies may develop over time in around 20% of patients (96, 293, 296). There is some evidence of an increased risk of cerebrovascular complications, which is of concern particularly in younger patients (297), but not all studies agree and further studies are required (298). The incidence of ischemic infarcts after fractionated radiotherapy for pituitary adenomas was reported in the mean of 6.7% of patients (0-11.6%) in the systematic review of 11 studies including 4394 patients. Four studies on complications of gamma-knife surgery described no ischemic events (299) (see below). The risk of optic neuropathy is low and probably less than 1% as long as low-dose fractions are used. Although meningiomas and gliomas have been reported after pituitary radiotherapy (295, 300), a recent analysis suggests that external beam radiotherapy induces second tumors in around 4% of patients with pituitary tumors compared to 2% in controls (301) .

Stereotactic radiotherapy using a gamma-knife or Cyber-knife (‘radiosurgery’) is used to optimize the tumor dose and minimize radiation to other areas by delivering a single high dose (average dose of 20-25Gy) to a small tumor. This approach seeks to avoid the complications of optic neuritis and cortical necrosis associated with larger total and fractional doses (302), not to mention convenience for the patient receiving therapy in one treatment. It has been less well investigated so far, but has a number of theoretical advantages, including a possible reduction in risk of cerebrovascular disease. It is hard to make a direct comparison in effectiveness between methods because of the difference in size of the treated tumors (302, 303). Most patients still develop endocrine deficiencies in the years after treatment (304-306). Because of the high dose of delivered radiation, it is not suitable for large lesions because of the large volume of exposed tissue, or for lesions near to radiosensitive tissues, such as the optic chiasm or optic nerves (recommended at least 3-5mm distance), because of the potential for visual damage. Otherwise, if the adenoma is not close to the optic pathway, it may be superior to conventional fractionated therapy. Gamma knife radiosurgery is probably the most widely used of these techniques. As adjunctive therapy after failed transsphenoidal surgery it achieves biochemical remission in about 48-55%, although follow-up times have not been as long as for conventional radiotherapy (296, 306, 307). It can also be used as salvage therapy in difficult tumors (307, 308). Radiosurgery of the pituitary gland using proton beams has similar efficacy as second-line therapy (309), and while possibly more precise is not widely available. Cyber-knife radiotherapy for Cushing’s disease is less well described, but there are reports of some success in a small number of patients (310). As with other forms of radiotherapy, new hormone deficiencies are the major side-effect. It should be emphasized again that stereotactic radiotherapy cannot be used when the tumor is close to the optic chiasm. There is a difference in tolerance of radiation between cranial nerves, with optic nerves most sensitive. A dose above 8Gy should be avoided and a clearance of 3-5mm from the optic nerves is required, while for other cranial nerves doses of 19-23Gy are acceptable (311). Data on the use of proton beam therapy are sparse, but in time this may come to replace other forms of radiosurgery (312).

Treatment for the Ectopic ACTH Syndrome

If the ectopic ACTH-secreting tumor is non-metastatic and amenable to surgical excision, such as in a lobectomy for a bronchial carcinoid tumor, the chance of cure of Cushing’s syndrome is high.

Local radiotherapy following surgical resection of an ectopic ACTH-secreting source, may also be beneficial, particularly in non-metastatic thoracic carcinoid tumors (313, 314), but is not usually required. The course of the disease is mainly determined by the type of tumor, the presence of metastases, and degree of hypercortisolism. The lowest survival rate comes with small cell lung cancer, medullary thyroid cancer, and gastrinomas (17, 18). In patients with metastases solely in the liver, cryoablation, resection, or even liver transplantation can be curable. Prognosis is the best in patients younger than 50 years of age, with primary bowel or lung carcinoids (19, 315, 316). However, if significant metastatic disease is present, surgery is not curative, although it may still be of benefit in selected cases. Therapy for residual or metastatic disease should be based on current guidelines for neuroendocrine tumors (317).

Regardless of the prognosis, control of the hypercortisolism should be established medically by inhibiting steroidogenesis. If medical management fails, surgical bilateral adrenalectomy may be an option, but should be at least considered in the majority of cases where long-term treatment of the neuroendocrine tumor is considered. Patients in whom control over hypercortisolism is established can develop thymic hyperplasia (318), which should be distinguished from tumor metastases or a primary thymic tumor. In cases where primary tumor origin remains unknown, adrenal inhibitor therapy can be maintained as long as the patient undergoes to periodic re-examination for tumor localization (17, 18).

The ectopic CRH syndrome is rare and usually is associated with pulmonary carcinoid tumors, following the same therapeutic principles as ACTH-secreting tumors (319).

Treatment of ACTH-Independent Cushing’s Syndrome

Adrenalectomy is the treatment of choice for all cases of ACTH-independent Cushing’s syndrome. This is either unilateral in the case of an adrenal adenoma or carcinoma, or bilateral in cases of bilateral hyperplasia, either micronodular or macronodular. The only exception can be the case of milder hypercortisolism in macronodular hyperplasia, when unilateral adrenalectomy may provide hormonal control, at least temporarily (320, 321). Pre-operatively, adrenal enzyme inhibitor therapy can be used such that the clinical state of the patient is improved thus reducing the risk of complications. In cases where macronodular hyperplasia comes as a consequence of aberrant hormonal receptor expression, eucortisolemia can be achieved by using the appropriate receptor blockade (322, 323), but this is unlikely to be useful in the long-term.

In adrenal adenomas, cure following surgery in skilled hands approaches 100% (324), and is associated with low morbidity and mortality (325).

Laparoscopic adrenalectomy, both unilateral and bilateral, has been shown in experienced hands to be a safe procedure and in most centers has become the approach of choice for non-malignant disease. Its complication rate is lower than with the open approach, and the in-patient stay is significantly reduced (326, 327). A study comparing three surgical techniques (anterior laparoscopic, posterior laparoscopic, and robotic surgery) for bilateral adrenalectomy for Cushing’s syndrome showed similar morbidity in all approaches (328).

When the adrenal lesion is more than 6cm and suggestive of malignancy, open adrenalectomy remains the gold standard (329). In adrenal cancer, more aggressive surgical approaches probably account for the increase in life span reported in this disease (330). This approach may require multiple operations to resect primary lesions, local recurrences, and hepatic, thoracic, and, occasionally, intracranial metastases, and is usually accompanied by adjuvant mitotane, as discussed below. Overall, there is no significant evidence that radiotherapy improves survival in adrenocortical carcinoma, although in the literature there are sporadic reports that it may be helpful adjuvant treatment to radical surgery in selected cases and may decrease local recurrence (331-333).

Medical Therapy of Cushing’s Syndrome

Although the primary therapy of hypercortisolism in Cushing’s disease is surgical, medical therapy can be required in cases when surgery is delayed, contraindicated, or unsuccessful. The most common therapy is the use of adrenal enzyme inhibitors, less frequently somatostatin and dopamine receptor agonists and glucocorticoid receptor antagonists.

The role of medical treatment of Cushing’s syndrome is an important one. It is practice of many groups to pre-treat Cushing's syndrome patients with severe disease prior to surgical treatment to reverse the hypercortisolemia and its metabolic sequelae, and to hopefully reduce the complications of the definitive procedure. However, it is not routine practice for most patients with Cushing’s disease. Similarly, medical treatment is desirable in patients with Cushing's disease whilst awaiting for pituitary radiotherapy to take effect. In patients where surgery and/or radiotherapy have failed, medical management is often essential prior to (or long-term as an alternative to) bilateral adrenalectomy. Sometimes, in the occult ectopic ACTH syndrome, it may not always be possible to identify the source of secretion, and therefore medical management is desirable pending re-investigation. Finally, medical therapy is helpful as a palliative modality in patients with metastatic disease-causing Cushing's syndrome, at least in the short-term.

The most commonly used agents are adrenal enzyme inhibitors, but adrenolytic agents, pituitary-targeted therapies, or glucocorticoid-receptor antagonists are also used (Table 4). Drugs can be used in combinations in lower doses, aiming for side effect reduction with synergistic effects.

When determining the approach to treatment, the first step is to determine whether the final goal is reducing the level of serum cortisol to normal values or complete cortisol secretion blockade. The latter approach is convenient for patients with more variable secretion, while patients showing less variability can benefit more from lowering the values to the normal range and therefore avoiding the necessity of steroid replacement therapy, as well as a possibility of side effects connected to the higher dosages required with that strategy. A meta-analysis of 35 studies including 1520 patients reported pooled effectiveness of most commonly used medical agents in treatment of Cushing's syndrome, with mitotane being most effective in normalizing cortisol levels in 81.8% of patients and cabergoline (see below) being least effective and normalizing cortisol in 35.7% (334). However, as noted below, mitotane is not a simple drug to use or monitor, and generally it is reserved for adrenocortical carcinoma. The use of multiple agents achieved normalization of cortisol in 65.7% of patients.

ADRENAL ENZYME INHIBITORS

These agents are primarily used as inhibitors of steroid biosynthesis in the adrenal cortex (Figure 5), and thus can be utilized in all cases of hypercortisolemia regardless of cause, but most commonly in ACTH-dependent forms, often with rapid improvement in the clinical features of Cushing's syndrome. The most commonly used agents are metyrapone, ketoconazole, and in certain circumstances etomidate. In the UK ketoconazole and metyrapone are licensed for the treatment of Cushing's syndrome, while mitotane is licensed for the treatment of hypercortisolemia due to adrenocortical carcinoma. The use of etomidate or mifepristone in Cushing's syndrome is off-license. Osilodrostat has also been approved for treatment of Cushing’s syndrome in USA and in Europe in 2020 and NICE-approved it in UK in 2021. However, the regulations could differ in different countries. When used in combinations, they have a synergistic therapeutic effect, lowering the rate of side effects.

Figure 5. Steroidogenesis with main adrenal enzyme inhibitors point of action marked; SCCE – side-chain cleavage enzyme, HSD – hydroxysteroid dehydrogenase, OH – hydroxylase, DHEA – dehydroepiandrosterone, AR – aromatase, AS – aldosterone synthetase.

Metyrapone

Metyrapone acts primarily to inhibit the enzyme 11β-hydroxylase, thus blocking the production of cortisol from 11-deoxycortisol in the adrenal gland (335) (Figure 5). As a consequence of the blockade of cortisol synthesis, levels of adrenal androgens and deoxycorticosterone rise. The subsequent elevation of 11-deoxycortisol can be monitored in the serum of patients treated with metyrapone. It should be noted that there may be cross-reactivity from 11-deoxycortisol with some cortisol radioimmunoassays: this may result in an unnecessary increase in the metyrapone dose and subsequent clinical hypoadrenalism (336). It is preferable to measure the serum cortisol via liquid chromatography-tandem mass spectrometry in patients treated with metyrapone (337). The fall in cortisol is rapid, with trough levels at 2 hours post-dose, and sometimes administration of a test dose of 750 mg with hourly cortisol estimation for 4 hours is performed, although not strictly necessary in our opinion (338). Maintenance therapy is usually in the range 750-6000 mg/day in 3-4 divided doses daily. Metyrapone has been used to good effect to reduce the hypercortisolemia in patients with Cushing's syndrome from adrenal tumors, the ectopic ACTH syndrome, and Cushing's disease. In the former, patients can be very sensitive to low doses of this agent, whilst in Cushing’s disease higher doses are often required. In Cushing's disease this can be due to the compensatory rise in ACTH in patients not having received pituitary radiotherapy. During short-term follow-up (1-16 weeks) of 54 patients with Cushing’s disease, cortisol normalized on the metyrapone treatment in 75% of participants and in 81% of 16 patients with adrenocortical carcinoma or adenoma (338). A subsequent multicenter study on 164 patients with Cushing’s disease reported that 43% achieved control of hypercortisolism at the mean of 8 months of treatment (339).A meta-analysis of 18 retrospective studies including patients with CD showed an average remission rate of 75.9% (31.3-83.2%) (334). The recent prospective study PROMPT including 50 patients with Cushing’s syndrome reported remission in 47% participants (340).

There have not been serious maternal or perinatal complications connected with the use of metyrapone in pregnant women, but the question of safety remains open (341-343). However, metyrapone and ketoconazole are the medications most commonly used in the treatment of Cushing’s syndrome in pregnancy (344).

The principal side effects with metyrapone are hirsutism and acne (as predicted by the rise in adrenal androgens) and reported by 70-83% of women. Dizziness and gastrointestinal upset occurring in 5% and 15% respectively. Because of the androgen effect the drug is not considered appropriate for the first-line therapy of long-term treatment in women (345, 346). However, it is hypoadrenalism that remains the most important potential problem, and careful monitoring of treatment and education of the patient is required. If there is uncertainty as to whether the measured cortisol is valid, and not over-estimated by cross-reactivity, it may be appropriate to consider a ‘block-and-replace’ regimen. Hypokalemia, edema, and hypertension due to salt retention because of mineralocorticoid activity of raised levels of 11-deoxycorticosterone are infrequent (338), but may require cessation of therapy (347).

Ketoconazole

Ketoconazole is an imidazole derivative originally developed as an oral anti-fungal agent. It is a potent inhibitor of sex steroids (androstendione and testosterone) production by its action on C17-20 lyase, and cortisol secretion by 11β-hydroxylase inhibition (348-350). It also inhibits 17-hydroxylase and 18-hydroxylase activity, amongst other enzymes (351). It has also been reported to have a direct effect on ectopic ACTH secretion from a thymic carcinoid tumor (352), and possibly corticotroph ACTH release.

The treatment for Cushing's syndrome is usually started at a dose of 200 mg twice daily, with an onset of action that is probably slower than metyrapone. The usual maximum dose is 400 mg three times a day. It has been used successfully to lower cortisol levels in patients with Cushing's syndrome of various etiologies including adrenal carcinoma, the ectopic ACTH syndrome, and invasive ACTH-producing pituitary carcinoma, with doses required between 200-1200 mg/day in up to 4 divided daily doses (353, 354), although 2-3 times daily is more usual. Although there have not been consequences on human fetuses, considering animal teratogenicity and toxicity the drug is not recommend for use during pregnancy (343, 355, 356). The normalization of cortisol levels was achieved in 71.1% of patients in pooled meta-analysis of all causes of Cushing's syndrome including 220 individuals and in 49% of patients with Cushing’s disease (334). A subsequent meta-analysis of 270 patients with CD treated with ketoconazole after failed transsphenoidal surgery included in 10 studies (all but 1 retrospective) reported control of hypercortisolism in 63% of individuals (95% CI 50-74%) (357).

The principal side effect of ketoconazole is hepatotoxicity (358, 359). A reversible elevation of hepatic serum transaminases occurs in approximately 5-20% of patients, with the incidence of serious hepatic injury at around 1 in 15,000 patients (360, 361). The hepatotoxicity appears to be idiosyncratic, but has been reported within first 4 weeks of the initiation of treatment in a patient with Cushing's syndrome and resolves within 2-12 weeks after dose reduction or discontinuation of treatment (361, 362). Prior to the start of therapy liver function tests should be performed. The alanine aminotransferase (ALT) level should be monitored weekly within the first month of therapy, then once a month in the following trimester and afterwards sporadically or when the dose is changed. If levels reach 3-times above the upper normal range, therapy should be discontinued. Other adverse reactions of ketoconazole include skin rashes and gastrointestinal upset, and one must always be wary of causing adrenal insufficiency (362-364).

Ketoconazole is a CYP3A4 inhibitor and increases the availability of medications metabolized by that enzyme. Hence, the reduction of the dose of affected medications maybe required. Ketoconazole is a mixture of levo- and dextro- enantiomeric forms. Currently, the levo-enantiomer of ketoconazole is less likely to be hepatotoxic than the racemic mixture (see below).

Due to its C17-20 lyase inhibition and consequent anti-androgenic properties, ketoconazole is particularly useful in female patients where hirsutism is an issue, which may be worsened with metyrapone. Conversely, gynecomastia and reduced libido in male patients may be unacceptable as a first-line long-term treatment and require alternative agents. However, replacement therapy is an option. On the other hand, women having lower levels of estradiol and testosterone do not experience clinically manifest disorder because of the usually present menstrual irregularity. Ketoconazole requires gastric acid for absorption, so should not be given with proton-pump inhibitors. One further advantage of ketoconazole is its inhibition of cholesterol synthesis, particularly LDL cholesterol (365), and in 34 patients with Cushing's syndrome the mean total cholesterol was reduced from 6.1 to 5.0 mmol/l on ketoconazole (363).

The triazole antifungal, fluconazole can also be effective in treatment of Cushing’s syndrome, but experience is limited to single case reports. They described an effective control of hypercortisolism on 200-1200mg daily dose of fluconazole (366, 367). Fluconazole was reported in vitro to be 40% less effective in inhibition of 11β-hydroxylase and 17-hydrohylase than ketoconazole (368). The side effects of fluconazole are similar to those of ketoconazole.

Osilodrostat

Osilodrostat is a novel steroidogenesis inhibitor. FDA approved osilodrostat for treatment of Cushing's disease in 2020 and NICE in 2021 in the UK. It is a selective inhibitor of 11β-hydroxylase, an aldosterone synthase and a non-steroidal aromatase. It causes a decrease in cortisol and aldosterone levels and an increase of 11-deoxycorticosterone and 11-deoxycortisol. Osilodrostat was evaluated in phase II trial as a potential anti-hypertensive agent in patients with primary hyperaldosteronism and essential hypertension (369). In 10-week study in patients with Cushing's disease (n=12) who were not cured by previous surgery, osilodrostat normalized urinary free cortisol (UFC) in 92% of subjects with more than 50% decrease in UFC in all participants (370). In 22-week phase II trial in patients with Cushing’s disease (n=19) and UFC >1.5 of the upper normal limit, osilodrostat (10-60mg/day) normalized UFC in 79% of patients. It also produced no significant change in blood pressure and an increase of ACTH 3-4-fold. Adrenal insufficiency was seen in 32% of subjects leading to the reduction of the dose, while an increase of testosterone and hirsutism was reported in around 30% of women (370). The phase III study was a double-blind randomized trial with a withdrawal phase after 24 weeks of treatment followed by continuation of osilodrostat mean dose of 5mg twice a day from 40 to 48 weeks (371). Fifty-three percent of participants in the osilodrostat arm (n=36) maintained UFC in the normal range without increasing the dose at 24 weeks, compared to 29% in the placebo group (n=35). Sixty-six patients were not randomized to withdrawal of treatment and continued osilodrostat due to higher cortisol levels. Of 137 individuals with Cushing's disease, 66% maintained UFC in the normal range after 48 weeks (6 months) (371). The extension study up to 70 months (6 years) showed maintained complete remission of hypercortisolism in 50-88% of participants and partial control in additional 18% of individuals (372, 373). The most frequent side effects included nausea (42%), headache (34%), fatigue (28%) and adrenal insufficiency (28%). Forty two percent of patients had reported hypertension and hypokalemia due to increased adrenal precursors and 11% of women noted increased hirsutism. The side effects related to hypoadrenalism reduced to 27.3% in the extension study (373).

Levoketoconazole

Levoketoconazole is a stereoisomer of ketoconazole and its efficacy and safety has been assessed in the SONICS study, phase III open-label trial of 94 individuals with Cushing's syndrome (85% with Cushing’s disease) and mean UFC 4.9 times upper normal range (374). The starting dose was 150mg twice a day and titrated up to a total daily dose of 1200mg aiming for normal UFC. Thirty-one percent maintained normal UFC by 6 months of treatment and 36% during maintenance phase. However, only 55 patients completed the maintenance phase and of those 61% were in remission (374). The phase III placebo-controlled randomized-withdrawal study, LOGICS, included 79 patients with Cushing’s syndrome on a levoketoconazole maintenance dose, 40.9% lost the control of hypercortisolemia comparing to the placebo arm where 95.5% became hypercortisolemic (375). Most common adverse effects were nausea (29-32%), headache (23-28%), and deranged liver function in 11-44% of participants. However, it remains to be seen whether it proves in practice to be less hepatotoxic than the racemic mixture. Levoketoconazole has been approved for treatment of Cushing’s syndrome in adults by the FDA but not currently by the EMA.

Etomidate

Etomidate is an imidazole-derived anesthetic agent which was reported to have an adverse effect on adrenocortical function in 1983 (376). Compared to the other imidazole derivative ketoconazole, etomidate more potently inhibits adrenocortical 11β-hydroxylase, has a similar inhibition of 17-hydroxylase, but has less of an effect on C17-20 lyase (377). At higher concentrations it also appears to have an effect on cholesterol side-chain cleavage (378, 379). Following their initial report in 1983, Allolio and colleagues showed that intravenous non-hypnotic etomidate dose (2.5 mg/hour) normalized cortisol levels in 5 patients with Cushing's syndrome of various etiologies (380). Since then, there have been a number of case reports on the use of etomidate in successfully reducing hypercortisolemia in seriously-ill patients with either Cushing's disease or the ectopic ACTH syndrome (381-384).

It is usually given at a dose of 2.5-3.0 mg/hour, which is adjusted based on the serum cortisol levels. It usually takes several hours for cortisol to be lowered to within the normal range (385). Etomidate is an effective agent that acts rapidly, but is limited in its use by the fact it has to be given parenterally and requires intensive care settings to safely manage and monitor cortisol and potassium levels 4-6 hours to adjust the infusion rate (386). Similar to metyrapone and osilodrostat, high levels 11-deoxycortisol may cross-react with many assays. A simultaneous infusion of hydrocortisone of 0.5-2 mg/h may be required to maintain normal cortisol levels. However, in this situation it may be lifesaving. The preparation available in the USA contains the vehicle propylene glycol with the potential for nephrotoxicity and lactic acidosis, as opposed to the preparation available in Europe which contains alcohol.

Mitotane

Mitotane (o’p'DDD), an isomer of DDD (belonging to the same family of chemicals as the insecticide DDT), was developed following the observation of adrenal atrophy in dogs administered DDD. Mitotane inhibits steroidogenesis by reducing cortisol and aldosterone production by blocking cholesterol side-chain cleavage and 11β-hydroxylase in the adrenal gland (387). It also acts as an adrenolytic drug, causing medical adrenalectomy, after being metabolized into an acyl chloride that binds in mitochondria and causes necrosis of adrenocortical cells (388).

Mitotane is used as a treatment for adrenocortical carcinoma and causes tumor regression and improved survival in some patients (389, 390). It has a beneficial effect on endocrine hypersecretion in approximately 75% of patients (391). It is also utilized in Cushing's syndrome of non-malignant origin, and in this regard lower doses can be utilized (up to 4 g/day), thus reducing the incidence of side effects, particularly gastrointestinal (392). At these lower doses the onset of the cortisol-lowering effect takes longer (6-8 weeks) than with higher doses. Mitotane should not be used in pregnant women, and reproductively active women must use reliable contraception while on therapy (393). A pooled meta-analysis of all causes of Cushing's syndrome in 173 patients reported the normalization of cortisol levels on mitotane treatment in 79.8% of all patients and in 81.8% of participants with Cushing’s disease (334).

The main side effect of mitotane treatment include nausea, vomiting and lethargy. One problem even with low-dose mitotane is the hypercholesterolemia (principally an increase in LDL-cholesterol), which appears to be due to the impairment of hepatic production of oxysteroids, normally a brake on the enzyme HMG CoA reductase (394). However, simvastatin, an HMG CoA reductase inhibitor, can reverse the hypercholesterolemia, and it or a similar agent should be used, if necessary, in patients treated with mitotane. Other side effects of mitotane include neurological disturbances; elevation of hepatic enzymes; hypouricemia; gynecomastia in men; and a prolonged bleeding time (391, 395). Most importantly, it elevates cortisol-binding globulin, such that levels of total serum cortisol are misleading. Control should be titrated using urinary free cortisol or salivary cortisol. Monitoring of serum levels of mitotane should be undertaken due to its narrow therapeutic window and the risk of toxicity. In the long-term, measurement of blood levels can allow dose titration and reduction as appropriate. A therapeutic level of 14-20 mg/L has been recommended for adrenocortical carcinoma, but lower levels can be sought for simple control of elevated cortisol levels. Mitotane is taken up by fatty tissues, sometimes being released gradually several months after discontinuing therapy, therefore requiring adjustments in glucocorticoid therapy dosage (396). Mitotane shows cytotoxic activity on both normal and tumorous tissue causing primary adrenal insufficiency and therefore requiring glucocorticoid replacement therapy. It tends to spare the zona glomerulosa, but in long-term use mineralocorticoid replacement is also needed (397). In general, despite effective in other forms of Cushing’s syndrome, its use has been limited outside of adrenocortical carcinoma, in which cases it has been shown to prolong life (390).

Table 4. Currently Available Medical Therapy for Cushing’s Syndrome (CS)
Medication	Action	Dosage	Side effects	Contra-indications	Comments
Steroidogenesis inhibitors
Metyrapone	11b-hydroxylase inhibitor	250-1000mg tds-qds, max 6g/day po	Nausea, vomiting, acne, hirsutism, hypo- or hypertension, oedema, hypokalemia	Pregnancy, breast-feeding, porphyria, severe liver impairment	1^st line treatment when available, avoid long-term use in young women
Ketoconazole	11b-hydroxylase and 17,20-lyase inhibitor,	200-400mg tds po	Gynecomastia, alopecia, hypogonadism in men, hepatotoxicity, Gastrointestinal symptoms, rash	Liver impairment, pregnancy/ breast-feeding, porphyria	Slow in onset of action, 1^stline in children, stop PPI/H2-antagonist as gastric acid needed for absorption
Osilodrostat	11b-hydroxylase inhibitor,	2-7mg bd po	Hypertension, hypokalemia, hirsutism, asthenia, GI symptoms, adrenal insufficiency, headache	Pregnancy & breast feeding,	To use low dose in liver impairment, Risk of increasing QT interval
Mitotane	Adrenolytic	500-1000mg tds-qds, gradually increased from 500-1000mg/day to max 6g/day po	Gastrointestinal symptoms, deranged LFTs and TFTs, hyper-cholesterolemia, ataxia, orthostatic hypotension	Pregnancy/ breast-feeding, stage 4-5 renal failure, severe liver impairment	Slow in action, hyperglycemia, mitotane level monitoring required, accumulates, now rarely used for CD, high rate of withdrawal due to intolerance
Etomidate	11b-hydroxylase inhibitor	0.01-0.5mg/kg/h iv	Sedation, nausea and vomiting, temporary uncontrolled muscle movements, rash, angioedema	Pregnancy, breast-feeding, porphyria	Parenteral, rapid onset of action, anesthetic agent so ITU settings required, frequent monitoring of cortisol and K⁺
Modulators of ACTH release
Cabergoline	Dopamine agonist	1-7mg/week po	postural hypotension, nausea, increased tendency of gambling, hallucinations, oedema, depression, possibility of heart valve sclerosis (only very high doses)	Porphyria, pregnancy, hyper-sensitivity to ergot derivates, valvulopathy	Effective in <40% of patients, which wears off with time, cheap
Pasireotide	Somatostatin analogue	600-900mg twice daily sc	Hyperglycemia, cholelithiasis, diarrhea, headache	Severe liver impairment, Avoid in poorly controlled diabetes	Effective only in mild CD, treatment of hyperglycemia frequently required
Glucocorticoid receptor antagonist
Mifepristone	Glucocorticoid receptor antagonist	300-1200mg daily po	nausea, vomiting, dizziness, headache, arthralgia, increased TSH, decreased HDL, endometrial thickening, rash, oedema	Severe asthma, porphyria, renal failure, severe liver impairment, breast-feeding	Cortisol and ACTH levels remain high so hypokalemia may persist, also anti-progesterone, monitoring difficult
Investigational status in some countries
Levoketoco-nazole	11b-hydroxylase and 17,20-lyase inhibitor	300-1200mg, bd po	Headache, oedema, GI symptoms, increased liver enzymes, adrenal insufficiency	Liver impairment, pregnancy/ breast-feeding, porphyria	FDA & EMA orphan drug status

CBG – cortisol binding globulin, CD – Cushing’s disease, tds – 3 times a day; qds – 4 times a day, LFTs – liver function tests, TFTs – thyroid function tests, PPI – proton pump inhibitor, K+ - potassium, ACTH – adrenocorticotrophin hormone, po – orally, iv- intravenous, sc – subcutaneous, ITU – intensive care unit, FDA – Food and Drug Administration (USA), EMA – European Medicines Agency.

MODULATORS OF ACTH RELEASE

Pasireotide

Somatostatin receptors have been demonstrated on both corticotroph adenomas, and some ectopic ACTH-secreting tumors. However, although octreotide has been helpful in reducing ACTH and cortisol levels in selected case reports of ectopic ACTH-secreting tumors there has been much more limited success in patients with Cushing's syndrome probably through down-regulation of receptor sub-type 2 in these tumors by hypercortisolemia (398).

There has been renewed interest with the introduction of pasireotide, a somatostatin analogue with a broader spectrum of activity for somatostatin receptor subtypes, including type 5, which is not down-regulated during hypercortisolemia. Ever since this agent was shown in vitro to reduce human corticotroph proliferation and ACTH secretion (399, 400), there have now been a number of clinical trials published. In an initial phase II trial, pasireotide 600µg injected twice daily for 15 days reduced urinary free cortisol (UFC) levels in 76% of 29 patients and normalized levels in 17% (401). A multicenter phase III dose-randomized trial in 162 patients with either new, persistent, or recurrent Cushing's disease has shown at six months a reduction in UFC levels in 91 of 103 evaluable patients, with a median UFC reduction of 48%. Normalization of UFC levels were achieved in 14.6% of patients on the 600µg dose twice daily, and 26% of patients on the 900µg twice-daily dose. Patients who showed <50% reduction in UFC levels from baseline by month two were unlikely to show improvement by month 6 or 12.

The most clinically relevant adverse events were hyperglycemia (73%), with 46% developing frank diabetes mellitus related to decreases in both insulin and incretin secretion, and hypocortisolemia (8%) (401, 402). Other side effects included elevated liver enzymes, cholelithiasis, nausea and diarrhea at the rate expected from experience with other somatostatin analogues (402).

There is now also experience with pasireotide long-acting repeatable (pasireotide LAR), a monthly injection of 10 or 30mg, reporting around 41% of patients achieving normal UFC levels at 7 months of treatment and a similar safety profile to the subcutaneous form (403). More than a 20% reduction in size of the pituitary adenoma was described in 45% of patients and an increase by more than 20% in 10% of individuals (403). Long-term extension studies of monthly pasireotide showed improvement of cortisol levels up to 5 years (404). Pasireotide LAR decreased median volume of the corticotroph adenoma by 16.3-17.8% in 43-47% of patients (403).

Pasireotide is not recommended as a first-line treatment but can be considered as add-on therapy or second-line treatment if other medications are not tolerated. In cases where there is no clinical response, it should be discontinued.

Pasireotide at a lower dose of 250 µg three times daily has also been used in stepwise combination therapy with the dopamine agonist cabergoline (previously been demonstrated to have modest but variable efficacy as monotherapy in Cushing's disease (405), and ketoconazole. Pasireotide monotherapy induced normalization of UFC levels in 5 of 17 patients (29%). The addition of cabergoline normalized UFC levels in an additional 4 patients (24%). The further addition of ketoconazole in the remaining 8 patients induced normalization of UFC levels in 6 of these. Thus, in total, remission was achieved in 88% of patients using combination therapy out to 80 days of treatment (405). Therefore, pasireotide represents a potential new treatment for mild Cushing's disease or in combination therapy for individuals with higher hypercortisolemia, although the frequency of hyperglycemia is of major concern.

Corticotroph adenomas with USP8 mutations had been reported to have higher SST5 receptor expression which may suggest higher response rate to pasireotide treatment in this subgroup (406, 407).

Cabergoline

The presence of dopamine receptors (D2) on around 80% of corticotroph adenomas supported the use of cabergoline in patients with Cushing’s disease (408). Cabergoline at a dose of 1-7mg weekly was reported to control hypercortisolemia due to Cushing’s disease in 25-40% of patients in small case series (409). A multicenter retrospective study of 53 patients treated with a median dose of 2.3mg/week normalized UFC in 40% of individuals in the first year of treatment, which was reduced to 23% at 32.5 months (410).

It is usually well tolerated and the most common side effects include nausea and dizziness. At the doses used for the treatment of pituitary tumors, the incidence of cardiac valve sclerosis and subsequent regurgitation was not increased in one large study, and therefore echocardiograms are not routinely needed unless high, long-term treatment is required (411). However, escape is seen in some patients, so the percentage of patients with long-term control is low. Another side effect is an impulse control disorder for which patients should be counselled before initiation of treatment (412).

Temozolomide

Temozolomide is an oral alkylating prodrug that is converted in vivo to the DNA repair inhibitor, dacarbazine. Traditionally, this chemotherapy agent has been used in the treatment of malignant gliomas, but recent evidence suggests it is also useful in selected aggressive pituitary tumors including corticotroph pituitary carcinomas (413, 414). Although, some reports suggested that the response to temozolomide in pituitary tumors can be predicted by low expression of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT), possibly related to MGMT gene promotor methylation (415, 416), not all studies have confirmed this (417, 418). However, the therapeutic response can usually be determined after 3 cycles of chemotherapy. Reported partial or complete response from case reports is around 80%, with improvement seen after 2 months with tumor size reduction from stable to 50% (419). Side effects include cytopenia, GI symptoms, headaches, hearing loss and dizziness.

OTHER AGENTS

Retinoic Acid

Retinoic acid has been found to inhibit ACTH-secretion and cell proliferation both in vitro in ACTH-producing tumor cell lines and cultured human corticotroph adenomas, and in vivo in nude mice (420). However, clinical trials in man are limited, and it is unlikely to be a major contributor to control.

Rosiglitazone

The thiazolidinedione rosiglitazone, a PPAR-γ agonist, was shown in supra-pharmacological doses to suppress ACTH secretion in human and murine corticotroph tumor cells. In addition, the development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, were prevented (421). It appears this is not specific to corticotroph adenomas, but also applies to other forms of pituitary tumor (422). However, the results in human subjects with Cushing's disease have been disappointing (423-425). This may be because doses used in the animal studies were much higher than the equivalent licensed dose in humans. Its use cannot be recommended.

Receptor Antagonists to GIP, β-adrenergic and LH/hCG Receptors

In the rare causes of Cushing’s syndrome due to bilateral macronodular adrenal hyperplasia (BMAD) and aberrant receptor expression of GIP, β-adrenergic and LH/hCG receptors, specific receptor antagonists may prove to be useful (426). Although octreotide has been shown to have a therapeutic response in GIP-related BMAD as mentioned above (31), others have found neither this somatostatin analogue nor pasireotide to be helpful in inducing a sustained response (427).

Glucocorticoid Receptor Antagonist(s)

Mifepristone (RU 486), is a potent antagonist of glucocorticoid and progesterone receptors that blocks the peripheral actions of glucocorticoids and progestogens (428, 429). As a consequence it also blocks glucocorticoid-induced negative feedback at the hypothalamo-pituitary level, inducing a rise in ACTH, arginine-vasopressin (AVP) and hence cortisol (430). It has occasionally been given to patients with all forms of Cushing's syndrome (431, 432), showing effectiveness in rapidly reducing symptoms of cortisol-induced psychosis (433, 434), and improving glycemic control and hypertension (432). Although, it has been proven to be effective in the treatment of hypercortisolemia-related symptoms and signs (431, 435), the major drawback is the lack of biochemical markers to assess either therapeutical effectiveness or possible hypoadrenalism. Adrenal insufficiency is challenging to treat, because the drug, besides blocking endogenous cortisol, also blocks the action of synthetic steroids as replacement therapy. Hypokalemia is a frequent problem due to the saturation of 11β-HSD type 2 and cortisol action on the mineralocorticoid receptor, although it responds well to spironolactone. The daily dose of mifepristone ranges between 300 and 1200mg. It showed a significant improvement of glucose and HbA1c in 60% of patients with impaired glucose tolerance or diabetes (432). Mifepristone could be used as add-on therapy for Cushing’s syndrome with associated hyperglycemia. Endometrial thickening and vaginal bleeding secondary to the anti-progestin effect are likely to be seen in women. However, a new derivative of mifepristone with less anti-progestogen blocking activity, relacorilant, is currently under trial.

Relacorilant (CORT125134)

Relacorilant is a glucocorticoid receptor inhibitor with no effect on the progesterone receptor. A phase II study (GRACE) included 130 patients with Cushing’s syndrome and type 2 diabetes and/or hypertension. Half of the patients receiving higher doses (range of 100mg-400mg daily) of relacorilant for 16 weeks and the HbA1c was reduced by ≥0.5% or the dose of insulin/sulfonylurea reduced by ≥25%. A reduction of systolic BP by at least 5mmHg was reported in 64% of participants receiving a higher dose of medication. A Phase III multicenter, placebo-controlled randomized withdrawal trial is still on-going and expected to be completed in 2024 (clinicaltrials.gov code: NCT03697109).

It should be noted that the use of all these novel agents may be limited by their expense and availability.

MONITORING TREATMENT

It is important to monitor all patients on medical therapy for Cushing’s syndrome in order to assess the effectiveness of treatment, and in particular to avoid adrenal insufficiency. Serum cortisol level and/or urine cortisol level are used in order to estimate steroid inhibitor therapy. One way is to assess the mean of 5 serum cortisol measurements across the day, although others favor measurement of urinary free cortisol (UFC). A mean serum cortisol between 150 and 300 nmol/L (5.5-11 μg/dL) corresponded to a normal cortisol production rate (436), and this range should be the aim of therapy, although this figure may be an overestimate as it is based on older cortisol assays. As mentioned above, a liquid chromatography tandem mass spectrography cortisol assay is preferable in patients on metyrapone, osilodrostat and etomidate.

When mitotane is used, only measurement of 24-hour urinary free cortisol reflects therapy effectiveness and concentration of serum free cortisol, because mitotane reduces 17-OHCS excretion. Because it raises the level of cortisol binding globulin (CBG), the level of total serum cortisol is inappropriate for monitoring of cortisol secretion, as it can be two to threefold elevated (437, 438). The high level of CBG explains why replacement dosage of steroids needs to be increased in cases of adrenal insufficiency, although there is also a contribution from increased hepatic steroid metabolism.

CUSHING’S SYNDROME IN SPECIFIC GROUPS

Chronic Renal Failure

Cushing’s syndrome in the setting of chronic renal failure is poorly described, but may pose diagnostic difficulties. In chronic renal failure serum levels of cortisol are generally normal but with some radioimmunoassays may be increased (439, 440). ACTH levels are increased (441). Glomerular filtration rates of less than 30 mL/min result in decreased cortisol excretion and spuriously low UFC values (442). The ACTH and cortisol responses to CRH may be suppressed in patients with renal failure, except for those undergoing continuous ambulatory peritoneal dialysis (443). The metabolism of dexamethasone is normal in chronic renal failure, but the oral absorption can be altered in some patients. There is a reduced degree of suppression of cortisol by dexamethasone suggesting a prolonged half-life of cortisol. Normal suppression during the overnight 1-mg LDDST is uncommon, and the 2-day LDDST is better in this regard (439, 444).

Pediatric Cushing’s Syndrome

The most common presentation of Cushing’s syndrome in children is growth retardation, with weight increases (445). However, one proviso is that patients with virilizing adrenal tumors may show growth acceleration (446). Other virilizing signs such as acne and hirsutism are seen in approximately 50% of patients regardless of etiology (445). Hypertension and striae are seen in approximately 50% of cases (447). Muscle weakness may be less common in the pediatric patient due to increased exercise (448). Psychiatric and cognitive changes may affect school performance; however, children may show “compulsive diligence” and actually do quite well academically (449). Headaches and fatigue are common(445). Cushing’s disease accounts for the between 75% and 80% of Cushing’s syndrome in older children, but before the age of 10 years ACTH-independent causes of Cushing’s syndrome are more common (450). Cushing’s disease has a male predominance in pre-pubertal children. Two causes of ACTH-independent Cushing’s syndrome, McCune-Albright syndrome and PPNAD, are typically diseases of childhood or young adults. Signs of virilization in the very young (<4 years) suggest adrenal carcinoma. Ectopic secretion of ACTH occurs rarely in the pediatric population and is usually due to bronchial or thymic carcinoids (2).

As mentioned previously, late night salivary cortisol measurement has particular logistic benefits in children (451, 452). Serum midnight cortisol measurements in in-patients has high sensitivity (453). UFC should be corrected for body surface area (454). The standard 2-day LDDST adult protocol can be used in children weighing 40kg or more, otherwise the dexamethasone dose is adjusted to 30µg/kg/day (455). As in adults, there is a good correlation between the cortisol suppression on the LDDST and the HDDST for the differential diagnosis and thus the latter is unnecessary (456). Although it can be argued that the ectopic ACTH syndrome is so rare in children that BIPSS is not necessary, it does add reassurance in those with a negative pituitary MRI, which is the case in more than 50% of cases. In addition, BIPSS has arguably better accuracy in lateralization of the pituitary tumor (385). MRI is at least as useful as CT in the evaluation of adrenal causes (457).

Transsphenoidal surgery is the treatment of choice in children with Cushing's disease, with similar rates of remission as in adults in expert hands (458). Conventional radiotherapy after non-curative transsphenoidal surgery performs even better than in adults, with reported remission rates as high as 100%, with remission usually occurring within 12 months (459). Following pituitary surgery, plus or minus radiotherapy, the incidence of growth hormone deficiency is high, but prompt diagnosis and treatment with human growth hormone ensure acceptable growth acceleration and catch-up growth, although an abnormal body composition often persists (460). Normalization of reduced bone mineral density can also be achieved (384). Adrenalectomy is first-line therapy in ACTH-independent Cushing's syndrome.

Cushing’s Syndrome in Pregnancy

Cushing’s syndrome in pregnancy is fortunately rare, because ovulatory disorders and consequently infertility constitute the clinical picture in 75% of untreated patients with Cushing’s syndrome (341, 342). The epidemiology in pregnant women is different to that in the non-pregnant population, in that pregnant patients show a 60% prevalence of ACTH-independent Cushing's syndrome (48% adenoma and 10% carcinoma) followed by Cushing’s disease and bilateral adrenal hyperplasia, and rarely ectopic disease (342, 343, 461). The onset of adrenal-dependent Cushing’s syndrome may relate to the aberrant expression of LH receptors on the tumor, cross-reacting with hCG. The diagnosis is challenging because of the symptoms and signs common to both Cushing’s syndrome and normal physiological changes in pregnancy; such as weight gain, fatigue, striae, hypertension, and glucose intolerance. In addition, the hormonal changes, which occur during pregnancy may confuse the interpretation of the biochemical test procedures (343).

Total serum cortisol levels increase in pregnancy, as a result of induced production of corticosteroid-binding globulin by estrogens, beginning in the first trimester and peaking at 6 months, with a decrease only after delivery. Levels of free cortisol are also raised. Late night salivary cortisol levels are 2-fold higher in normal pregnancy. In contrast to patients with pathologic hypercortisolism, levels of urinary 17-OH-corticosteroid excretion are within the normal range and the cortisol diurnal rhythm is maintained, but with a higher nadir (461). UFC excretion is normal in the first trimester and then rises up to three-fold by term (462). Suppression to dexamethasone testing is blunted, especially after the first trimester (135). Plasma ACTH levels are slightly decreased in the beginning of the pregnancy, but later tends to rise, partially because of placental ACTH and CRH secretion. The circadian rhythm of cortisol is usually maintained in the first 2 trimesters of pregnancy and becomes blunted in the 3^rd trimester.

In general, biochemical evaluation follows the same principles as with the non-pregnant patients. However, there are no agreed guidelines in interpreting results of hormonal measurements in pregnant Cushing’s patients, considering normal physiological deflection of cortisol metabolism in pregnant women. As mentioned above, UFC excretion is normally increased, so if there is less than a 3-fold rise it cannot be diagnostic, and the dexamethasone response is blunted therefore cannot be used as screening test because of the possibility of a false positive result. Late night salivary cortisol is an alternative screening test for pregnant women and probably the most reliable investigation (463, 464). In pregnant women with Cushing’s syndrome, higher cut-offs for LNSC are suggested, depending on the trimester, of 7, 7.2 and 7.9nmol/L for the 1^st, 2^nd and 3^rd trimester respectively (465). Therefore, the differential diagnosis regarding the possible etiology of Cushing’s syndrome can be quite demanding. If suppressed, levels of ACTH can point to adrenal origin, but lack of suppression does not eliminate the possibility of ACTH-independent cause. The high-dose dexamethasone test may be useful to distinguish an adrenal cause, because women with adrenal causes tend not to suppress, while those with Cushing’s disease do (461, 466, 467). As an initial evaluation the basal levels of ACTH and the high-dose dexamethasone test may be performed. Furthermore, due to the high prevalence of primary adrenal disease, it is reasonable to perform an abdominal ultrasound at an early stage.

The CRH test has also been used to identify patients with Cushing's disease, and there is no evidence of harm both in animal studies and the small number of pregnant patients studied with CRH. There are 2 case reports of desmopressin test being carried out in pregnancy with significant ACTH increment suggesting Cushing’s disease, later confirmed on post-TSS histology (468, 469).

MRI without gadolinium enhancement is considered safe in the third trimester, and its use in combination with the non-invasive tests above should be able to resolve most diagnostic issues. Current guidelines allow use of contrast only if it is going to change fetal or maternal outcomes (470). BIPSS with appropriate additional radiation protection for the fetus should be reserved only for the rare cases where diagnostic uncertainty remains. Ultrasound of the adrenals can be used as a first-line imaging in ACTH-independent Cushing's syndrome.

Maternal hypercortisolism is associated with 40-70% hypertension, 14-26% preeclampsia, 25-37% diabetes mellitus, 5% osteoporosis and fractures, 3% cardiac failure, 4% mental health disorders and rarely (2%) death (471, 472).

Although the fetus is partially protected from maternal hypercortisolism by placental 11-B-hydroxisteroid dehydrogenase type 2, which converts 85% of cortisol to inactive cortisone (405), the untreated condition is associated with miscarriage, premature delivery, and neonatal adrenal insufficiency (472).

Because of both maternal and neonatal risk, definitive surgical treatment of adrenal or pituitary disease is recommended to achieve eucortisolemia. The second trimester is probably the safest time for adrenal surgery or transsphenoidal operation, although adverse fetal outcomes after the successful treatment may still persist, such as intrauterine growth restriction and premature birth, but it does appear to prevent stillborn deliveries (472) (396).

Medical treatment carries potential risks to the fetus and should be considered only as second-line therapy when the benefit outweighs the risk, and generally only as an interim measure to operation or awaiting the pre-pregnancy pituitary radiation effect. Metyrapone is probably the adrenolytic agent of choice, although an association with pre-eclampsia has been reported (343). Ketoconazole has been utilized successfully in a small number of patients but is teratogenic in animals, and therefore should be used with caution. Cabergoline is probably a safe potential treatment option for mild hypercortisolism during pregnancy.

Pseudo-Cushing’s Syndrome

Pseudo-Cushing’s states (PCS) or more recently called non-neoplastic hypercortisolism are conditions which cause increased cortisol production, manifest with some features of Cushing’s syndrome but are reversible by resolution of the causal state. Distinguishing pseudo-Cushing’s state from a true Cushing’s syndrome could often be challenging even for the endocrinologist. The detailed history taking is the key in diagnosis of PCS.

The states causing PCS could be physiological or related to other disorders. The physiological ones include severe persistent stress (emotional or related to severe illness), major surgery, persistent strenuous exercise or prolonged fasting/eating disorders. Non-physiological causes of PCS are alcoholism, severe depression or anxiety, poorly controlled diabetes, polycystic ovaries syndrome or obesity (473).

In alcoholism the majority of individuals have facial plethora, proximal weakness, central obesity or hypertension but rarely have purple striae (474). The hypercortisolism results from the elevation of CRH and stimulation of the HPA axis, an increased activity of 11B-HSD type 1, and reduced cortisol clearance due to liver disease (475). The abstinence from alcohol for more than 1 month resolves hypercortisolism.

In severe depression hypercortisolism is seen in 20-30% of patients but clinical features of Cushing’s syndrome are usually rare. The hypercortisolism is due to stimulation of HPA axis and reduced activity of 11B-HSD type 2 (476). Successful treatment of depression resolves the hypercortisolism.

Poorly controlled type 2 diabetes, polycystic ovary syndrome, and obesity may also be associated with increased cortisol levels and lack of suppression on overnight dexamethasone suppression test. Although the majority of individuals with those disorders have hypertension, hyperlipidemia and other features of metabolic syndrome, they are unlikely to have proximal myopathy, purple striae or bruising (473, 475).

In anorexia nervosa cortisol levels are often increased but features of hypercortisolism are absent. High levels of CRH but normal ACTH, reduced cortisol clearance and usually preserved cortisol circadian rhythm are reported in eating disorders (477).

As discussed in the second line investigations for Cushing’s syndrome, a mid-night cortisol, LDDST-CRH test and desmopressin test were helpful differentiating Cushing’s syndrome from pseudo-Cushing’s states. Overnight dexamethasone suppression test usually fails in most of patients with pseudo-Cushing’s states with specificity of 58%. The LDDST has slightly better specificity of 74% (473).

Due to shortage of CRH, desmopressin test is the next line test. The study of 173 subjects including 76 with Cushing’s disease, 30 with non-neoplastic hypercortisolism, 36 with obesity and 31 of controls proposed cut-off criteria for positive desmopressin test as ACTH increment of >6pmol/L (30ng/L) (143). Subsequently, another study of 52 patients with Cushing’s syndrome and 28 controls suggested new criteria with ACTH increment of 4pmol/L and basal cortisol above 331nmol/L providing sensitivity of 90.3% and specificity of 91.5% (144). The meta-analysis of 3 studies described use of desmopressin test in differentiation of Cushing’s disease and non-neoplastic hypercortisolism with cut-off for ACTH increment by 6 pmol/L in 2 studies and ACTH increment of 4 pmol/L and basal cortisol more than 331nmol/L gave pooled sensitivity of 88% and specificity of 94% (143-145). However, there was high patient selection bias and low certainty of evidence in that meta-analysis (145).

PROGNOSIS AND COURSE AFTER EFFECTIVE TREATMENT

Before treatment was readily available, the mortality rate for Cushing’s syndrome was 50% after the first symptoms appeared, mainly due to cardiovascular, thromboembolic, infectious or hypertensive complications (478).

Even today, patients with severe hypercortisolism have a raised mortality rate due to increased coagulability and it’s the consequences or opportunistic infections (112, 479, 480), emphasizing the need for controlling the hormonal situation as soon as possible. The prognosis is mainly a reflection of the underlying condition. The life expectancy of patients with non-malignant causes of Cushing's syndrome has improved dramatically with effective surgical and medical treatments.

Even when cured by strict criteria, Cushing’s disease may often recur over time (481). From a number of studies in patients with Cushing’s disease treated in the era of transsphenoidal surgery, it initially appeared that after curative transsphenoidal surgery long-term mortality was not significantly different from that in the general population (480, 482). However, another population-based study suggested that mortality is marginally increased (4),while even more recently a very significantly increased mortality was shown even in patients who remained cured. A large European Registry of 1564 patients with Cushing’s syndrome, including 1045 patients with Cushing's disease, reported a 3.1% 90-day mortality in this group generally (483). The main cause of death was progression of the main disease (36%), infections (31%), and cardio- and cerebro-vascular disease (17%). As expected, the highest mortality was in individuals with ectopic Cushing's syndrome (20.2%), 2.2% in patients with Cushing's disease and 1.6% in those with ACTH-independent Cushing's syndrome. However, a large-scale meta-analysis showed that patients with Cushing’s disease who were cured at their first operation showed a normalized standardized mortality ratio, further emphasizing the importance of this modality of treatment and the necessity for an experienced surgeon. Nevertheless, while abdominal obesity may improve, hypertension and insulin resistance leading to increased cardiovascular risk with evidence of atherosclerotic disease persists when measured 5 years after remission of Cushing’s disease (96). It is therefore important to aggressively treat associated conditions such as hypertension and diabetes, even when the Cushing’s per se has been controlled. Unlike some signs and symptoms that disappear gradually over the next year after successful treatment, co-morbidities such as diabetes mellitus and hypertension improve, but may not resolve completely, requiring further aggressive treatment. There is also some evidence that the outcome from Cushing's disease may be worse in males (53). Some of the signs and symptoms of Cushing’s syndrome are expected to disappear gradually over the following year after the treatment; skin thickness improves in weeks, but for some it may take longer, as does muscle strength.

The outcome of pediatric Cushing’s disease is excellent if treated at centers with appropriate experience (447, 484).

Cushing's syndrome results in significant impairment in quality of life (485, 486), psychiatric symptoms (487), and cognitive deficits (488), as previously noted. However, in general these are only partially improved with treatment, and often do not resolve completely in either children or adults.

There is some evidence that deficits in bone mass may be partially reversed after treatment of hypercortisolemia (489, 490). Bisphosphonate treatment may induce a more rapid improvement in bone mineral density (491), and should be considered (along with calcium and vitamin D supplements), but it is unclear whether they are needed for the majority of patients with osteoporosis. Osteoporosis starts to improve after 6 months, with rapid improvement over the next two years, but with the possibility of residual disease to some extent (492). However, in general the prognosis is good without any specific treatment, and the care should be expectant.

The prognosis of the potentially malignant causes of Cushing's syndrome is more variable. Adrenal cancer associated with Cushing's syndrome has an extremely poor prognosis. Tumors that produce ectopic ACTH tend to have a poorer prognosis, compared with tumors from the same tissue that do not produce ACTH. Small cell lung cancer, islet cell tumors, and thymic carcinoids illustrate this phenomenon: up to 82% of patients with small cell lung cancer and Cushing’s syndrome were reported to die within 2 weeks from the start of chemotherapy (493), although currently a survival in terms of months should be expected.

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Gestational Diabetes

ABSTRACT

Gestational Diabetes (GDM) is characterized by glucose intolerance first manifesting during pregnancy and is an important risk factor for abnormal birthweight including large-for-gestational age birth, birth injury, and neonatal metabolic alterations--particularly when persistent maternal hyperglycemia exists. Individuals with GDM face short-term pregnancy complications, such as cesarean section and hypertensive disorders, and long-term complications, including an increased lifetime risk for type 2 diabetes and cardiovascular disease. Many of these complications associated with GDM can be moderated with lifestyle changes and pharmacotherapeutic interventions to reduce maternal hyperglycemia and thereby improve maternal and neonatal health.

PREVALENCE AND PATHOPHYSIOLOGY

Gestational diabetes (GDM) is a major problem in the US with a rapidly rising prevalence ranging from 6 to 20% of pregnancies across the world (1–4). The prevalence is highest in racial and ethnic groups that have a higher incidence of type 2 diabetes mellitus (T2DM): Hispanic, Black, American Indian, and Asian or Pacific Islander individuals (1). In the US, the prevalence of GDM was 7.8 per 100 births in 2020 with a higher annual percent change from 5% annually from 2016-2019 to 13% in 2020 (5). There are significant differences in the rate of GDM also by rural/urban status, age, body mass index (BMI), and state of residence (5,6).

Insulin resistance is paired with increased insulin secretion during pregnancy; however, among individuals with GDM, inadequate β-cell compensation relative to the level of insulin resistance results in failure to maintain euglycemia (7). GDM is caused by carbohydrate intolerance due to abnormalities in at least 3 aspects of fuel metabolism: insulin resistance, impaired insulin secretion, and increased hepatic glucose production (8,9).

Although insulin resistance is a universal finding in pregnancies with GDM, the cellular mechanisms for insulin resistance are multifactorial. Insulin binding to its receptor is unchanged in pregnant individuals (10). Pregnancy reduces the capacity for insulin-stimulated glucose transport independent of obesity, due in part to a tissue-specific decrease in insulin receptor phosphorylation and decreased expression of Insulin Receptor Substrate-1 (IRS-1), a major docking protein in skeletal muscle (11). In addition to these mechanisms, in muscle specimens from individuals with GDM, IRS-1 is further decreased and there are reciprocal and inverse changes in the degree of serine and tyrosine phosphorylation of the insulin receptor (IR) and IRS-1, further inhibiting insulin signaling (12). Individuals with GDM also have higher circulating free fatty acids (FFA) and reduced peroxisome proliferator-activated receptor (PPAR) expression in adipose tissue, a target for thiazolidinediones (13). There is evidence for a decrease in the number of glucose transporters (GLUT-4) in adipocytes in individuals with GDM and an abnormal translocation of these transporters that results in the reduced ability of insulin to recruit them to the cell surface, which contributes to the overall insulin resistance with GDM(14). In individuals with GDM, serum adiponectin levels decrease and leptin, IL-6, and TNFα increase (15).

Although dysglycemia usually remits after pregnancy, individuals with a history of GDM have a nearly 10-fold higher risk of progressing to type 2 diabetes than those without GDM and up to 70% of individuals diagnosed with GDM will develop T2DM later in life (16–18). Both GDM and T2DM are further exacerbated by increasing obesity and age. Thus, pregnancy is a “stress test” for the eventual development of glucose intolerance outside of pregnancy, and GDM may represent an unmasking of the predisposition of T2DM induced by the hormonal changes of pregnancy (19,20).

DATA TO SUPPORT THE SCREENING, DIAGNOSIS, AND TREATMENT OF GESTATIONAL DIABETES

As early as the 1940s, glucose intolerance and GDM distinct from pregestational DM were recognized to have adverse maternal and perinatal outcomes (21). Over the course of the following eight decades, candidates for screening or testing as well as the diagnostic criteria of GDM were debated (22,23). Early on, value was placed on recognition of GDM to identify individuals at risk for T2DM (24). More recently, robust studies have demonstrated the more immediate obstetric and perinatal benefits of screening, diagnosing, and treating GDM (1,24,25).

The first was a landmark trial conducted in Austria and New Zealand referred to as the ACHOIS trial (Australian Carbohydrate Intolerance Study in Pregnant Women), which demonstrated reduced serious perinatal outcomes with intervention/treatment of GDM versus no intervention (1% versus 4%) (24). This RCT enrolled 1000 pregnant individuals with either ≥1 risk factor for GDM or positive 1-hour 50 gm glucose challenge test (GCT) (≥140mg/dL) after completion of a blinded 75 gm glucose tolerance test (GTT) at 24-34 weeks gestation and demonstrated no severe glucose impairment. Individuals were randomized to receive dietary advice, self-monitoring of blood glucose (SMBG), and insulin therapy as needed to achieve fasting glucose <99 mg/dL and 2-hour postprandial values <126 mg/dL versus routine care. The primary outcome of fetal or neonatal death, shoulder dystocia, bone fracture, and nerve palsy were reduced in the intervention group compared with routine care (1% versus 4%). Although the induction of labor rate was higher in the intervention group, the cesarean delivery rate was not different.

A second landmark randomized controlled trial (RCT), the National Institute of Child Health and Human Development Maternal- Fetal Medicine Units Network study (NICHD MFMU Network), demonstrated significant differences in meaningful secondary outcomes (mean birthweight, neonatal fat mass, large for gestational age infants, birthweight >4000 g, shoulder dystocia, cesarean delivery, and hypertensive disorders of pregnancy) by treating mild GDM (25). A total of 958 pregnant individuals who met criteria for mild GDM between 24-31 weeks were randomly assigned to usual prenatal care (control) or dietary interventions, SMBG, and insulin therapy if necessary (treatment group). Although there was no significant difference in groups in the frequency of the composite outcome and no perinatal deaths in this population with very mild GDM, there were significant reductions with treatment in several pre-specified secondary outcomes. Furthermore, treatment of mild GDM was also associated with reduced rates for hypertensive disorders of pregnancy.

There is also compelling data that the risk of adverse maternal and fetal outcomes from maternal carbohydrate intolerance is along a graded continuum (26,27). The Hyperglycemia and Adverse Outcomes (HAPO) trial enrolled 25,505 pregnant individuals at 15 centers in nine countries, with participants completing a 2-hour 75 gm GTT at 24-32 weeks’ gestation (27). Data remained blinded if the fasting glucose ≤105 mg/dL and the 2-hour plasma glucose was ≤200 mg/dL. This trial demonstrated that a fasting blood glucose (FBG) ≥92 mg/dl, a 1-hour value ≥180 mg/dl, or a 2-hour value of ≥153 mg/dl increased the risk by 1.75-fold for large for gestational age (LGA or more than 90^th percentile for weight of all babies of the same gestational age) and an elevated cord-blood C-peptide consistent with fetal hyperinsulinemia. Furthermore, the fasting glucose was more strongly predictive of these outcomes than the 1-hour or 2-hour value stressing the importance of fasting glucose levels in predicting poor perinatal outcomes. The results also indicated a strong and continuous association with these outcomes and maternal glucose levels below those considered diagnostic of GDM.

DIAGNOSIS OF GESTATIONAL DIABETES

The implications of diabetes recognized for the first time in pregnancy on both maternal and perinatal outcomes have been known for nearly a century (21,28). Nevertheless, substantial controversy persists when considering which individuals warrant screening or outright diagnostic testing, at which gestational age this should occur, and the laboratory cutoffs which should confirm the diagnosis and prompt possible intervention.

Evaluation for what we currently define as GDM, for “early GDM” or for T2DM first diagnosed in pregnancy may take place in a risk-based or universal manner. In general, the basic tenants of screening as defined by the World Health Organization (WHO) are met: GDM and DM are significant health problems with significant consequences if left untreated, a suitable test exists, with benefits of screening outweighing the risks (29). The lack of consensus generally results from concerns about cost-effectiveness of differing strategies and psychological and public health burdens with increased prevalence of the condition.

Unfortunately, the historical definition of GDM as a glucose-intolerant state with onset or first recognition during pregnancy allows for inclusion of both unrecognized, pregestational, overt diabetes in addition to “true” gestational diabetes resulting from the physiologic and hormonal changes of pregnancy. Since individuals with undiagnosed pregestational diabetes are at increased risk for both maternal and fetal complications, including major malformations if their hemoglobin A1c is ≥ 6.5% in the first trimester, the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) recommends that GDM be only diagnosed if the glucose intolerance was identified in pregnancy and the pregnant individual did not qualify for pre-existing (overt) diabetes (30). The details and nuanced considerations of the current understanding of GDM as well as screening and testing modalities are described in the literature (31–33).

In the US, the US Preventive Services Task Force (USPSTF) and the American College of Obstetricians and Gynecologists (ACOG) recommend universal screening for all pregnant individuals at 24-28 weeks gestation since prior use of historic factors alone failed to identify 50% of patients with GDM (1). ACOG further supports a two-step process involving a 50 gm,1-hour glucose challenge test (GCT) followed by a 100 gm, 3-hour oral glucose tolerance test (GTT) (1). The diagnosis of GDM is made if two or more abnormal values are seen in the 3-hour GTT. Although elevation of just one out of four values in the 3-hour GTT is still associated with adverse outcomes, there is not clear evidence that this subset of patients would benefit from treatment (1,34). The one-step International Association of the Diabetes and Pregnancy Study (IADPSG) approach is utilized more frequently internationally and is supported by organizations such as National Institute for Health and Care Excellence (NICE) in UK and Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZOG) (35,36). The American Diabetes Association (ADA) continues to recognize that there is no clear evidence which supports IADPSG versus traditional ACOG two-step screening approach (37).

Table 1. Gestational Diabetes. Screening and Diagnostic Criteria, performed at 24-28 weeks’ gestation for individuals without evidence of pregestational diabetes^a
One-step approach
Perform a 75 gm GTT, with plasma glucose measurement when patient is fasting, at 1 and 2 hours. Test should occur in the morning following ≥8 hour fast
Diagnosis of GDM is made with ≥1 of the following:
Fasting ≥92mg/dL	1 hour ≥180mg/dL	2 hour ≥153mg/dL
Benefits: Single diagnostic test
Disadvantages: Must be fasting, increased prevalence of GDM without clear perinatal or long-term differences in outcomes compared to two-step approach, increased healthcare costs
Supported by: IADPSG, ADA, NICE, RANZOG
Two-step approach
Perform a non-fasting 50 gm GCT, with plasma glucose measurement at 1 hour
If glucose level measured 1 hour after the load is ≥130, 135, or 140 mg/dL ^β, proceed to a 100 gm GTT.
Perform a 100 gm GTT, with plasma glucose measurement when patient is fasting, at 1, 2 & 3 hours. Test should occur in the morning following ≥8 hour fast
The diagnosis is made when ≥2^¥ of the following (Carpenter/Coustan criteria): recommended by ACOG and ADA
Fasting ≥95mg/dL	1 hour ≥180mg/dL	2 hour ≥155mg/dL	3 hour ≥140mg/dL
The diagnosis is made when ≥2^¥ of the following (National Diabetes Data Group criteria):
Fasting ≥105mg/dL	1 hour ≥190mg/dL	2 hour ≥165mg/dL	3 hour ≥145mg/dL
Benefits: Increased compliance with “milder” initial test, no fasting required on GCT
Disadvantages: No consensus on cutoffs for GCT
Supported by: ACOG, ADA

α: Note that while most international and national guidelines have moved toward universal testing, the United Kingdom’s National Institute for Health and Care Excellence continues to recommend risk-based GDM testing (35).

β: Cutoff of 140mg/dL results in sensitivity of 70–88% and specificity of 69–89% and requires GTT in ~15% patients; cutoffof 130mg/dL results in sensitivity of 88–99% and specificity of 66–77% specific and requires GTT in ~25% patients.

¥: ACOG allows for consideration of diagnosis with ≥1 criteria met.

The controversy with the diagnosis of GDM relies heavily on the outcomes studied. The IADPSG recommendations are based on the HAPO trial, which showed that a single value on a 75 gm 2-hour GTT resulted in a 1.75-fold increased risk of LGA and thus should be the basis for the diagnosis; however, critics disagree (38,39). Critics contend that a 2.0-fold increase in LGA risk instead of 1.75 could have been chosen which would not have appreciably increased the prevalence of GDM over the ACOG criteria (40,41). Nearly 90% of all individuals who met criteria for GDM using the 75 gm 2-hour GTT were diagnosed based on the fasting blood glucose (FBG) and 1-hour values, raising the question of whether the 2-hour value is worth the extra time and cost (42). Additionally, evaluation of higher glycemic criteria (fasting glucose ≥99 and 2-hour level glucose ≥162 mg/dl) for the diagnosis of gestational diabetes by the Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS) trial group did not increase the risk for LGA infant (43).

Currently there is no consensus about the adoption of the IADPSG criteria over the ACOG criteria. The NIH held a Consensus Conference in March of 2013 (44). They acknowledged that the HAPO study was the first to demonstrate that glycemic thresholds currently lower than the ACOG diagnostic criteria thresholds correlated with LGA and adopting the 75 gm GTT would be beneficial in standardizing diagnostic criteria internationally. However, they concluded that there were insufficient data from RCTs demonstrating that adopting the lower glucose thresholds would significantly benefit the much larger population of women who make the diagnostic criteria for GDM based on the IADPSG criteria and such adoption could markedly increase cost of treatment. Further, there was a concern that adopting the IADPSG criteria could triple the prevalence of GDM, potentially outstripping the resources to treat it. Recent clinical trials comparing screening strategies confirm that the one-step approach has been associated with an upwards of threefold increase in the prevalence of GDM compared to the two-step approach, but there is no clear evidence that the increased diagnosis is associated with improved maternal or perinatal outcomes (37,39,45,46).

At the consensus conference, it was also argued that it is not clear how much the increased risk of LGA at lower glucose thresholds observed in the HAPO trial on which it was based was due to maternal obesity or mild hyperglycemia. A retrospective review of nearly 10,000 individuals who were diagnosed with GDM using the IADPSG criteria showed an overall GDM prevalence of 24%. After excluding individuals who required treatment for GDM, 75% of GDM individuals were overweight or obese. Although GDM nearly doubled the risk of LGA over obesity alone (22.3% versus 12.7% respectively), in individuals without GDM, 21.6% of LGA was attributable to being overweight and obese. The combination of GDM in addition to being overweight or obese did not add much to the attributable risk for LGA and accounted for 23.3% of LGA infants (47).

The threshold levels for the 3-hour GTT have been debated. The initial diagnostic thresholds for the 3-hour GTT were initially established by O’Sullivan and Mahan (48). National Diabetes Data Group and Carpenter and Coustan criteria have subsequently been developed since with Carpenter and Coustan criteria suggesting more stringent thresholds (49,50). Further retrospective investigations have shown that the lower Carpenter and Coustan criteria may diagnose more patients that could benefit from treatment of GDM (51–53). Therefore, ACOG and ADA recommend the Carpenter and Coustan criteria (37,54).

Recently, Hillier et al published the results of their pragmatic, randomized trial comparing one-step screening with two-step screening in which nearly 24,000 individuals were randomized (45). The diagnosis of GDM was roughly doubled using the one-step approach versus the two-step approach, at rates of 16.5% and 8.5% respectively (unadjusted relative risk, 1.94; 97.5% confidence interval [CI], 1.79 to 2.11) (40). Importantly, there were no significant differences between diagnostic approaches with the primary outcomes (LGA infants, perinatal composite, gestational hypertension or preeclampsia, and primary cesarean delivery). Potential limitations include a sample size underpowered to detect differences in the groups, treatment of individuals with a single elevated GTT value, and suboptimal adherence to protocols (38). A meta-analysis comparing one-step and two-step screening methods showed a twofold risk of the diagnosis of GDM with the one-step approach without a difference in the risk of LGA infants (39).

Screening Prior to 24 Weeks Gestation- Who, Why, and How?

Several factors have contributed to newer recommendations to consider early screening for diabetes: the rising incidence of T2DM because of the obesity epidemic, in addition to a better understanding of the risks associated with hyperglycemia early in pregnancy, such as congenital anomalies and miscarriage (55). In an obstetric setting, the best time to screen for and diagnose T2DM is as early as possible in the pregnancy, ideally in the first trimester before the placental effects causing insulin resistance have begun. There is not a recognized lower gestational age cutoff at which insulin resistance can be attributed to placental effects, though this likely occurs prior to the GDM screening range of 24-28 weeks.

There is conflicting evidence that screening for GDM prior to 24 weeks gestational age is beneficial. A RCT of 962 individuals examining early screening for GDM in individuals living with obesity compared to standard of care did not show reductions in composite perinatal outcomes (56). Even if an individual is diagnosed with GDM prior to 20 weeks, only modest benefit in composite perinatal outcomes was seen with early treatment (57). As a result, early screening for GDM is not routinely recommended, but screening high-risk individuals for overt diabetes is recommended. The 2024 ADA guidelines recommend screening individuals at the first prenatal visit if BMI >25 kg/m2 (or >23 kg/m2 in Asian Americans) and one or more risk factors (Table 2). Universal screening of pregnant individuals <15 weeks of gestation for undiagnosed pregestational diabetes could also be considered especially in populations with a high prevalence of undiagnosed diabetes. The IADPSG/ADA recommends that individuals diagnosed for the first time in pregnancy prior to 24 weeks should be considered as having overt diabetes following the same criteria for diabetes outside of pregnancy (Table 3) (37,42). ACOG does not recommend screening for GDM prior to 24 weeks, but in line with ADA recommendations it does recommend screening for overt diabetes early in pregnancy (54). The USPSTF concludes there is insufficient evidence to recommend screening for GDM before 24 weeks gestation (58).

The method of screening for diabetes in early pregnancy is also controversial. The ADA recommends screening for abnormal glucose metabolism in early pregnancy may be accomplished with fasting glucose <110 mg/dL or A1c <5.9% (37). ACOG recommends following the same diagnostic criteria for diabetes outside of pregnancy including A1c value³6.5% or higher, fasting plasma glucose value ³126 mg/dL, or 2-hour plasma glucose value ³200 mg/dL during a 75-g GTT, or random plasma glucose value ³200 mg/dL in patients with classic hyperglycemia symptoms (54). Individuals with evidence of impaired glucose tolerance or prediabetes such as A1c value 5.7–6.4% or 2-hour glucose value between 140 and 199 mg/dL on the 75-g GTT, ACOG recommends nutrition counseling when resources are available (54). If overt T2DM is not diagnosed on early screening, then routine screening for GDM between 24-28 weeks is still recommended.

Table 2. Risk Factors for Early Diabetes Screening

ADA and ACOG 2024 (37,54)

· Overweight or obesity (BMI >25 kg/m² or >23 kg/m² in Asian Americans) who have one or more of the following risk factors:

· First-degree relative with diabetes

· High-risk race/ethnicity (e.g., African American, Latino, Native American, Asian

· American, Pacific Islander)

· History of cardiovascular disease

· Hypertension

· History of hyperlipidemia (HDL cholesterol level <35 mg/dL and/or a triglyceride level >250 mg/dL)

· Women with polycystic ovary syndrome

· Physical inactivity

· Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)

· Age 35 years or greater

· Patients with prediabetes (A1C >5.7% IGT, or IFG)

· Women who were diagnosed with GDM in prior pregnancy

· People with HIV

Table 3. Early Screening: Identification of Prediabetes and Diabetes
Risk-based testing performed at the first prenatal visit using standard diagnostic criteria
Diagnostic for diabetes (any one of the following):
Fasting: ≥126 mg/dL	75 gm GTT with 2- hour value ≥200 mg/dL		HbA1c ≥6.5%		Random plasma glucose ≥200 mg/dL in the setting of classicsymptoms of hyperglycemia or hyperglycemic crisis
If diagnostic criteria for diabetes are met, no additional GDM testing required
Diagnostic for prediabetes or abnormal glucose metabolism (any one of the following):
Fasting:100-125 mg/dL^α Fasting: 110-125 mg/dL^β		75 gm GTT with 2-hour value 140-199 mg/dL^α		HbA1c ≥5.7-6.4% HbA1c ≥5.9-6.4%^β

α: ACOG recommends the following values for prediabetes.

β: ADA Standards of Care 2024 suggests that using a threshold fasting glucose of 110 or HbA1c of 5.9% can identify individuals who are at higher risk of adverse pregnancy and neonatal outcomes.

RISKS TO THE MOTHER AND INFANT WITH GESTATIONAL DIABETES

The pregnancy-associated risks to the individual with GDM are an increased incidence of cesarean delivery (~25%), hypertensive disorders of pregnancy (~20%), and polyhydramnios (~20%) (59–62). The long-term risks are related to recurrent GDM pregnancies and the substantial risk of developing T2DM. Individuals with GDM represent a group with an extremely high risk (~50-70%) of developing T2DM in the subsequent 5-30 years (1,16–18,63,64). Individuals with fasting hyperglycemia, obesity, those belonging to a racial/ethnic group with a high prevalence of T2DM (in particular those who self-identify as Asian and Pacific Islander and Hispanic), or who demonstrate impaired glucose tolerance or fasting glucose at 6 weeks postpartum, have the highest risk of developing T2DM (1,3,63). Counseling about diet, weight loss, and exercise is essential and is likely to improve insulin sensitivity.

Thiazolidinediones, metformin, and lifestyle modifications have all been demonstrated to decrease the risk of developing T2DM in GDM women who have impaired fasting glucose or glucose intolerance postpartum (65–67).

The potential risks to the infant from GDM are similar to those in pregnancies complicated by T1DM or T2DM with suboptimal control in the second half of pregnancy (stillbirth, macrosomia, shoulder dystocia, premature delivery, neonatal hypoglycemia, hyperbilirubinemia, and NICU admission). Notably congenital malformations and miscarriage risks would not be observed with later-onset insulin resistance with GDM (1,62,68,69). Like pregestational DM, the degree of hyperglycemia correlates with perinatal risk. Among diet-controlled GDM pregnancies the risk of stillbirth is not increased compared to the general population (70). The developmental origin of health and disease suggests that there can be an association with maternal health on the future health of the child (71,72). In addition to immediate postnatal risks, infants of individuals with GDM are themselves at increased risk for childhood and adult-onset obesity and diabetes (73).

MEDICAL NUTRITION MANAGEMENT AND EXERCISE

Individuals with GDM should be taught home glucose monitoring to ensure that their glycemic goals are being met throughout the duration of pregnancy. The same goals are utilized in GDM pregnancies as in pregestational DM: a fasting glucose <95mg/dL, 1-hour postprandial <140mg/dL and 2-hour postprandial <120mg/dL (1,37). The best therapy for GDM depends on the severity of the glucose intolerance, the individual’s response to non-pharmacologic or pharmacologic treatment, as well as effects on fetal growth. Diet and exercise alone will maintain the fasting and postprandial blood glucose values within the target range in at least 50% of individual with GDM. A 2018 meta-analysis evaluating diet modifications illustrated improvements in fasting and postprandial glucose values and lower need for medical treatment when compared with controls (74). Furthermore, diet modifications were also associated with lower infant birth weight and less macrosomia (74).

Nevertheless, data are limited regarding the optimal GDM diet to achieve euglycemia and avoid perinatal complications of GDM. The current recommended diet for GDM includes consumption of at least 175 gm of carbohydrate, with complex carbohydrates favored over simple carbohydrates, a minimum of 71 gm of protein, and 28 gm of fiber to provide adequate macronutrients and avoid ketosis (75). There is little evidence to support one dietary approach over another, but common practice is three meals and 2-3 snacks daily to distribute carbohydrate intake and reduce postprandial hyperglycemia. The caloric intake and weight gain recommendations are also consistent with what is recommended in individuals with obesity or T2DM. We recommend multidisciplinary care with a dietician or nurse educator familiar with GDM to individualize a dietary plan.

In 2009, the Institute of Medicine (name changed to National Academy of Medicine in 2015), published recommended gestational weight gain (GWG) based on pre-pregnancy BMI, with less GWG recommended for overweight and obese individuals compared to those with normal BMI (76). Nevertheless, follow up studies demonstrated a large proportion of pregnant individuals worldwide had GWG above (27.8%) and below (39.4%) the IOM guidelines, with highest mean GWG and pre-pregnancy BMI observed in North America (77). Furthermore, a variety of adverse outcomes have been observed in the setting of excess GWG, including LGA and macrosomic infants in the GDM population (78–80). As a result, the question has been raised whether weight gain less than the IOM guidelines in GDM pregnancies could improve outcomes. There are studies suggesting that weight gain less than IOM recommendations for overweight GDM women may decrease insulin requirements, cesarean delivery, and improve pregnancy outcomes without appreciably increasing small for gestational age (SGA) (81–83). Further, a third study suggesting that slight weight loss (mean of 1.4 kg) in overweight GDM women decreased birth weight without increasing SGA (84). Larger meta-analyses confirmed these findings but failed to identify an ideal weight gain range for optimal outcomes (85). These findings have yet to be included in GWG guidelines specific to pregnant individuals living with diabetes.

Since postprandial glucose levels have been strongly associated with the risk of macrosomia it has been suggested that carbohydrate restriction to ~33-40% of total calories may be helpful to blunt the postprandial glucose excursions, in addition to preventing excessive weight gain (86). However, the actual dietary composition that optimizes perinatal outcomes is unknown. There is also growing concern that individuals are substituting fat for carbohydrates which hasbeen associated with adverse fetal programming including oxidative stress as well as an insulin resistant phenotype (87,88). Although a low carbohydrate, higher fat diet has been conventionally recommended to minimize postprandial hyperglycemia, a review of the few randomized controlled trials examining nutritional management in 250 GDMindividuals suggested that a diet higher in complex carbohydrate and fiber, low in simple sugar and lower in saturated fatmay be effective in blunting postprandial hyperglycemia, preventing worsened insulin resistance, and excess fetal growth (89). A more recent trial challenged the traditional low-carb/higher-fat diet and demonstrated that a diet with higher complex carbohydrates and lower-fat reduced fasting blood glucose and infant adiposity (90). Given these trials, a diet of complex carbohydrates is recommended over simple carbohydrates primarily due to slower digestion time which prevents rapid increases in blood glucose.

The role of exercise in GDM may be even more important than in individuals with preexisting diabetes given exercise in some individuals may lessen the need for medical therapy. This idea is similar to the evidence in non-pregnant individuals with diabetes which supports weight training due to increases in lean muscle and increased tissue sensitivityto insulin. A 2013 review showed that in individuals with GDM, five of seven (~70%) activity-based interventions showedimprovement in glycemic control or limiting insulin use (91). In most successful studies (3 times/week), insulin needs decrease by 2-3-fold, and overweight or obese women benefited the most with a longer delay from diagnosis to initiation of insulin therapy. Moderate exercise is well tolerated and has been shown in several trials in individuals with GDM to lower maternal glucose levels (92–94). Using exercise after a meal in the form of a brisk walk may blunt the postprandial glucose excursions sufficiently in some individuals that medical therapy might be avoided.

Establishing a regular routine of modest exercise during pregnancy, per ACOG of 30 minutes of moderate-intensity aerobic activity at least 5 days/week, may also have long lasting benefits for the individual with GDM who clearly has an appreciable risk of developing T2DM in the future (1).

MEDICAL TREATMENT OPTIONS

Once the diagnosis of gestational diabetes is confirmed and glycemic control exceeds target ranges despite dietary education and lifestyle changes, pharmacotherapy must be considered. Prior to the 21st century, insulin was the sole medical option for GDM. After the introduction of oral agents such as glyburide and metformin, initiation of these agents increased, with addition or transition to insulin therapy if glycemic control remained suboptimal. In 2018, ACOG joined the ADA in endorsing insulin as first-line therapy and this was reaffirmed in the 2024 ADA Standards of Care. In contrast, the Society of Maternal-Fetal Medicine (SMFM) released a statement recommending metformin as a reasonable first-choice therapy in addition to insulin (1,75,95). The optimal use of oral agents for the management of GDM is an area of ongoing investigation (96,97).

Although there are few data from randomized controlled trials to determine the optimal therapeutic glycemic targets, the standard of care is that individuals who have fasting blood glucose levels >95 mg/dl, 1-hour postprandial glucose levels >140 mg/dl or 2-hour postprandial glucose levels >120 mg/dl be started on medical therapy. In 5 randomized trials it was demonstrated that if insulin therapy is started in individuals with GDM whose maternal glucose values are at target levels on diet alone but whose fetuses demonstrate excessive growth by an increased abdominal circumference (AC) relative to the biparietal diameter (BPD) i.e. body to head disproportion, the rate of fetal macrosomia can be decreased (81). This fetal based strategy using ultrasound at 29-33 weeks to measure the AC in order dictate the aggressiveness of maternal glycemic control has been recommended by the Fifth International Workshop-Conference on Gestational Diabetes and the IADPSG (30,98,99). Evidence also suggests that higher glycemic targets may have similar outcomes to lower glycemic targets (100). The threshold to initiate pharmacologic therapy by maternal fetal medicine specialists can differ, but most providers recommend initiation of pharmacologic therapy if 30-50% of blood glucose values are elevated (101).

Continuous glucose monitoring (CGM) has also been proposed as an adjunct to traditional glucose monitoring. CGM use has proven beneficial in type 1 diabetes in pregnancy, and its use is recommended by ADA and ACOG (75,102,103). However, there is no clear evidence of its benefit in the setting of GDM. One meta-analysis including 6 trials of 482 individuals with GDM showed that CGM use may achieve lower average blood glucose levels, lower maternal weight gain and infant birth weight, but the studies were limited by overall small sample sizes (104). The specific metrics of CGM data, including pregnancy-specific time-in-range, has not been clearly established and further research should be done before widespread implementation of CGM in GDM.

GDM can often be treated with twice daily injections of intermediate or long-acting insulin (i.e., NPH, glargine, detemir) and mealtime injections of lispro or aspart as necessary for postprandial hyperglycemia. Short acting insulin (i.e., lispro or aspart) is preferred over regular insulin due to time of onset and duration to better control postprandial glycemic excursions. See Endotext chapter “Pregestational Diabetes” for details regarding antepartum, intrapartum, and postpartum insulin dosing regimens (105).

Metformin

One of the largest experiences with metformin in the setting of GDM was with metformin initiated later in pregnancy (106). In this randomized, controlled Metformin in Gestation (MIG) trial, 751 individuals with GDM were randomized to metformin versus insulin. Individuals that did not get adequate glycemic control on metformin received insulin. There was no difference in both groups concerning the primary composite outcome (neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5- minute APGAR <7), or premature birth. As such, metformin did not appear to increase any adverse outcomes, although it was associated with a slight increase in preterm birth; however, this did not appear to be clinically relevant.

Importantly, 46% of the individuals in the metformin group required supplemental insulin to achieve adequate glycemic control. This study demonstrated interesting metformin benefits including reduced maternal weight gain, improved patient satisfaction, and reduced incidence of gestational hypertension. In a smaller RCT, Ijas et al demonstrated metformin had a 32% rate of requiring supplemental insulin (107). They also noted individuals needing supplemental insulin added to metformin were more likely to be obese, have higher fasting blood glucose levels, and initiated pharmacotherapy earlier. Spaulonci et al randomized 47 individuals with GDM to metformin or insulin and demonstrated significant metformin benefits including: less gestational weight gain, lower mean glucose levels, and lower rates of neonatal hypoglycemia (108). Overall, meta-analyses have demonstrated largely reassuring outcomes for metformin compared to insulin and glyburide (109–112). Early initiation of metformin after diagnosis of GDM did not show benefit in fasting BGs over standard of care (113).

Metformin should be avoided in individuals with renal insufficiency. It is typically prescribed in divided doses starting with 500 mg once or twice daily for 1 week and then increasing to a maximum dose of 2500 mg daily in divided doses with meals. Common side effects include gastrointestinal complaints (occurring in 2.5-45.7% of pregnant individuals in studies) (109). These randomized trials have shown short-term efficacy and safety of metformin use in pregnancy for GDM treatment.

Until recently, long-term safety data of in-utero metformin exposure has been lacking, though several studies have been published commenting on infant and childhood weight, BMI, cardiovascular health, and neurodevelopmental outcomes. The earliest follow-up studies in metformin-exposed infants suggested they had larger measures of subcutaneous fat when compared to those exposed to insulin (110). Another study in PCOS women comparing metformin to placebo showed that although women randomized to metformin gained less weight during pregnancy, at 1 year postpartum the women who used metformin in pregnancy lost less weight and their infants were heavier than those in the placebo group (112). These fetal and neonatal results are likely because metformin is concentrated in the fetal compartment with umbilical artery and vein levels being up to twice those seen in the maternal serum (114,115). Hypothetically if metformin increases insulin sensitivity in the fetus, it might be possible for excess nutrient flux across the placenta to result in increased fetal adipogenesis. More recent studies also identified slight increased weight in metformin-exposed infants, a relationship that may no longer be present after 4 years of age (116,117). Long-term follow up of BMI is conflicting (112,117). A very large study in New Zealand evaluated outcomes at 4 years of age in nearly 4000 individuals, with no differences in growth and development assessments compared to insulin-exposed children (118). The metabolic and weight differences warrant further investigation since similar patterns of low birth weight followed by accelerated growth are associated with adverse long-term outcomes (119). At least one study has failed to demonstrate such a relationship in this population (120). A study of 211 individuals with GDM randomized to insulin versus metformin during pregnancy found similar developmental outcomes by 2 years of age (111).

In review, the ADA and ACOG note that insulin is the first-line agent for treatment of GDM if lifestyle changes have not achieved glycemic targets (1,75). The ADA notes that although individual RCTs have shown short-term benefits and safety of metformin and glyburide, long- term safety data are lacking (75). Both organizations acknowledge that 20-45% of women fail metformin monotherapy necessitating that insulin be added (1). Counseling is necessary to explain to women that although current data do not demonstrate any adverse short-term outcomes, there are concerns about placental transfer of metformin, potential increased preterm birth, and lack of data on long term outcomes of fetuses exposed to metformin in-utero, metformin’s effect on fetal insulin sensitivity, hepatic gluconeogenesis, and the long-term fetal programming implications are unknown. SMFM suggests that metformin is a reasonable and safe alternate first line pharmacologic treatment (95). The UK NICE guidelines also suggest that metformin as a first-line medication for patients with GDM who require pharmacologic therapy (121).

Glyburide and Other Agents

Glyburide is the only sulfonylurea that has been studied in a large, randomized trial in individuals with GDM. It was approved by the 5th International Workshop and IADPSG as a possible alternative to insulin in individuals with GDM due to several RCTs (122). The dose ranges from 2.5-20 mg daily in divided doses.

Glyburide exposure in most RCTs is limited to the second and third trimesters, so the effect on embryogenesis was not studied, but there are no convincing reports that it is a teratogen. Due to its peak at 3-4 hours, many individuals have inadequate control of their 1- or 2-hour postprandial glucoses and then become hypoglycemic 3-4 hours later and data suggest that serum concentrations with usual doses are lower in pregnant individuals. If used, it should be given 30 mins-1-hour before breakfast and dinner and should not be given before bedtime due to the risk of nocturnal or early morning hypoglycemia considering its 3–4-hour peak (similar to regular insulin). For individuals unwilling to administer multiple daily insulin injections who have postprandial glucoses well controlled by glyburide but have fasting hyperglycemia, adding intermediate or long-acting insulin before bedtime to the glyburide can sometimes be useful. If both postprandial and fasting glucoses remain elevated, the individual should be switched to insulin.

The earliest RCTs offered glyburide as a safe alternative to insulin, without significant differences in perinatal outcomes(123). In the last 20 years, growing evidence has suggested there is increased risk of both maternal and neonatal hypoglycemia with glyburide use (109,124–127). In some trials, maternal glycemic control, macrosomia, neonatal hypoglycemia, and neonatal outcomes were not different between groups although in others, there was a significantly greater rate of macrosomic infants in the glyburide group ((123,128,129)). In a meta-analysis examining metformin versus insulin versus glibenclamide (glyburide) treatment for individuals with GDM, there were higher rates of macrosomia (risk ratio 2.62) and neonatal hypoglycemia (risk ratio 2.04) among those treated with glibenclamide compared with insulin (109). This is the same publication reviewed above that showed the increased risk of preterm birth in individuals treated with metformin compared with insulin. This meta-analysis in addition to a second meta-analysis showed significantly worse neonatal outcomes among offspring of individuals with GDM treated with glyburide compared to insulin (109,128). There were higher rates of neonatal hypoglycemia, respiratory distress syndrome, macrosomia, and birth injury without significant differences in glycemic control (124,128).

A RCT compared the efficacy of metformin with glyburide for glycemic control in GDM (124). In the individuals who achieved adequate glycemic control, the mean glucose levels were not statistically different between the two groups. However, 26 individuals in the metformin group (34.7%) and 12 individuals in the glyburide group (16.2%) did not achieve adequate glycemic control and required insulin therapy (p=0.01). Thus, in this study, the need for insulin supplementation with metformin was twice as high as the failure rate of glyburide when used in the management of GDM (124). These findings are consistent with the general finding that approximately, 15% of individuals will fail maximum dose glyburide therapy and need supplemental insulin, especially if dietary restriction is not carefully followed. Although it was initially thought not to appreciably cross the placenta or significantly affect fetal insulin levels, examination using HPLC mass spectrometry suggested a modest amount of glyburide does cross (114).

There is not sufficient information available on thiazolidinediones, meglitinides, dipeptidyl peptidase IV (DPP-4) inhibitors, glucagon like peptide 1 (GLP-1) agonists, sodium-glucose transport protein 2 (SGLT-2) inhibitors, and such agents should only be used in the setting of approved clinical trials as their teratogenic potential is unknown. Acarbose was studied in two very small studies in individuals with GDM and given its minimal GI absorption is likely to be safe, but GI side effects are often prohibitive (130). Safety studies of GLP-1 agonists and SGLT2 inhibitors have shown potential teratogenicity and adverse pregnancy outcomes mostly derived from animal studies (131). Limited observational studies in humans have not shown significant adverse outcomes with periconceptional use of GLP-1 agonists (132,133). The effect of use in later pregnancy and for gestational diabetes is unknown. Additional information about the use of these medications outside of pregnancy can be found in the chapter entitled “Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes” in the Diabetes Mellitus and Carbohydrate Metabolism section of Endotext (134).

FETAL SURVEILLANCE AND DELIVERY OPTIONS IN GESTATIONAL DIABETES

Individuals with GDM who require pharmacotherapy but do not have other comorbidities should initiate once or twice weekly antenatal fetal surveillance at 32 weeks gestation

(135). There is no consensus regarding antepartum testing in individuals with diet-controlled GDM (1). For those individuals with diet-controlled GDM extending pregnancy beyond 40 weeks gestation, consideration could be made to initiate antenatal testing (135).

An ultrasound for growth to look for head to body disproportion (large abdominal circumference compared to the biparietal diameter) and evidence of LGA should be considered at ~29-32 weeks (1). The documented risks associated with attempted vaginal delivery with a fetal estimated weight >4500 gm in the setting of pregestational diabetes have resulted in a reasonable practice of offering cesarean delivery (136). This recommendation is extended to those with GDM and a fetal estimated weight >4500 gm (1). Nevertheless, a Cochrane review found insufficient evidence in using fetal biometry to assist in guiding the medical management of GDM to improve either perinatal or maternal health outcomes (137).

When GDM is well-controlled with either diet or medications, delivery <39 weeks gestation is not warranted. Delivery is usually recommended by 40 6/7 weeks for uncomplicated diet-controlled GDM and by 39 6/7 weeks for well-controlled GDM on medication(138). Earlier delivery should be considered with suboptimal glucose control or other complicating factors such as hypertension (138). The framework of evaluating the risks and benefits of induction of labor to expectant management in both high-risk and low-risk individuals has shifted from a historical lens of induction of labor compared to spontaneous labor; multiple studies have demonstrated no increased risk of cesarean delivery with induction of labor <40 weeks gestation (139–141).

POSTPARTUM ISSUES IN WOMEN WITH GESTATIONAL DIABETES

Re-Evaluating Glucose Tolerance Postpartum and Future Risk of Diabetes

Identification of poor glycemic control in pregnancy to predict risk for T2DM was present in the earliest screening and diagnostic strategies. Up to 70% of individuals with GDM are estimated to ultimately develop T2DM within 20-30 years after delivery. Differentiation of GDM from previously undiagnosed T2DM should be performed via a 75-gram 2-hour GTT within 4-12 weeks postpartum as recommended by the ADA, Canadian Diabetes Association (CDA), Fifth International Workshop, and ACOG since most individuals with impaired glucose intolerance will be missed if only a FBG is checked (142). A 2-hour value of at least 200 mg/dl establishes a diagnosis of diabetes and a 2-hour value of at least 140 mg/dl but less than 200 mg/dl makes the diagnosis of impaired glucose tolerance. Additionally, individuals who have been diagnosed with GDM should be screened at least every 3 years for overt diabetes (37).

An alternative approach that is endorsed by ACOG in a 2024 Clinical Practice Update is to perform the 75-gram GTT on postpartum day 2 prior to hospital discharge, since completion of postpartum screening is historically low (54). A large series of ~23,000 individuals who received lab testing through Quest diagnostics suggested that only 19% of individuals receive postpartum diabetes testing within a 6-month period (143). Waters et al. demonstrated a negative GTT prior to hospital discharge excluded T2DM diagnosis at 4-12 weeks postpartum (144). Werner et al. showed similar diagnostic value of 2-day postpartum GTT to the standard 4-12 weeks postpartum GTT (145)

A weight loss program consisting of diet and exercise should be instituted for individuals with GDM to improve their insulin sensitivity and hopefully to prevent the development of T2DM (146). Hyperglycemia generally resolves in most individuals during this interval but up to 10% of patients will fulfill criteria for T2DM. At the minimum, a fasting blood glucose should be done to determine if the woman has persistent diabetes (glucose >125 mg/dl) or impaired fasting glucose (glucose ≥ 100 mg/dl). Of note, breastfeeding has been shown to improve insulin resistance and glucose values in postpartum individuals with GDM (147,148).

Utility of using the A1c postpartum to predict the subsequent occurrence of T2DM in individuals with a history of GDM has not been studied extensively and may be affected by glycemic control during pregnancy if done before 3 months postpartum (149). A study looking at utility of using A1c vs 2h GTT vs FPG for screening of individuals with recent GDM showed that A1c and A1c plus FPG did not have the sensitivity and specificity to diagnose impaired carbohydrate metabolism postpartum (150,151). The importance of diagnosing impaired glucose intolerance lies in its value in predicting the future development of T2DM. In one series which mainly studied Hispanic individuals, a diagnosis of impaired glucose tolerance was the most potent predictor of the development of T2DM in individuals with a history of GDM; 80% of such women developed diabetes in the subsequent 5-7 years (152). Intensified efforts promoting diet, exercise and weight loss should be instituted in these individuals.

Other studies have shown other risk factors for development of prediabetes and/or T2DM after GDM including earlier diagnosis of GDM in pregnancy, insulin therapy during pregnancy, and BMI (64,153,154). A study in Italy showed pre-pregnancy BMI and PCOS as strong predictors of postpartum impaired glucose tolerance (155,156). A1c within 12 months postpartum may be useful in addition to GTT to diagnose some women with history of GDM and normal glucose tolerance. A study of 141 individuals in Spain with recent GDM found that 10% had normal glucose tolerance, normal FPG, and isolated A1c 5.7-6.4% suggesting that A1c is a useful tool to diagnose prediabetes in individuals with a history of GDM with normal glucose tolerance postpartum (156). Interestingly, in this study the group of individuals with isolated A1c 5.7-6.4% with normal glucose tolerance and normal FPG were more likely to be non-Hispanic White and more likely had higher LDL-C values. A1c is a sensitive test in detecting prediabetes and overt diabetes in postpartum individuals with history of GDM (157).

The TRIPOD study demonstrated that the use of a thiazolidinedione postpartum in individuals with a history of GDM and persistent impaired glucose intolerance decreased the development of T2DM (158). The rate of T2DM in the 133 individuals randomized to troglitazone was 5.4% versus 12.1% in the 133 individuals randomized to placebo at a median follow-up of 30 months (159). The protection from diabetes was closely related to the degree of reduction of insulin secretion three months after randomization and persisted 8 months after the medication was stopped. In the PIPOD study, use of Pioglitazone to the same high-risk patient group stabilized previously falling β-cell function and revealed a close association between reduced insulin requirements and low risk of diabetes (7,67). However, using thiazolidinediones for the purpose of preventing the development of T2DM in individuals with a history of GDM has not been recommended. The Diabetes Prevention Program (DPP) Trial analyzed their data in individuals with a history of GDM (66). A total of 349 individuals had a history of GDM, and such a history conferred a 74% increased risk for the development of T2DM compared with individuals without a history of GDM. In the placebo arm, individuals developed T2DM at an alarming rate of 17% per year but this rate was cut in half by either use of metformin or diet and exercise.

The DPP, TRIPOD, and PIPOD studies support clinical management that focuses on identifying individuals who meet criteria for metabolic syndrome, achieving postpartum weight loss, and instituting aggressive interventions beginning with lifestyle changes to decrease insulin resistance for the primary prevention of T2DM. Individuals with a history of GDM who display normal testing postpartum should undergo lifestyle interventions for postpartum weight reduction and receive repeat testing at least every 3 years (37). For individuals who may have subsequent pregnancies, screening more frequently has the advantage of detecting abnormal glucose metabolism before the next pregnancy to ensure preconception glucose control (1).

Breastfeeding

Breastfeeding should be encouraged in all individuals with a history of GDM for improving maternal and offspring health outcomes. Lactation completes the reproductive cycle and is associated with significant short- and long-term cardiometabolic benefits for both mother and infant, with most demonstrating a dose-dependent relationship (160). Professional society recommendations recommend exclusive breastfeeding for the first 6 months of life, then ongoing breastfeeding with complementary foods through the second year or as long as desired by both mother and child (160–162).

Initially the correlation between breastfeeding and reduced incidence of T2DM were based on self-reported lactation status and diabetes diagnoses. Subsequent larger studies have confirmed this relationship. Over 1200 individuals who had at least 1 live birth and reported lactation duration were followed in a community-based prospective study over 30 years, with diabetes screening performed up to 7 times (CARDIA study) (163). Not only was there a three-fold increased incidence of T2DM in those with no breastfeeding compared to any breastfeeding, but the relative hazard was also graded based on duration of breastfeeding (163). These findings were also reported in the most recent meta-analysis evaluating the relationship between lactation and maternal risk of T2DM (164).

For children, breastmilk intake also appears to decrease the risk of developing obesity and impaired glucose tolerance (165). In the large EPOCH study (Exploring Perinatal Outcomes Among Children Study), offspring of individuals with diabetes (primarily GDM) who were breastfed for at least 6 months had a slower BMI growth trajectory during childhood and a lower childhood BMI than those who were not breastfed (166). There is a growing literature suggesting that some of the protective benefits on childhood obesity and programming the infant immune system from breast milk may be influenced by appetite regulatory hormones, biomarkers of oxidative stress and inflammation, and the milk microbiome (167–170).

Contraception

Discussing contraception and family planning during pregnancy is an effective way to promote safe pregnancy interval, with optimal outcomes observed when delivery and conception are at least 18 months apart (171). For individuals with GDM, the postpartum and inter-pregnancy periods offer a tremendous opportunity to employ diet, lifestyle, and other therapeutic changes to reduce the risk of subsequent GDM or T2DM (171). All pharmacologic options for contraception are considered safe in the setting of recent or remote GDM, though estrogen-containing methods should be delayed until ≥21 days postpartum to reduce the risk of thromboembolism (172). Estrogen may negatively impact breast milk production, so consideration of infant feeding method should also be weighed against initiation. We recommend a patient-centered approach to counseling and selecting a contraceptive method.

There is limited data on the influence of various contraceptive methods on long-term risk of T2DM, insulin sensitivity, glycemic control, weight gain, and hypercholesterolemia (173). Extensive research evaluating these relationships concludes the adverse outcomes observed with methods such as Depo-Provera in the GDM population are more closely associated with initial BMI and pregnancy weight gain than with GDM.

CONCLUSION

Different organizations recommend different screening and diagnostic strategies for GDM reflecting variations in geographic settings. Treatment with lifestyle or medication to achieve glycemic targets improves obstetric and perinatal outcomes. Due to the obesity epidemic, the incidence of GDM is only expected to rise, with subsequent or eventual T2DM diagnosis increasing accordingly. Further investigation on the benefits of specific pharmacologic therapies and glucose monitoring strategies with CGM are ongoing.

The development of T2DM in individuals with a history of GDM as well as obesity and glucose intolerance in the offspring of those with preexisting DM or GDM set the stage for a perpetuating metabolic cycle that must be aggressively addressed with effective primary prevention strategies that begin in-utero. Pregnancy is a unique opportunity to implement strategies to improve the mother’s lifetime risk for adverse cardiometabolic health outcomes in addition to that of her offspring and offers the potential to decrease the intergenerational risk of obesity, diabetes, and other adverse cardiometabolic outcomes.

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Lipodystrophy Syndromes: Presentation and Treatment

ABSTRACT

Lipodystrophy syndromes are a heterogeneous group of diseases, characterized by selective absence of adipose tissue. In one sense, these diseases are lipid-partitioning disorders, where the primary defect is the loss of functional adipocytes, leading to ectopic steatosis, severe dyslipidemia, and insulin resistance. These syndromes have attracted significant attention since the mid-1990s as the understanding of adipose tissue biology grew, initially spurred by the discovery of the pathways leading to adipocyte differentiation and maturation, and then by the discovery of leptin. Although lipodystrophy syndromes are known since the beginning of the 20th century, significant progress in understanding these syndromes were made in the last two decades, placing these syndromes at the forefront of the translational metabolism field. Currently, more than 20 distinctive molecular etiologies have been attributed to cause human diseases most of which map to adipocyte differentiation or lipid droplet pathways. Seemingly acquired syndromes are recently reported to have a genetic basis, suggesting that our “pre-genome” understanding of the syndromes was inadequate and that we need to likely change our classification schemes. Regardless of the etiology, it is the selective absence of adipose tissue and its function, leading to the reduced ability to store long-term energy that perturbs insulin sensitivity and lipid metabolism. The treatment of these syndromes has also attracted considerable interest. The most successful example of the treatment of these syndromes came from the demonstration that leptin replacement strategy improved insulin resistance and dyslipidemia in the most severely affected forms of the disease, leading to an FDA approved therapy for generalized lipodystrophy syndromes. In the partial forms of the disease, the phenotypes are more complex, and the efficacy of leptin is not as uniform. Currently, standard treatment-resistant partial lipodystrophy is an EMA-approved indication, and numerous trials are in progress, either evaluating the efficacy of leptin in familial partial lipodystrophy or aiming to develop potential new treatments for the partial forms of the disease. These rare metabolic diseases are likely to continue to fuel novel breakthroughs in the field of metabolism in the foreseeable future.

INTRODUCTION

Lipodystrophy syndromes comprise a heterogeneous group of disorders characterized by either generalized or partial lack of adipose tissue depending on the type of lipodystrophy (1, 2). Lipodystrophy classically has been classified as congenital or acquired. Patients with partial lipodystrophy may exhibit excess adipose tissue accumulation in preserved areas of the body. Lipodystrophy syndromes usually manifest with several metabolic abnormalities associated with severe insulin resistance that include diabetes mellitus, hypertriglyceridemia, and hepatic steatosis which can progress to steatohepatitis. Other common manifestations are acanthosis nigricans, polycystic ovarian syndrome (PCOS), and eruptive xanthomas (due to severe hypertriglyceridemia) (3, 4). Metabolic derangements are mostly responsible for the serious comorbidities associated with lipodystrophy; some of which are chronic complications of poorly controlled diabetes, acute pancreatitis, hepatic cirrhosis, proteinuria and renal failure, and premature cardiovascular disease (Fig.1) (1, 2). Typically, standard treatments fail to achieve good glycemic control in most patients with lipodystrophy, although episodes of diabetic ketoacidosis have rarely been reported (5). The severity of the comorbidities depends on the subtype, extent of fat loss, and other clinical characteristics such as gender and age. Major causes of mortality are cardiovascular diseases (6-9), liver diseases (2, 10), acute pancreatitis (2), renal failure (10), and sepsis (3). In certain areas of the world, infectious etiology also rises to the surface suggesting that perturbed immune function may be at play (11). Clinical features of lipodystrophy are shown in Table 1. It is important to note that there are additional components of the disease that may be specific to each molecular etiology. In addition, we are beginning to recognize that patients often report reduced quality of life with increased overall pain (requiring frequent use of pain medications), sleep disturbances and sleep apnea, gastrointestinal dysmotility, mood disturbances such as depression and anxiety and psychiatric diseases (12, 13).

Figure 1. Consequences of Lipodystrophy.

Table 1. Shared Clinical Features That Raise Suspicion for Lipodystrophy
Loss or absence of adipose tissue in a partial or generalized fashion
Disproportionate hyperphagia (inability to stop eating, waking up to eat, fighting for food)
Muscle hypertrophy and prominent veins (phlebomegaly)
Cushingoid appearance (e.g., familial partial lipodystrophy)
Pseudo-acromegaloid appearance
Progeroid appearance (progeroid forms)
Acanthosis nigricans (associated with insulin resistance)
Proteinuria, renal dysfunction
Reproductive dysfunction (reduced fertility, hyperandrogenism, oligomenorrhea, hirsutism and/or polycystic ovaries)
Musculoskeletal abnormalities (occasionally)
Cardiomyopathy (occasionally)
Metabolic abnormalities · Relatively early onset of insulin resistant diabetes which can be severe in some patients with requirement for high doses of insulin, e.g., requiring ≥200 U/day, ≥2 U/kg/day, or U-500 insulin, early development of complications. · Dyslipidemia which is characterized by elevated triglycerides and low HDL cholesterol. Hypertriglyceridemia can be very severe (≥500 mg/dL) and is unresponsive to treatment with associated history of acute pancreatitis. · Hepatomegaly and/or elevated transaminases in the absence of a known cause of liver disease (e.g., viral hepatitis). Hepatic steatosis (e.g. radiologic evidence), Hepatomegaly, Metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis.

Lipodystrophy is an intriguing rare disease that helps us obtain a better understanding of the pathophysiology of metabolic abnormalities associated with insulin resistance. The main cause of insulin resistance in lipodystrophy is the fact that the excess energy cannot be stored in adipose tissue, which is secondary to either the near total lack of adipocyte storage in patients with generalized lipodystrophy or a limited capacity to store in partial lipodystrophy. Limited lipid storage capacity causes the failure of buffering for postprandial lipids and secreting substantial adipokines, which in turn results in excessive levels of triglycerides and lipid intermediates in circulation. The body stores fat at ectopic sites such as the liver because of inability to store energy in the subcutaneous adipose depots. Levels of adipokines and hormones secreted from the adipose tissue, most characteristically leptin, are decreased in these patients especially if fat loss is extensive (1, 2, 9, 14, 15). Leptin has a fundamental role in glucose and lipid homeostasis, but more importantly, leptin is the key hormone responsible for regulating food intake (16). Low levels of leptin in lipodystrophy trigger hyperphagia, which is often extreme (17-19). In addition, leptin protects pancreatic beta cells from lipotoxicity at least in rodent models (20, 21). Leptin improves insulin sensitivity by increasing glucose uptake in peripheral tissues such as muscle via sympathetic nervous system activation. Leptin also decreases hepatic gluconeogenesis (22-24).

DIAGNOSIS

The diagnosis of lipodystrophy is usually made clinically based on history, body distribution of adipose tissue, physical examination, and metabolic profile. Lipodystrophy should be suspected in any person with partial or complete lack of subcutaneous adipose tissue. However, the diagnosis of lipodystrophy is often delayed because of the rarity of these syndromes and the failure of the physicians to recognize this disease. Although patients with congenital generalized lipodystrophy lack subcutaneous adipose tissue from birth, specific diagnosis is usually made during childhood or even adulthood when they start developing metabolic abnormalities. This is at least partly because the awareness of lipodystrophy is still low among physicians. The problem of recognition is much more common for partial lipodystrophy. The distribution of fat loss varies in different types of partial lipodystrophy. At first glance, certain types of partial lipodystrophy cannot be clearly distinguished from other common metabolic diseases (e.g., poorly controlled diabetes mellitus with truncal obesity) based on phenotype unless the physician is suspicious for lipodystrophy and checks carefully for certain characteristic such as the appearance of the limbs which look thinner than in a normal person. Also, the onset of fat loss may be gradual and delay the diagnosis both in genetic and acquired forms (3, 4). Lipodystrophy syndromes should be considered in the differential diagnosis in patients with relatively early onset insulin resistant diabetes mellitus, persistent hypertriglyceridemia, hepatic steatosis, PCOS, and hepatosplenomegaly. Other diseases that should be considered in the differential diagnosis of lipodystrophy are listed in Table 2.

Table 2. Differential Diagnosis of Lipodystrophy Syndromes
Generalized Lipodystrophy Syndromes	Constitutional thinness
	Uncontrolled type 1 diabetes mellitus
	HIV-associated wasting
	Anorexia nervosa, cachexia and starvation
	Chronic infections
	Adrenocortical insufficiency
	Thyrotoxicosis
	Acromegaly
	Diencephalic syndrome
Partial Lipodystrophy Syndromes	Cushing’s syndrome
	Truncal obesity
	Type 2 diabetes (lipodystrophy like phenotype)
	HIV associated lipodystrophy
	Multiple symmetric lipomatosis
	Progeroid syndromes
	Acromegaly

A thorough physical examination is required for clinical diagnosis of lipodystrophy. Clinicians should pay specific attention to evaluating the extremities and the gluteal region for leanness and muscularity. In addition, other body parts should be examined for accumulation of excessive amounts of fat. Due to marked abdominal obesity and excessive fat accumulation in the neck, patients with familial partial lipodystrophy (FPLD) may be misdiagnosed as Cushing’s syndrome (2).

The absence of subcutaneous fat can be quantified by using conventional anthropometric measurements, dual energy x-ray absorptiometry (DXA) scan, whole-body magnetic resonance imaging (MRI), and computed tomography (CT) scan (4). Anthropometry including skinfold thickness and limb circumference measurements are easy and affordable ways to estimate the fat loss and redistribution (9). Use of skin calipers may aid, but when unavailable, simple inspection and palpation of skin thickness may be very useful. We have used a cut-off of 11 mm in men and 22 mm in women in mid-thigh thickness as a screening point to suspect clinical presence of lipodystrophy that warrants further detailed work-up. For facial fat loss, serial photography may be used to evaluate the gradual loss of facial fat. DXA, MRI, and CT scans are non-invasive modalities that may be used for quantification of fat on a tissue-specific basis, but at least in the United States, none are covered for this purpose by insurance companies (3, 4, 25).

New Diagnostic Strategies and Technological Tools

Due to the complex nature, heterogeneity, and rarity of lipodystrophy syndromes, the need for accurate and objective diagnostic tools is increasing. Imaging techniques play an important role in visualizing fat distribution and assisting in the diagnosis of lipodystrophy. While measuring subcutaneous fat tissue thickness with high-resolution ultrasound is a practical and non-invasive method, results vary significantly depending on age, gender, and ethnicity (26).

Body fat distribution can be quantitatively determined using whole body Dual Energy X-ray absorptiometry (DXA scans). Work from our group indicates that images obtained with the "Fat Shadows" method, based on highlighting only the fat tissue in DXA images, can support the diagnosis of FPLD and generalized lipodystrophy (GL). Using this approach, FPLD was distinguished from control subjects with 85% sensitivity and 96% specificity, while GL was distinguished from nonobese control subjects with 100% sensitivity and specificity (27). In addition, Garg and colleagues reported that the DXA-derived lower limb fat (%) is diagnostic of FPLD2 with 99% specificity and 100% sensitivity in adult females below the 1st percentile (28).

A study by our group also suggests that the combined use of measurements performed on pelvic MRI images can be promising for the reliable diagnosis of FPLD. The combination of gluteal fat thickness ≤13 mm and pubic/gluteal fat ratio ≥2.5 was found to have 97% sensitivity and 91% specificity in the overall cohort and 100% sensitivity and 90% specificity in females for the diagnosis of FPLD (29).

Technological applications are also being developed to increase awareness of lipodystrophy and provide practical solutions for non-experts. LipoDDx, designed as a new mobile app, stands out with its 80% effectiveness in recognizing lipodystrophy subtypes when screening patients with adipose tissue loss, but more research is still needed in this area (30).

In addition, integrating artificial intelligence (AI) into medical diagnosis may hold promise for diagnosing lipodystrophy syndromes in the future. In this regard, a study by da Cunha Olegario NB et al. (31) was designed to enable the identification of the CGL phenotype from patient images with a deep learning model, analyzing more than 330 images, including individuals of different ages with phenotypically confusing features. After a fourfold cross-validation technique, the CGL phenotype could be identified with a mean accuracy, sensitivity, and specificity of over 90% (31).

These developments in diagnostic methods and technological tools for lipodystrophy syndromes not only increase diagnostic accuracy but also pave the way for creating a more personalized and effective treatment algorithms.

Laboratory Testing

Laboratory testing is a valuable tool for physicians to support the diagnosis. If the physical phenotype is not recognized, hyperglycemia, insulin resistance, and severe hypertriglyceridemia that is non-responsive to therapy may provide important clues for the diagnosis. When fat loss is not confirmed by the physical examination or by an imaging modality, hyperglycemia and hypertriglyceridemia that are resistant or unresponsive to conventional treatment may serve as surrogate indicators to the clinician that a patient may have lipodystrophy. Lipodystrophy should be suspected in patients with uncontrolled diabetes (e.g., requiring ≥200 units/day (≥2 units/kg/day) of insulin) or triglyceride levels that remain persistently elevated (e.g., ≥500 mg/dL) despite fully optimized therapy and diet modifications. All patients except those with localized lipodystrophy, should be tested for blood glucose levels, glycated hemoglobin (HbA1c), serum lipids (especially triglyceride levels), and liver function tests on the initial evaluation and during subsequent encounters. In addition to these laboratory evaluations, leptin levels may be used in support of the diagnosis. However, it should be noted that leptin assays are not standardized, and low leptin levels may be observed in other conditions such as hypothalamic amenorrhea and malnutrition. Thus, low leptin level is not specific for the diagnosis lipodystrophy (4, 32). Circulating adiponectin though not a clinically available test, may be helpful in differentiating patients with generalized lipodystrophy from those who have constitutional leanness, fat loss due to calorie imbalance or excessive exercise as well as poorly controlled diabetes mellitus with insulin deficiency. In all of the cases except lipodystrophy, adiponectin levels will be normal or even higher than normal whereas in lipodystrophy including familial partial lipodystrophy, serum adiponectin levels are usually low.

Genetic Testing

In the genetic forms of lipodystrophy, parental consanguinity and the mode of inheritance should be questioned (2). Genetic testing is available for known genetic forms of lipodystrophy. In our earlier version of this review, we had mentioned that genetic tests to be available only in certain clinical and research laboratories; however, there has been incredible growth in the availability of genetic testing through commercial or certified clinical labs in the US since 2016. Because additional loci for genetic lipodystrophy syndromes are presumed to be present, negative genetic tests do not rule out a genetic condition. When commercial panels are not positive, an attempt for whole exome or even whole genome testing with mitochondrial gene evaluation has evolved as viable and increasingly more available strategies. If these latter tests cannot be undertaken commercially, ongoing research in specialty centers can be considered where pipelines to analyze VUS (variant of uncertain significance) and evaluate transcriptomic profiles from PBMCs or tissues may be considered.

Gauging Disease Severity in Lipodystrophy: Roadmap for Clinical Follow Up

Given that lipodystrophy syndromes are complex and may impact multiple organs and systems, it is important to start a follow-up schedule while paying attention to all aspects of the conditions. To help assess the status and disease progression of patients with lipodystrophy, the LD Severity Score study group has developed the 'LD Severity Score (LDS)', an online tool easily accessible to all clinicians. This online application generates an overall score using multisystem assessments across eight domains (diabetes and its complications, lipid status, cardiovascular conditions, liver and kidney function, reproductive system status, and other conditions) to capture the various clinical manifestations of the disease holistically. The Clinical Global Impression (CGI) and the global improvement (GI) scores were generated based on the subjective assessments of all these categories by a group of experts during a representative patient visit as part of the app's validation. The LDS demonstrated high content validity and feasibility, along with high reliability indicated by interclass correlation coefficients greater than 0.95 (33). The results of the lipodystrophy severity scores calculated for each patient in the app are shown in a figure, compared to the Clinical Global Impression scores generated by the experts. The LD Scoring tool, developed to predict the clinical outcomes and/or treatment effects of lipodystrophy, can be accessed at https://ldscoring.com/.

CLASSIFICATION OF LIPODYSTROPHY SYNDROMES

Lipodystrophy syndromes can be classified as genetic or acquired. However, they are simply classified as generalized and partial in clinical practice most of the time (Table 3).

Table 3. Classification of Lipodystrophy Syndromes
Type	Lipodystrophy Phenotype	Subtype (Genes Involved)	Key Clinical Features
*Generalized lipodystrophy syndromes*
Congenital Generalized Lipodystrophy (CGL)	Near total absence of the body fat starting at birth or shortly after, generalized muscularity, metabolic abnormalities	CGL1 (AGPAT2) Autosomal recessive	Loss of metabolically active fat with sparing of mechanically functioning fat
		CGL2 (BSCL2) Autosomal recessive	Generalized absence of adipose tissue
		CGL3 (CAV1) Autosomal recessive	Short stature, vitamin D resistance, hypocalcemia, hypomagnesemia, achalasia
		CGL4 (PTRF) Autosomal recessive	Myopathy, skeletal abnormalities, pyloric stenosis and gastrointestinal motility problems, cardiac arrhythmias
	Other genes associated with GL phenotype		LMNA (e.g., T10I, biallelic lamin A specific variants), PPARG (biallelic variants), PCYT1A, PLAAT3
Acquired Generalized Lipodystrophy (AGL)	Near total absence of the body fat commonly develops during childhood or adolescence, metabolic abnormalities	Autoimmune	AGL follows an autoimmune disease, e.g. JDM
		Panniculitis-associated	Tender subcutaneous nodules that herald the onset of AGL
		Idiopathic	No history of auto-immune disease or panniculitis
*Partial lipodystrophy syndromes*
Familial Partial Lipodystrophy (FPLD)	Loss of fat from the limbs, metabolic abnormalities	FPLD1, Kobberling (Unknown)	Loss of subcutaneous fat from the limbs, although they usually have truncal obesity. Palpable “ledge” formation between the normal and lipodystrophic areas
		FPLD2, Dunnigan (LMNA) Autosomal dominant	Increased muscularity and loss of fat in the limbs, excess fat accumulation in the face and neck
		FPLD3 (PPARG) Autosomal dominant	Loss of subcutaneous fat from the limbs, specifically distally
		FPLD4 (PLIN1) Autosomal dominant	Loss of subcutaneous fat from the limbs, histologically; small adipocytes, macrophage infiltration and fibrosis of adipose tissue
		FPLD5 (CIDEC) Autosomal recessive	Loss of subcutaneous fat from the limbs, small, multilocular lipid droplets in adipocytes
		FPLD6 (LIPE) Autosomal recessive	Increased visceral fat, dyslipidemia, hepatosteatosis, insulin resistance, and diabetes, some may present with muscular dystrophy and elevated serum creatine phosphokinase
Acquired Partial Lipodystrophy (APL)	Loss of subcutaneous fat starts from the face, neck, upper extremities, and progresses to the trunk. Lower limbs are typically spared, some patients have excess fat over the gluteal region, thighs and calves	Autoimmune	Coinciding autoimmune disorders; dermatomyositis/polymyositis and SLE are most associated disorders
		MPGN-associated	Low serum complement 3, glomerulonephritis, hematuria, urinary casts, proteinuria, nephritic syndrome, renal failure
		Idiopathic	No history of auto-immune disease or MPGN
Progeria associated lipodystrophy		LMNA, ZMPSTE24, POLD1, WRN, MTX2, FBN1, BANF1, KCNJ6, SPRTN, ALDH18A1, ERCC8, ERCC6 (34) BUD13 (35) , EPHX1 (36), OPA3 (37), PDGFRB (38), SLC25A24 (39), SUPT7L (40)	Progeroid features: most present with partial lipodystrophy, though in rare cases, fat loss can occur in a more generalized fashion
Other genes associated with lipodystrophy		AKT2, PCYT1A, PIK3R1, MFN2, PSMB8, ADRA2A	Various presentations of lipodystrophy

GENERALIZED LIPODYSTROPHY SYNDROMES

Generalized lipodystrophy syndromes are rare disorders that are either inherited (Berardinelli-Seip Syndrome) (41-43) or acquired (Lawrence Syndrome) (9).

Congenital Generalized Lipodystrophy

Congenital Generalized Lipodystrophy (CGL) or Berardinelli-Seip syndrome is a rare syndrome which manifests with near total absence of adipose tissue. It is inherited in an autosomal recessive manner. Fat loss is usually recognized shortly after birth or in the first years of life, although patients may be diagnosed later during teenage years or adulthood. There have been over 300 reported cases to date (14, 44, 45).

In addition to lack of subcutaneous fat, patients may present with hepatomegaly and umbilical protuberance during infancy. Extensive acanthosis nigricans and prominent musculature may also contribute to the striking phenotype of these patients (46). Affected females may have irregular menstrual cycles, oligomenorrhea, clitoromegaly, and hirsutism. Premature menarche and pubarche are also rarely seen. Most males were reported to be fertile whereas only a few females had successful pregnancies (47). Sperm abnormalities have been reported in CGL. Other clinical manifestations include advanced bone age, bone cysts which may progress over time, mild mental retardation, cardiomyopathy, and cardiac rhythm disturbances (48-50). A significant association has been found between diabetic foot ulcers and, specifically, generalized lipodystrophy; foot ulcer complications may arise earlier in GL than in partial lipodystrophy (PL) (51).

Children with CGL usually have a voracious appetite and accelerated growth. Basal metabolic rate may be increased. Patients also report heat intolerance, especially after meals and sometimes gustatory sweating. Hypertriglyceridemia usually presents with high levels of chylomicrons and very low-density lipoproteins (VLDL) and reduced levels of high-density lipoproteins (HDL). Low HDL cholesterol levels are the most common lipid abnormality (49). Severe hypertriglyceridemia usually results in recurrent acute pancreatitis. Insulin resistance commonly results in diabetes in adolescence or later. Diabetes is rarely responsive to insulin therapy. Serum leptin levels are very low (32). Metabolic dysfunction–associated liver disease (MASLD) and steatohepatitis are common in individuals with CGL and have the potential to advance to cirrhosis at relatively early stages of life (49, 52). A study conducted in Brazil determined that the average age of death of 20 CGL patients who died between 1997-2017 was 27.1±12.4 years. In this patient group, most of whom were CGL2, the most common causes of death were infectious causes (35%), such as pneumonia and liver complications (35%), such as cirrhosis (11).

The genetic defect can be determined in the majority of patients with CGL. There are at least four molecularly distinct types of CGL. However, it is noteworthy that there are some cases of CGL reported without any pathogenic variants in any of the four genes described below.

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 1 (CGL1)

1-acylglycerol-3-phophate O-acyltransferase 2 (AGPAT2), a key enzyme in triglyceride synthesis, is deficient in CGL1. AGPAT2 gene is located on chromosome 9q34. AGPAT2 catalyzes the acylation of lysophosphaditic acid to form phosphaditic acid, a key intermediate in the biosynthesis of triglyceride and glycerophospholipids (53). Precisely how AGPAT2 deficiency causes lipodystrophy remains unsolved, but possible mechanisms include impaired lipogenesis, altered differentiation of preadipocytes to adipocytes, altering normal activation of phosphatidylinositol 3-kinase (PI3K)/Akt and PPARG pathways in the early stages of adipogenesis, and apoptosis/necrosis of adipocytes (2, 54, 55). More recent findings suggest that lysophosphatidic acid (LPA) could potentially trigger inflammation and fibrosis in the adipose tissue, leading to eventual loss of adipose tissue. In addition, LPA accumulation in the liver can also trigger the progress of metabolic dysfunction-associated fatty liver disease (MAFLD) to MASH (56).

Adiposity is preserved in certain body parts such as orbits, palms and soles, which constitute the mechanical adipose tissue (32, 57-59) (Fig.2). AGPAT2 pathogenic variants along with BSCL2 pathogenic variants are responsible for the majority of the CGL cases.

Figure 2. CGL1. Near total absence of adipose tissue in CGL1 (2A, 2C, 2D). Magnetic resonance images document the lack of subcutaneous fat (2B). Liver biopsy reveals severe hepatic steatosis with both micro and macrovesicular steatosis (Hematoxylin and eosin staining; magnification 200X), 2E).

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 2 (CGL2)

CGL2 is caused by pathogenic variants in the BSCL2 gene which have been mapped to chromosome 11q13. This gene encodes a 398-amino acid integral endoplasmic reticulum membrane protein called seipin (60). This protein is assumed to take part in lipid droplet formation and adipocyte differentiation (61, 62). Patients with BSCL2 pathogenic variants have the most severe disease and are born without any adipose tissue. Hypertriglyceridemia and hepatic steatosis can be detected in early childhood; and hepatic involvement can be more severe in CGL2 than other subtypes (49, 63). Intellectual disability and cardiomyopathy are more common than in CGL1. CGL2 patients are also distinguished from the CGL1 patients with the loss of mechanical adipose tissue (64) (Fig.3). Although the mechanism is not clear, adiponectin levels are relatively higher in patients with CGL2 despite severely suppressed leptin levels which can help in the differential diagnosis (65).

In addition, rare specific variants of the BSCL2 gene that lead to the skipping of exon 7 are associated with Celia’s encephalopathy (Progressive Encephalopathy with/without Lipodystrophy, PELD), a severe progressive neurodegenerative disorder that also presents with a GL phenotype. (66-68).

Figure 3. CGL2. Near total absence of adipose tissue in a patient with CGL2 (3A, 3B). Also note that the patient shown now deceased was only 29 years old at the time the picture was taken, suggesting the possibility of accelerated aging.

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 3 (CGL3)

CGL3 is caused by pathogenic variants in the CAV1 gene which are located on chromosome 7q31 (9, 15, 69). This gene encodes the protein caveolin-1, which is an integral part of caveolae found in plasma membranes. Caveolin 1 binds fatty acids on the plasma membranes and translocates them into lipid droplets. Mutated caveolin 1 disrupts lipid droplet formation and adipocyte differentiation (70). CGL3 is distinguished from other CGLs by the presence of unique features such as preserved bone marrow fat, vitamin D resistance, hypocalcemia, hypomagnesemia, and decreased bone density (48). In addition to this classical presentation, whole exome sequencing has identified de novo heterozygous null CAV1 pathogenic variants in two patients of European origin with generalized fat loss, thin mottled skin, and progeroid features at birth; however, no differences in the number and morphology of caveolae have been found in dermal fibroblasts (71), which suggests that this observation needs to be confirmed in further pedigrees. Heterozygous CAV1frameshift mutations have also been reported to be associated with partial lipodystrophy (Fig.4) (72). Several features such as congenital cataracts and cerebellar progressive ataxia were also present (73). Apart from this, a novel p.(His79Glnfs*3) CAV1 variant was identified in four consanguineous patients diagnosed with CGL3. In addition to typical findings, two patients had esophageal achalasia, while the other had atypical retinitis pigmentosa findings (74).

Figure 4. Partial LD with Heterozygous CAV1 Pathogenic Variant.

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 4 (CGL4)

Type 4 CGL (CGL4) is caused by pathogenic variants in the PTRF gene. The product of this gene, CAVIN, is a polymerase 1 and transcript release factor which regulates caveolae 1 and 3 (75). CGL4 can be recognized by distinct clinical characteristics. The majority of CGL4 patients that have been documented so far have had null mutations in the CAVIN1/PTRF gene. However, a novel homozygous mutation (c.21T>A; p.Tyr7Ter) was described in this gene in two pediatric siblings who exhibited slight variations in their phenotypical presentation, and whose clinical manifestations were compatible with CGL4 (76).

This rare subtype of CGL is associated with myopathy, pyloric stenosis, gastrointestinal dysmotility, arrhythmias that include exercise-induced ventricular tachycardia and sudden death, and skeletal abnormalities such as atlantoaxial instability and scoliosis (77-79) (Fig.5). Regardless of metabolic illness, patients with CGL4 are more prone to suffering life-threatening arrhythmias and cardiac problems throughout childhood (49).

Figure 5. CGL4. Lack of subcutaneous fat (5A), scoliosis (5A), gastrointestinal dysmotility (5B), and exercise-induced ventricular arrhythmia (5C) in CGL4.

OTHER GENES ASSOCIATED WITH GENERALIZED LIPODYSTROPHY

Biallellic loss-of-function pathogenic variants in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in the Kennedy pathway of de novo phosphatidylcholine synthesis, have been reported to be associated with generalized lipodystrophy, severe hepatic steatosis and low HDL cholesterol levels (80). Although widely involved in the familial partial lipodystrophy pathogenesis, several pathogenic variants in the LMNA and PPARG genes have been associated with generalized lipodystrophy. Heterozygous LMNA p.T10I pathogenic variant was reported to be associated with generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly (Fig.6) (81). Biallelic pathogenic variants in PPARG has also been reported to cause generalized lipodystrophy (82).

Furthermore, research has shown that a deficiency of phospholipase A/acyltransferase 3 (PLAAT3), an enzyme that modifies phospholipids and is predominantly found in neural and white adipose tissue (WAT), leads to monogenic lipodystrophy syndrome. Patients with biallelic loss-of-function variants in PLAAT3 show varying degrees of fat loss, from partial to generalized, insulin resistance, diabetes, hypertriglyceridemia, fatty liver, and polycystic ovary syndrome. Additionally, these patients exhibit numerous neurogenic symptoms, including demyelinating neuropathy, migraines, and intellectual disability, along with musculoskeletal dysmorphisms (83).

Figure 6. Heterozygous LMNA p.T10I Pathogenic Variant. Generalized lack of subcutaneous fat (6A), eruptive xanthomata (6B), and lipemia retinalis (6C) secondary to severe hypertriglyceridemia in a patient with heterozygous LMNA p.T10I pathogenic variant.

Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy (AGL), also known as Lawrence Syndrome, is very rare. Generalized fat loss is not present at birth but develops later in life. It occurs over a variable period, ranging from a few weeks to years (Fig.7) (9).

Figure 7. AGL. Generalized loss of subcutaneous fat in two patients with AGL (7A-D). Note the distal fat loss around the feet as opposed to patients with CGL phenotypes.

Although the pathogenesis of AGL has been elusive previously, it has always been hypothesized to be linked to autoimmune destruction of adipocytes. Autoantibodies against adipocyte membranes have been reported (84-86). Recently, the presence of antibodies against the lipid droplet surface protein perilipin-1 (PLIN1), an essential regulator of the lipolytic pathway, has been demonstrated in some AGL patients (87-90). Anti-PLIN1 autoantibodies in AGL patients were first detected in 2018 in three out of five patients (90). Subsequently, in a study focused on anti-PLIN1 antibodies, 50% of the 40 AGL patients examined exhibited the antibodies, whereas in another investigation, 37% of the 46 patients were found to have these antibodies (88, 89). Interestingly, one of the AGL patients with perilipin-1 antibody also had a mutation in the AIRE gene that causes autoimmune polyendocrine syndrome type 1 (APS1) (88). Considering these studies, whether perilipin-1 antibodies can be a potential biomarker in AGL patients and the relationship between APS1 and lipodystrophy are still curious.

AGL is associated with panniculitis in approximately 25% of the patients. This type may manifest with subcutaneous inflammatory nodules (panniculitis), which heal by localized loss of fat and eventually results in complete loss of subcutaneous fat (9). Another one fourth of the AGL patients present with an autoimmune disease that include juvenile dermatomyositis (JDM), Sjogren’s syndrome, rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus (9, 85). Of these, JDM particularly correlates with AGL. 8-40% of patients with JDM develop AGL (Fig.8) (86, 91, 92). In the remaining 50% of the cases, AGL is not associated with any autoimmune or inflammatory condition (9). Some patients with AGL exhibit low serum complement 4 levels and auto-immune hepatitis, sometimes together with type 1 diabetes, which suggests the involvement of classical complement pathway in AGL pathogenesis (93). Recently, with the groundbreaking and increasing use of immune checkpoint inhibitors in cancer treatments, it has been reported in the literature that acquired generalized lipodystrophy developed after anti-PD-1 treatment (nivolumab and pembrolizumab) in four patients (94-96).

As mentioned above, it is of note that some of the patients with AGL are recently recognized to have additional progeroid features and may harbor a specific pathogenic of LMNA gene at position 10 (p.T10I). We have reported clinical presentations of these patients recently in a case series report. One of these patients also had biopsy proven juvenile dermatomyositis suggesting that the long-recognized association between AGL and JDM may be linked through distinctive molecular mechanisms (81).

In patients with AGL, metabolic abnormalities associated with severe insulin resistance that include hypertriglyceridemia, diabetes mellitus, hepatic steatosis, acanthosis nigricans, menstrual irregularities and PCOS may develop soon after the recognition of fat loss. Patients have suppressed levels of leptin and adiponectin (9, 32).

Figure 8. Juvenile Dermatomyositis and AGL. Generalized loss of subcutaneous fat in a patient with juvenile dermatomyositis associated AGL (8A, 8B). Note the absence of muscle tissue as well in this severely affected patient.

PARTIAL LIPODYSTROPHY

Fat loss affects only part of the body in partial lipodystrophy. Partial lipodystrophy is categorized into inherited (familial partial lipodystrophy, FPLD) and acquired forms (acquired partial lipodystrophy, APL). Both patients with FPLD and APL start losing fat at some point during their life. Lower limbs are most frequently affected in FPLD. There might be accumulation of adipose tissue in the face and neck. On the other hand, APL is characterized by fat loss that spreads through a cephalocaudal distribution from the face, neck, shoulders, arms, and forearms and that extends to the thoracic region and upper abdomen. There are numerous genes associated with FPLD. Despite the growing number of proven genetic markers, about half of the patients do not have a discernible single gene variation.

Inherited Partial Lipodystrophy Syndromes

Patients with these syndromes usually notice partial fat loss around puberty. Fat loss pattern is very heterogeneous in patients with FPLD. Even among patients with pathogenic variants of the same gene, fat loss patterns may vary.

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 1 (FPLD1)

The loss of adipose tissue is mainly limited to the extremities in patients with FPLD1 or Kobberling-type lipodystrophy (97). There is a normal or slightly increased fat in the face and neck. Truncal obesity is a common finding. The hallmark of this syndrome is the formation of a palpable “ledge” between the normal and lipodystrophic areas (98). It is believed that women are diagnosed more easily as they usually present with a more severe disease. Metabolic complications usually develop in early adulthood. Insulin resistant diabetes and metabolic syndrome are common and may cause premature coronary artery disease. Hypertriglyceridemia may trigger episodes of acute pancreatitis. Acanthosis nigricans is commonly seen. Leptin levels are variable and correlate with body mass index (BMI), which suggests that the levels of leptin are appropriate for the fat content in FPLD1 (98). The Cambridge group recently reported that this form of lipodystrophy may have a polygenic etiology (99). There is a remarkable phenotypical heterogeneity among patients with FPLD1. In this spectrum of FPLD1, patients with significant central obesity are likely polygenic. This type of presentation is relatively more common, and it is sometimes difficult to make a distinction between FPLD1 and truncal obesity complicated with metabolic syndrome (100). The use of radiological methods such as DXA, CT, or MRI can help in this population to further define body fat distribution in addition to physical examination and skinfold measurements. On the other hand, some FPLD patients with no increase in truncal fat are classified as FPLD1, if no gene is identified. These patients can still have a monogenic form of FPLD that has not been discovered. Two different presentations of FPLD1 are shown in Fig.9.

Figure 9. FPLD1. Heterogeneity in FPLD1. Patient in A to D presented with decrease in peripheral fat depots and preservation of abdominal fat. Patient in E to H has increased abdominal adiposity. The formation of a palpable “ledge” between the normal and lipodystrophic areas is shown (9C and 9E). (Images E-H used with permission by Dr. Jonathan Q. Purnell from publication Diabetes Care 2003;26(6):1819-24).

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 2 (FPLD2)

FPLD2 or Dunnigan Variety lipodystrophy is an autosomal dominant syndrome which is characterized by gradual onset of subcutaneous fat loss from the extremities during puberty. Affected individuals have prominent muscularity in their extremities. Excess fat accumulates in the neck causing a buffalo hump (Fig.10). This phenotype sometimes can be misdiagnosed as Cushing’s syndrome at first glance (15). Pathogenic variants in the LMNA gene, which is located on chromosome 1q21-22, cause FPLD2. The LMNA gene codes nuclear lamina proteins, lamin A and C. Pathogenic variants in the LMNA gene can be scattered across many exons of the gene and are missense mutations (101). Mutant lamins disrupt the interaction between nuclear lamina and chromatin and may result in apoptosis, which may be followed by premature adipocyte death (102).

Figure 10. FPLD2. Subcutaneous adipose tissue loss from the extremities, excess fat accumulation in the face and neck, and Cushingoid appearance in FPLD2 (10A-D; Note that one of the patients (10A) previously underwent liposuction for removal of unwanted excess fat from the neck).

Females have a more recognizable phenotype and more severe metabolic complications (103). Most patients with FPLD2 develop diabetes in their twenties and thirties. Other components of insulin resistance are usually present. Patients with FPLD2 are at high risk for cardiovascular diseases that usually develop at relatively younger ages (104). Arrhythmias such as atrial fibrillation or flutter are more common in patients with LMNA pathogenic variants and may occur at an earlier age. Detailed cardiac analyses among patients with LMNA pathogenic variants showed that individuals with non-482 LMNA variants exhibited a high possibility of suffering from vigorous cardiac complications such as myocardial infarction, atrial fibrillation/flutter, cardiomyopathy, and congestive heart failure (105). Our retrospective analysis of 494 patients with LMNA-associated lipodystrophy revealed that the most prevalent LMNA variants were R482Q and R482W. This paper also highlights that patients with the R482W variant are diagnosed with diabetes at a significantly younger age compared to those with the R482Q variant (27 years vs. 40 years, respectively) (106).

There is a phenotypic heterogeneity among patients with FPLD2. For instance, less severe loss of fat has been reported in patients with exon 11 LMNA pathogenic variants which affects only lamin A protein (107). LMNA R349W pathogenic variant (exon 6) is associated with facial fat loss which is uncommon in FPLD2 (104, 108, 109). Exon 1 variants are associated with severe cardiac disease that require cardiac transplant at an early age and may be coupled with arrhythmias and conduction system abnormalities. Variants across exon 4 through 8 have been noted to cause muscular dystrophy related symptoms together with fat distribution abnormalities. In a retrospective evaluation of 12 pediatric FPLD2 patients, although all patients had the same LMNA variant p.(R482W), there were marked differences in the severity of the phenotype. Despite the absence of comorbidities in patients under the age of ten, the earliest age of onset of diabetes in the cohort was 12, and the earliest age of onset of hepatic steatosis was observed to be 10 (110). LMNAgene pathogenic variants are also involved in the pathogenesis of progeroid disorders including Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia, and atypical progeroid syndrome (APS).

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 3 (FPLD3)

FPLD3 is caused by pathogenic variants in the PPARG gene, a key regulator of adipocyte differentiation. Patients with FPLD3 usually show milder fat loss; and there is no accumulation of adipose tissue in the face and neck (Fig.11); however, they manifest metabolic complications at a similar rate and severity to those with FPLD2 (104, 111-115). Even more, in a retrospective analysis, FPLD3 patients exhibited a notably greater prevalence of hypertriglyceridemia and diabetes, along with elevated levels of median serum triglycerides and mean HbA1c, compared to FPLD2 patients (116).

Figure 11. FPLD3. Moderate partial subcutaneous adipose tissue loss in a patient with FPLD3 (11A-C).

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 4 (FPLD4)

FPLD4 is caused by pathogenic variants in the PLIN1 gene encoding perilipin 1, which is an essential lipid droplet coat protein (117). Although frameshift mutations in PLIN1 are known to cause partial lipodystrophy, a recent comprehensive study suggests that null variants in the PLIN1 gene are not associated with the formation of lipodystrophy (118).

Perilipin plays a key role in coordinating access of lipases to the core triacylglycerol. It is characterized by the loss of adipose tissue which is most striking in the lower limbs and femorogluteal depot, severe insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis (119-121).

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 5 (FPLD5)

FPLD5 is an autosomal recessive syndrome caused by pathogenic variants in the CIDEC gene. It is characterized by partial lipodystrophy, acanthosis nigricans, severe insulin resistance leading to diabetes, and hepatic steatosis. The CIDEC gene is located on chromosome 3 (3p25.3) and encodes the CIDEC protein, which is expressed in the lipid droplets. Pathogenic variants of the CIDEC gene are postulated to result in the loss of ability of lipid droplets to store fat (122).

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 6 (FPLD6)

FPLD type 6 is caused by pathogenic variants in the LIPE (lipase E, hormone sensitive type) gene which has an autosomal recessive inheritance (123). This FPLD subtype is characterized by late-onset partial fat loss from the lower extremities and also multiple symmetric lipomatosis and progressive distal symmetric myopathy (123, 124). Hormone sensitive lipase is the predominant regulator of lipolysis from adipocytes. Pathogenic variants in the LIPE gene appear to result in impaired lipolysis which may induce lipomatosis and partial fat loss at the same time that is associated with hypertriglyceridemia, hepatic steatosis, and insulin resistant diabetes (124).

NEWER AND EMERGING GENES ASSOCIATED WITH FAMILIAL PARTIAL LIPODYSTROPHY

FPLD has also been reported to be caused by pathogenic variants in the AKT2 gene (125). AKT is a serine/threonine protein kinase, which is involved in cell signaling/growth, glycogen synthesis, and insulin-stimulated glucose transport. Lipodystrophy in patients with AKT2 mutations is thought to be due to defective adipocyte differentiation and post-receptor insulin signaling (126). Additional variants may be found through extensive sequencing platforms of ongoing studies such as UK Biobank (127), RADIANT (128) or All of Us (129) studies. Exome sequencing has identified a heterozygous variant in the adrenoceptor α 2A (ADRA2A) gene, which encodes the main presynaptic inhibitory feedback G protein–coupled receptor regulating norepinephrine release, in an African-American pedigree with atypical FPLD (130), which needs to be confirmed in additional pedigrees and to date, no additional cases have been reported with similar phenotypes.

Progeroid Syndromes and Lipodystrophy

Mandibuloacral Dysplasia (MAD) is a rare progeroid syndrome which manifests with craniofacial, skeletal and cutaneous abnormalities and lipodystrophy (Fig.12) (131). The clinical manifestations present gradually over time, most commonly during childhood. There are two types of MAD currently recognized. Mandibuloacral dysplasia type A (MADA) is characterized by the loss of subcutaneous fat from the extremities along with normal or excessive fat in the face and the neck. Mandibuloacral dysplasia type B manifests with a more generalized loss of subcutaneous fat (131-134).

Figure 12. Mandibuloacral Dysplasia. Hypoplasia of the mandible in a patient with Mandibuloacral Dysplasia.

MADA is caused by mutations in the LMNA gene which results in the accumulation of prelamin A protein (135). This, in return disrupts the interaction between nuclear lamina and chromatin (134-136). Compound heterozygous pathogenic variants in the zinc metalloproteinase (ZMPSTE24) gene have been reported to cause MADB associated lipodystrophy (137, 138). ZMPSTE24 is essential in the post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A and vimentin processing (137, 139, 140).

In addition, homozygous mutation in the MTX2 gene causes mandibuloacral dysplasia progeroid syndrome (MDPS), an autosomal recessive severe laminopathy-like disorder characterized by mandibular recession, clavicular hypoplasia and acroosteolysis, progeroid appearance and loss of subcutaneous fat (141).

MDP (mandibular hypoplasia, deafness and progeroid features syndrome) has been reported to be caused by pathogenic variants of the POLD1 gene that encodes catalytic subunit of DNA polymerase δ which play an essential role in the lagging-strand DNA synthesis during DNA replication (142). In addition to progressive lipodystrophy and severe insulin resistance, patients with MDP suffer from mandibular hypoplasia, sensorineural deafness, progeroid features, scleroderma and skin telangiectasia, ligament contractures, reduced mass of limb muscles, hypogonadism and undescended testes in males (142-145). We recently observed a mother daughter pair with a different POLD1 variant near the carboxyl terminal of the protein at a very highly conserved residue (Fig.13).

Figure 13. Partial Lipodystrophy in a Patient with POLD1 Variant.

Biallelic WRN null mutations linked to partial lipodystrophy with severe insulin resistance in adult progeria Werner syndrome (Fig.14) (146). The WRN gene encodes a RecQ DNA helicase which plays a critical role in repairing damaged DNA (147). An unusual Werner syndrome with the absence of progeroid findings, early-onset diabetes, severe dyslipidemia, and hepatic fibrosis has been reported in a patient with partial lipodystrophy who had a novel variant in the WRN gene (148).

Figure 14. Werner Syndrome.

Fibrillin-1 (FBN1) gene pathogenic variants are found in more than 90% of patients with Marfan syndrome (149). Pathogenic variants in the penultimate exon of FBN1 have been reported to be associated with a distinct phenotype of generalized lipodystrophy that share some clinical features with neonatal progeroid syndrome (Wiedemann–Rautenstrauch syndrome), a very severe disorder with only a few patients described who could reach their late childhood (150-152). Although these patients have marfanoid/progeroid appearance, skeletal features, dilated aortic bulb, bilateral subluxation of the lens, myopia in addition to the severe generalized lipodystrophy, no significant metabolic abnormality caused by the lack of adipose tissue has been reported (150, 151, 153).

Pathogenic variants in BANF1 have been reported to be associated with progeroid features, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. This disease is also called Néstor-Guillermo progeria syndrome (NGPS) (154).

Heterozygous pathogenic variants in KCNJ6 (GIRK2), which encodes an inwardly rectifying potassium channel, cause Keppen-Lubinsky syndrome that is characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, an open mouth, progeroid appearance, and generalized lipodystrophy (155).

Pathogenic variants of the Spartan (SPRTN) gene, which encodes a protein that is essential in the maintenance of genomic stability, have reported to be associated progeroid features, lipodystrophy and hepatocellular carcinoma (156).

Pathogenic variants in the ALDH18A1 gene, which encodes pyrroline-5-carboxylate-synthetase, a mitochondrial enzyme important in ornithine biosynthesis, cause Cutis Laxa Autosomal Dominant 3 syndrome. This syndrome is characterized by intellectual disability, hypotonia, retinal abnormalities, craniofacial dysmorphism, joint laxity, and abnormal fat distribution (34, 157).

Several other genes associated with progeroid lipodystrophy are listed in Table 3.

Complex Syndromes and Their Genes Associated with Lipodystrophy

Pathogenic variants in the phosphatidylinositol 3-kinase, regulatory subunit 1 (PIK3R1), which mediates insulin’s metabolic actions, have been reported in patients with SHORT syndrome (short stature, joint hyperextensibility, ocular depression, Rieger anomaly, and teething delay) that is associated with lipodystrophy in many patients (158, 159). It has also been reported that patients with C-terminal PIK3R1 pathogenic variants exhibit severe insulin resistance but normolipidemia and no hepatic steatosis (160).

Pathogenic variants in the proteasome subunit, beta-type, 8 (PSMB8) gene, which encodes a catalytic subunit of the 20S immunoproteasomes called β5i, has been linked to an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome) (161-163).

CANDLE syndrome is another rare autoinflammatory syndrome characterized by chronic atypical neutrophilic dermatitis, recurrent fever, and partial loss of adipose tissue from the upper limbs and face (164). An eponym for the syndrome was proposed as Nakajo–Nishimura syndrome (165, 166). Homozygous or compound heterozygous mutations in the gene PSMB8 have been reported in patients with CANDLE syndrome (167, 168).

Two families with AREDYLD syndrome that is characterized by acrorenal field defect, ectodermal dysplasia, generalized lipodystrophy, and multiple abnormalities have been reported (169, 170). The genetic basis of this very rare syndrome is still unknown.

Lipomatosis Syndromes

In studies conducted in 2016-2018, a pathogenic variant in the MFN2 gene that encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication, have been reported to be associated with partial lipodystrophy, upper body adipose hyperplasia, and suppression of leptin expression (171)(Fig.15). MFN2 gene-related Multiple Symmetric Lipomatosis (MSL) is an unusual type of lipodystrophy that includes both lipomatous masses and lipoatrophy (172). In these cases, one may observe various indicators, including insulin resistance, diabetes, non-alcoholic fatty liver disease, dyslipidemia, peripheral neuropathy, autonomic neuropathy, and extremely low leptin and adiponectin levels. Fibroblast growth factor 21 (FGF21) serum levels were found to be remarkably higher in these cases (173). Of note, there are additional etiologies linked to the development of lipomatosis, with or without lipodystrophy.

Figure 15. Disease progression in a patient with a pathogenic variant in the MFN2 gene (15A-D).

Acquired Partial Lipodystrophy

Acquired partial lipodystrophy (APL) is characterized by fat loss typically starting in childhood or early adulthood. Loss of adipose tissue first manifests in the face and gradually progresses to the upper extremities, thorax, and upper abdomen symmetrically. It typically proceeds in a cephalocaudal fashion but spares the lower extremities (Fig.16). There might be accumulation of fat in the lower abdomen, gluteal region, and lower extremities.

Although the etiology of APL is still unknown, some patients may have coinciding autoimmune conditions. Systemic lupus erythematosus and dermatomyositis/polymyositis are among the most frequently associated auto-immune diseases (174). In recent years, cases of APL associated with hematopoietic stem cell transplantation and total body irradiation have also been described. These patients are thought to constitute a subset of APL (175, 176). APL has been associated with abnormalities of the alternative complement pathway that may cause membranoproliferative glomerulonephritis (MPGN) (177). Subsequent chronic renal disease constitutes the major cause of morbidity in these patients. It has been suggested that C3-nephritic factor might be the cause for the lysis of adipocytes expressing factor D, although there is no solid evidence supporting this hypothesis (178). A comprehensive review of renal complications in lipodystrophy by the Turkish Lipodystrophy Study Group verified low complement C3 levels in more than 45% of APL patients (179, 180).

Rare variants in LMNB2 were previously reported in five patients with APL, but two of four variants were also present in normal controls (181). In addition, subcutaneous loss of fat from the legs and the gluteal region, presence of diabetes, type IV and V hyperlipoproteinemias were atypical presentations in these patients (181).

Metabolic complications are less common compared to other types of lipodystrophy syndromes (4). Not all patients develop insulin resistance, diabetes, or hypertriglyceridemia. Leptin levels vary from hypoleptinemia to normal range (32, 174). However, patients may develop metabolic abnormalities such as diabetes, hypertriglyceridemia, low HDL cholesterol levels, and hepatic steatosis in later stages of the disorder. In addition, several patients with APL have been reported to develop diabetes or other metabolic abnormalities at a relatively young age, which are apparently associated with insulin resistance (182). It is also known that metabolic complications such as hepatic steatosis, poorly controlled diabetes, and pancreatitis are severe in a group of APL patients who are thought to have advanced fat loss (180). Thus, patients with APL should also be followed for metabolic abnormalities, as is done for other subtypes of lipodystrophy.

ANIMAL MODELS OF LIPODYSTROPHY

Numerous animal models of lipodystrophy have shown that adipose tissue dysfunction triggers the development of severe insulin resistance, which is associated with metabolic abnormalities and end-organ complications as mentioned above and shown in Fig.1. Extensive and authoritative reviews of these studies can be found in articles by Drs. David B. Savage (183) and by Xavier Prieur (121). The introduction of these animal models has allowed researchers to explore the fundamental characteristics of lipodystrophy and insulin resistance and allowed studies of the effects of different treatment approaches. Regardless of the strategy used, ablation of white adipose tissue led to the development of insulin resistance, hypertriglyceridemia, and hepatic steatosis (sometimes 6-fold elevation in total liver weight). In now classical experiments of Reitman and colleagues, fat transplantation from littermates rescued metabolic derangements in the famous A-ZIP mice (184-186). Dr. Beutler’s group identified kelch repeat and BTB (POZ) domain containing 2 (KBTBD2) deficiency as a cause of lipodystrophy associated with insulin resistance and diabetes and they also showed that transplantation of wild-type adipose tissue rescued diabetes and the hepatic steatosis phenotypes of Kbtbd2^−/− mice (187). The administration of leptin into aP2–SREBP-1c transgenic mice from the Brown and Goldstein laboratory resulted in dramatic benefits in glycemic parameters, insulin action, and hepatic steatosis, which could not be explained by its effect on food intake alone, providing the premise to undertake leptin replacement in human patients (188). What was also striking was that if fat from the leptin deficient obese mice was transplanted into littermates of the A-ZIP mice, the metabolic rescue was far less effective, suggesting that leptin played an important role in the regulation of metabolism in lipodystrophy in rodents (189). The replacement of deficient leptin in a small but severely affected cohort of human patients with lipodystrophy with recombinant human leptin (metreleptin) was first reported in 2002 and brought further attention to lipodystrophy research (190). Longer-term studies subsequently confirmed the role of metreleptin therapy in lipodystrophy syndromes especially in the most severe forms (32, 41, 42).

Recent Animal Models Advancing Our Understanding of Lipodystrophy and Fat Dysfunction

While we are not intending to provide a comprehensive review of all animal models generated recently, we selected a few to highlight recent advances in this field. A study by Tapia et al.'s (191) showed that a generalized lipodystrophy gene and a critical enzyme in triglyceride synthesis AGPAT2 is essential for the expression of critical mitochondrial proteins. In this study, genes involved in the type-1 interferon response were overexpressed in differentiated Agpat2^−/−adipocytes, and this condition could be associated with their defective mitochondria. They also showed that differentiated Agpat2^−/− brown adipocytes have a lower proportion of lipid-laden cells, Adiponectin and Perilipin1 synthesis, indicating that these cells were able to initiate brown adipogenesis but could not carry it to further stages (191). Interestingly, another study of Agpat2 null mice, demonstrated the absence of caveolae in adipocytes lacking AGPAT2, which hints at a possible mechanistic connection between different Congenital Generalized Lipodystrophy (CGL) types (121, 192, 193).

The Macdougald lab and our group collaboratively developed adipocyte specific knock out of LMNA gene which recapitulates most of the features of human FPLD2 (194). Loss of adipocyte-specific lamin A/C in mice (Lmna^ADKO) caused a significant reduction in the weight of posterior subcutaneous white adipose tissue (WAT), gonadal WAT, pericardial WAT, renal WAT, and retroperitoneal WAT, as well as markedly reduced circulating adiponectin and leptin levels in both sexes. Hyperglycemia, hyperinsulinemia, liver enlargement, and ectopic fat accumulation in the liver were also noted in these mice under a high-fat diet, consistent with the clinical presentation of FPLD2 (194).

A novel mouse model was generated to explore whether maintaining intact BSCL2 expression in the liver prevents the onset of metabolic disorders in mice with specific BSCL2 deficiency in adipose tissue. BSCL2 was simultaneously targeted for ablation in adipose tissue and hepatocytes. It was observed that liver-specific seipin deficiency did not result in hepatosteatosis and insulin resistance. These results suggest that most of the metabolic pathophysiology is driven by the function of BSCL2 outside of hepatocytes, and likely in adipose tissue (195).

In an animal model created to elucidate the molecular mechanisms of lipomatosis and lipodystrophy associated with the MFN2 gene, which encodes an outer membrane GTPase required for mitochondrial fusion (196), no change in mitochondrial oxidative capacity was observed in homozygous Mfn2^R707W/R707W mice (197). Although the triggering of a cellular integrated stress response and selective impairment in mitochondrial morphology and function were detected in adipose tissues, no significant changes in glucose and lipid metabolism were observed in homozygous mice, unlike humans. Interestingly, leptin and adiponectin levels were low in these mice (197).

A new animal model study showed that a novel R133L heterozygous mutation in the LMNA gene causes signs of aging, such as impaired mitochondrial functions, decreased lipid storage capacity in subcutaneous adipose tissue, as well as metabolic disorders such as insulin resistance and ectopic lipid accumulation. Lmna^R133L/+mice exhibited findings consistent with lipodystrophy, such as a reduction in epididymal white adipose tissue (eWAT) mass, as well as smaller adipocytes and upregulated inflammation genes in the inguinal subcutaneous white adipose tissue (iWAT) (198).

Furthermore, the importance of the lipid kinase phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) in the function of white adipose tissues (WATs) and brown adipose tissues (BATs) has been demonstrated using adipocyte-specific Pik3c3 knock-out model. Deletion of PIK3C3 has been linked to lipodystrophy due to impaired adipocyte differentiation, autophagy, and thermogenesis mechanisms (199).

We have also covered recent animal models of novel gene therapies under a new heading: Emerging Therapeutic Technologies and Gene Replacement Therapy Approaches.

TREATMENT

Currently, treatment modalities are restricted to ameliorating or preventing the comorbidities of the lipodystrophic syndromes. There is no cure for these syndromes. For the metabolic disturbances, lifestyle modification (diet and exercise as needed), metformin, and fibrates (and/or statins) are generally required. Insulin or other antidiabetics (e.g., metformin, thiazolidinediones) can also be used if needed. Metreleptin, a leptin analog, is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with generalized lipodystrophy.

Lifestyle Modification

There is limited knowledge on the effectiveness of diet and exercise in the management of metabolic disturbances in patients with lipodystrophy. In general, a balanced macronutrient composition is recommended. In patients with severe hypertriglyceridemia, a balanced low- fat diet (<15% of daily caloric intake) is appropriate. To control diabetes, increased physical activity and carbohydrate restriction are advised. Dietary fiber intake and foods that are rich in omega-3 fatty acids are suggested (3).

Most patients with lipodystrophy are encouraged to be physically active. In patients with cardiomyopathy and cardiac arrhythmias strenuous exercise should be avoided. Patients with CGL4 should avoid exercise as they may develop exercise-induced ventricular arrhythmias (75, 79). Contact sports are not advised to patients with severe hepatosplenomegaly and CGL patients presenting with lytic bone lesions.

Patients should abstain from drinking alcohol due to the risk of developing acute pancreatitis and metabolic dysfunction-associated steatohepatitis (MASH). Patients should also be advised to avoid smoking and maintain an optimal blood pressure to decrease the risk of cardiovascular disease.

Insulin Resistance

In patients presenting with lipodystrophy and diabetes, both metformin and thiazolidinediones are somewhat effective to treat hyperglycemia and hyperlipidemia (200-204). Metformin is used as the first-line agent in insulin resistant diabetes. Thiazolidinediones may improve the metabolic profile in partial lipodystrophy syndromes (204). The very first thiazolidinedione to be approved in the United States troglitazone actually worked remarkably well in lowering both HbA1c and triglyceride levels in a cohort of patients with predominantly partial lipodystrophy syndromes. However, data on the currently approved thiazolidinediones are limited and contradictory (202, 205, 206). Thiazolidinediones should be considered in the management of diabetes in patients with partial lipodystrophy, however they should not be routinely used in generalized lipodystrophy as their efficacy has not been studied (3, 204). Insulin is usually needed in very high doses and concentrated forms, such as U-500. Patients with extreme insulin resistance, however, may not respond to concentrated insulin. Administration of insulin-like growth factor-1 (IGF-1) has been shown to be effective in maintaining glycemic control and insulin resistance in short-term studies, as well as in type 2 diabetes (207-209). A retrospective study found that administration of sodium-glucose cotransporter 2 (SGLT2) inhibitors resulted in a 0.8% drop in HbA1c levels after one year in individuals with partial lipodystrophy. Additionally, SGLT-2 inhibitors led to a significant decrease in both systolic and diastolic blood pressure (210). In clinical practice, it should be considered that combination therapy with metreleptin and SGLT2 inhibitors may contribute to prognosis by improving insulin resistance in adipose tissue and reducing the risk of cardiovascular events (211). Many other hypoglycemic agents have been used in lipodystrophy, but their efficacy has not been studied (3). Recently we published a retrospective review of GLP-1 agonist use in FPLD syndromes showing substantial improvement in glucose control and body weight (212). Dual incretin therapeutic tirzepatide is postulated to have even more efficacy due to the potential impact of GIP agonism and potentially improving inflammation.

Dyslipidemia

Statins are normally used as first-line agents to treat hypercholesterolemia but patients with FPLD have low tolerance to statins. Rosuvastatin and pravastatin have been proven to reduce total LDL cholesterol levels (213, 214). Statins are used with caution to prevent side effects such as myopathy and hepatotoxicity. Along with diet, fibrates and fish oil rich in omega-3 fatty acids, should be prescribed for serum triglyceride levels >500 mg/dL and may be considered for triglycerides >200 mg/dL. Combining fibrates with statins has proved to be effective in dyslipidemia; however, there is an increased risk for muscle toxicity. Therapeutic apheresis can be used in extreme hypertriglyceridemia to prevent recurrent episodes of acute pancreatitis in acutely life-threatening situations (190).

Cosmetic Treatment

Cosmetic correction of lipoatrophy and fat excess is associated with improved quality of life in patients with lipodystrophy. Autologous adipose tissue transplantation, facial reconstruction with free flaps and silicone or other implants have been used in lipoatrophic areas. In addition, liposuction or surgical excision is used for removal of unwanted excess fat from body parts such as the chin, buffalo hump and vulvar region.

Bariatric Surgery

Roux-en-Y Gastric Bypass Surgery (RYGB) is associated with effective weight loss and resolution of metabolic comorbidities in patients with obesity (215). RYGB was used with success in several patients with FPLD1 and with FPLD2 (216-218). RYGB resulted in weight loss and significant improvements in metabolic parameters in patients with FPLD1 that allowed patients to stop using insulin (216). FPLD2 patients also benefited from RYBG. Substantial improvements in metabolic parameters and a significant weight loss were reported after the surgery (218, 219).

Leptin

A large group of lipodystrophy patients present with low leptin levels. Metreleptin (r-metHuLeptin) is an analog of human leptin made through recombinant DNA technology. It has been tested in congenital and acquired forms of lipodystrophy and has been shown to ameliorate the metabolic derangements (43, 190).

Leptin replacement therapy is approved in Japan as a therapy indicated specifically for the treatment of diabetes and/or hypertriglyceridemia in patients with congenital or acquired lipodystrophy. In the United States, metreleptin, now called MYALEPT, has been approved by the FDA in 2014 for use in patients with congenital generalized or acquired generalized lipodystrophy for the treatment of complications of leptin deficiency as an adjunct to diet and lifestyle modifications. There is no lower age limit for initiation of Myalept nor a specific degree of metabolic abnormality so long as the diagnosis of generalized lipodystrophy can be substantiated. However, it is not approved for use in human immunodeficiency virus (HIV)-related lipodystrophy, or in patients with metabolic diseases such as diabetes and hypertriglyceridemia, or partial lipodystrophy in the US. Metreleptin is an approved treatment for generalized lipodystrophy (GL) and partial lipodystrophy (PL) in the European Union (EU), United Kingdom (UK), Canada, and Brazil. However, there is an age limit of ≥ 2 years for GL. The approval for PL states that patients with confirmed PL can initiate treatment if they are aged ≥ 12 years and only when standard treatments have not achieved adequate metabolic control. Based on this indication, in the EU, UK, Canada, Brazil, and Japan, patients with PL who do not respond to available diabetes and lipid-lowering agents can be treated with recombinant leptin therapy. It is still controversial whether basal endogenous leptin levels can be used to predict response to metreleptin treatment in lipodystrophy patients. However, a recent study revealed that baseline endogenous leptin levels are poor predictors for response to metreleptin therapy among individuals with partial lipodystrophy (220). The clinical effects of leptin treatment in patients with lipodystrophy are summarized below.

APPETITE

Metreleptin decreases hyperphagia, leading to weight loss that usually stabilize with long-term treatment (190, 221-223). This effect can be noted by the patients right after the treatment with metreleptin. Functional MRI studies combined with behavioral assessments showed that metreleptin treatment is associated with long-term improvements of hedonic and homeostatic central nervous networks regulating appetite and food intake (224-226). Food related neural activity and development of satiety were effectively restored by leptin replacement in lipodystrophy (227).

METABOLIC PARAMETERS

Metabolic changes become evident quickly within days to weeks of treatment with metreleptin. Metreleptin therapy has been shown to improve fasting plasma glucose levels starting from the first week. In the first set of patients with lipodystrophy treated with metreleptin, four months of therapy with metreleptin decreased average triglyceride levels by 60%. The absolute decrease in HbA1c was 1.9% among patients with diabetes. Liver volume reduced by an average of 28% and led to the discontinuation of or a large reduction in antidiabetic therapy (190). In the long term, more than three-fourths of patients with GL treated with metreleptin discontinued concomitant treatments, including insulin and oral antidiabetics (228).

In clinical studies, metreleptin led to significant improvements in patients with GL. After 1 year of treatment initiation, a mean change of -2.2% in HbA1c and a mean percent change of -32.1% in triglycerides were observed. Significant reductions in alanine aminotransferase levels occurred. Mean liver volume decreased by 33.8% at month 12. Nearly 80% of patients with GL achieved a ≥1% actual decrease in HbA1c or a ≥30% decrease in triglycerides after 1 year of treatment with 66% achieving decreases of ≥2% in HbA1c or a ≥40% in triglycerides. Among patients with baseline HbA1c of 7% or greater, the mean reduction at Month 12 was 2.8%. In subjects with baseline TG level 500 mg/dL or greater, the mean percent reduction in triglycerides at month 12 was 72%. Patients with GL overall sustained clinically significant reductions in HbA1c and triglycerides in the longer term follow up.

In patients with PL, metreleptin treatment led to statistically significant reductions in HbA1c (−0.6%), fasting TGs (−20.8%), and liver volume (−13.4%) after 1 year treatment. In a subgroup of patients with baseline HbA1c ≥ 6.5% or triglycerides ≥ 5.65 mmol/L, more prominent reductions were observed in HbA1c (−0.9%) and fasting TGs (−37.4%). In this subgroup, 68% of patients had a ≥ 1% decrease in HbA1c or ≥ 30% decrease in fasting TGs, and 43% had a ≥ 2% decrease in HbA1c or ≥ 40% decrease in fasting triglycerides. Longer-term treatment in the PL subgroup led to significant reductions at months 12, 24, and 36 in HbA1c and fasting triglycerides (229).

12 months of long-term metreleptin therapy has been shown to reduce mean fasting plasma glucose levels by 2.8 mmol/L in the generalized lipodystrophy group and 1.2 mmol/L in the partial lipodystrophy group (228, 229). In a subset of patients undergoing hyperinsulinemic-euglycemic clamp studies, leptin replacement therapy improved peripheral glucose disposal and decreased both hepatic glucose output and hepatic steatosis (230). It is generally recommended to lower the insulin doses by 50% on initiation of metreleptin therapy (especially in GL) to avoid hypoglycemia in well-controlled patients with diabetes. Metreleptin treatment has no suppressive effect on beta cell function in patients with lipodystrophy (231). On the contrary, it has been reported that metreleptin therapy improves insulin secretion in the setting of diabetes (232). A prospective study observed that metreleptin administration for two weeks suppressed basal gluconeogenesis (GNG) by reducing carbon sources for GNG and increasing insulin-mediated suppression of GNG. Peripheral insulin sensitivity increased significantly throughout the 6-month follow-up of these patients (233).

Apolipoprotein C-III and angiopoietin-like protein 8 (ANGPTL8), recognized as inhibitors of lipoprotein lipase, play a role in modulating hypertriglyceridemia. A notable reduction of these hepatokine plasma concentrations is observed, especially after six months of metreleptin treatment (234). While about a 60% decrease in TG values was detected in 1-year follow-up in GL patients using concomitant lipid-lowering medications, a 30% decrease was observed in patients with partial lipodystrophy. These reductions were less in individuals who did not take concomitant medication (235). In a real world study from France, during a follow-up period of more than 15 months, TG levels decreased by approximately 150 mg/dL in patients with generalized lipodystrophy (236). It should be noted that acute withdrawal of metreleptin therapy might result in acute pancreatitis episodes (237, 238). Metreleptin also decreased total cholesterol and LDL-cholesterol levels (237, 239). But did not alter HDL cholesterol levels (236, 237, 239).

As we have noted, the beneficial effect of metreleptin on glycemic and lipid measures in generalized lipodystrophy are clear and usually quite remarkable. Although the response is variable in patients with partial lipodystrophy and it is not approved for this indication in the US, studies have shown that some patients can benefit from metreleptin treatment. A selected cohort of partial lipodystrophy patients with moderately to severely low leptin and significant baseline metabolic abnormalities is more likely to benefit from metreleptin therapy (13, 235, 236, 240-242). Recent studies confirm that most partial lipodystrophy patients with inadequate metabolic control also respond to metreleptin treatment (235, 236). Furthermore, when comparing the metabolic responses to metreleptin treatment of patients with PPARG and LMNApathogenic variants in the FPLD group, both groups reported remarkable and similar reductions in HbA1c, insulin dose, and triglyceride levels after 12 months of treatment (243). However, the real-life study from France showed that leptin treatment did not significantly change HbA1c levels (7.7 [7.1‐9.1]% at baseline vs. 7.7 [7.4‐9.5]% at one year) in 19 patients with partial lipodystrophy. In the same group of patients, a significant decrease in the median value of fasting triglycerides from 3.3 mmol/L (1.9-9.9) to 2.5 mmol/L (1.6-5.3) was observed with short-term metreleptin treatment (p<0.01), whereas the median serum triglyceride levels were 5.2 mmol/L (2.2-11.3) at the last evaluation after long-term leptin treatment (p=0.94) (236). When a responder analysis is performed, however, 61% of the patients with PL showed improvements in glucose homeostasis, with responders exhibiting lower leptin levels compared to non-responders. Similarly, 61% of the PL patients in the French real-world study cohort were responders regarding hypertriglyceridemia.

LIVER

Starting from the earliest studies, leptin replacement therapy was observed to improve hepatic steatosis and lower serum transaminases within 6-12 months (Fig.17) (223, 230, 244).The liver volume decreases in parallel (222, 244). Metabolic associated steatohepatitis (MASH) score has been reported to improve after metreleptin treatment and no progression in hepatic fibrosis has been reported (245, 246). When treated at least for a year, the majority of patients showed improved liver histology, steatosis and hepatocyte ballooning, and only 33% of patients continued fulfilling the criteria for MASH after 1 year of treatment with metreleptin (247, 248). A significant improvement in the metabolic dysfunction-associated steatotic liver disease (MASLD) score has been reported after metreleptin treatment in pediatric patients who underwent liver biopsies (249). Also, our study showed that metreleptin can induce improvements in hepatic steatosis and injury in patients with MASH associated partial lipodystrophy (246). In a mechanistic study, leptin therapy resulted in significant increase in insulin suppression of hepatic glucose production (230). This improvement in insulin action helps reverse hepatic steatosis by decreasing triglyceride content (230). Other mechanisms associated with reducing hepatic steatosis may be leptin effectively increases hepatic VLDL-TG secretion via possibly vagal effect (250) and decreases de novo lipogenesis (251). These observations suggest that the effect of metreleptin on hepatic steatosis can be somewhat blunted when the autonomic innervation of the liver is not intact. However, it should be noted that the liver disease can still benefit from improving metabolic profile and hepatic steatosis can diminish as a result of controlled de novo lipogenesis after improved insulin sensitivity with leptin replacement. To support this view, metreleptin has also been reported to result in rapid clearance of fat from the liver and normalization of liver histology in an AGL patient with recurrence of MASLD in the first few months of liver transplantation (252).

Figure 17. Liver Histology Before and After Metreleptin. Liver histology shows regression of hepatic steatosis and ballooning injury after metreleptin treatment (left before metreleptin and right 4 months on metreleptin treatment, Hematoxylin and eosin staining; magnification 200X).

KIDNEYS

Patients with lipodystrophy may develop proteinuric kidney disease. Metreleptin decreases proteinuria in most patients (223, 253). The reduction in proteinuria coincided with improvement in hyperfiltration in 11 of 15 patients treated with metreleptin. However, four patients had worsening renal function. Hence, renal functions should be closely monitored during metreleptin therapy (253). In further studies, metreleptin significantly reduced proteinuria in patients with GL (254).

CARDIOVASCULAR SYSTEM AND OVERALL SURVIVAL

A study conducted in lipodystrophic mice showed that metreleptin treatment inhibited proatherosclerotic cytokine growth/differentiation factor 15 (GDF15) and reduced macrophage accumulation in atherosclerotic lesions via endothelial to mesenchymal transition. Thus, the positive effect of leptin on the endothelium by reducing inflammation has been reported (255). Metreleptin treatment provides a significant improvement in serum levels of atherogenic lipoproteins, which are known to be associated with increased cardiovascular disease risk (256). A potential increase in cardiovascular risk was detected in a prospective coronary calcium score (CCS) evaluation in 19 individuals diagnosed with CGL, although not sufficiently powered, this study did not report a significant change after metreleptin in CCS score (257). Another recent study, on the other hand, reported an approximately 30% regression in left ventricular hypertrophy and an improvement in septal e' velocity in the GL patients after leptin treatment (258). Cardiovascular problems are a significant risk of mortality in lipodystrophy patients. Our large retrospective evaluation from a large multicenter dataset, found that after adjusting covariates such as lipodystrophy diagnosis, triglyceride levels, elevated HbA1c, ≥1 episode of pancreatitis, and abnormalities in the heart or kidneys, metreleptin treatment resulted in a mortality reduction of over 60% (259).

CENTRAL NERVOUS SYSTEM AND OTHER EFFECTS

A functional MRI study revealed that leptin may induce alterations in brain activity in the subgenual area (Brodmann area 25), a region not strictly linked to eating behavior, known for its connections to the reward network. This suggests that leptin may also affect brain regions other than eating behavior (260). Another observational study of ten individuals with partial lipodystrophy who were naïve to metreleptin found a rapid decline in Beck's depression inventory score one week after metreleptin therapy. In the first 3-month follow-up of the individuals, a significant improvement was observed compared to their initial scores. Although this shows that metreleptin treatment may have an antidepressant effect, the findings need to be supported by long-term clinical studies (261). Metreleptin treatment also significantly contributes to improving indirect findings related to quality of life, such as hyperphagia, inability to go to work/school, and deterioration in physical appearance (262).

REPRODUCTIVE SYSTEM

In females, metreleptin was found to normalize gonadotropin secretion. It led to normal progression of puberty, normalized menstrual cycles, and improved fertility (223, 263-265). Leptin replacement improved low estradiol levels and corrected the attenuated luteinizing hormone (LH) response to luteinizing hormone-releasing hormone (LHRH) in young women with lipodystrophy and leptin deficiency (263). One-year treatment with metreleptin resulted a significant decrease in testosterone and sex hormone binding globulin (SHBG) levels in lipodystrophic women with PCOS (266). Several pregnancies have occurred in patients with lipodystrophy while they were on metreleptin without any evidence for teratogenicity (47, 267), although it has not been approved for use in pregnancy. Leptin replacement was associated with a small increase (clinically non-significant) in serum testosterone and SHBG in males. No change was observed in serum LH response to LHRH (264). No impact of leptin therapy on bone mineral density and content and bone metabolism has been reported in both sexes (244, 268, 269) .

ADVERSE EFFECTS

Majority of patients treated with metreleptin in clinical studies experienced ≥1 treatment-emergent adverse event, which mainly were mild-to-moderate in severity (228, 229). The most common side effects were hypoglycemia, nausea, decreased appetite and injection site reactions e.g. erythema and urticaria. Headache, fatigue, weight loss, and abdominal pain were also seen (228). During metreleptin treatment, iron parameters might be affected, and a decrease in ferritin levels might be observed (270). There may also be a need to make dose adjustments or cessation of concomitant treatments such as insulin, oral antidiabetics, and lipid lowering drugs after metreleptin therapy. In some cases, in vivo neutralizing antibodies to metreleptin have been reported (271, 272) and is the main reason underlying the FDA's restriction of metreleptin use. Anti-metreleptin antibodies developed in most patients with lipodystrophy; however, neutralizing activity concurrent with worsened metabolic control has been reported only in a small number of patients treated with metreleptin (267, 271). In addition, in the few patients who presented with neutralizing antibody formation, occurrence of severe infections such as sepsis has been reported. Two of these patients developed multiple sepsis episodes around the time of detection of neutralizing antibody (271). T-cell lymphoma has been reported in three patients with acquired generalized lipodystrophy receiving metreleptin (273). In acquired lipodystrophy patients with autoimmunity and immunodeficiency before metreleptin therapy, T-cell lymphoma development was also described (273, 274), suggesting that lymphoma development in acquired lipodystrophy is more likely to be associated with the disease itself rather than being related to metreleptin treatment.

In other cases with acquired generalized lipodystrophy, progression of kidney disease and liver disease have been observed while receiving metreleptin therapy (275). Since patients with AGL with distinct autoimmune conditions clearly benefit from metreleptin, treatment for their metabolic abnormalities should be considered in patients with AGL with close clinical follow up considering the cautionary preclinical data (276, 277).

More recently attention has been devoted to emergence of new cancers while on metreleptin therapy. Data on these parameters has been reported with the prospective, non-randomized, open-label clinical trial of metreleptin in lipodystrophy. Ten patients with general lipodystrophy had neoplasm development throughout the research period. These included peripheral T-cell lymphoma, granular cell tumor, breast cancer, ovarian neoplasm, papillary thyroid cancer, and basal cell carcinoma. However, only the anaplastic large cell lymphoma case was thought to be drug-related (228). During the study period, neoplasms (e.g., adrenal adenoma, benign ovarian germ cell teratoma, schwannoma, and a nervous system neoplasm) were observed to develop in five partial lipodystrophy patients. Still, none of them were considered drug-related (229).

Additionally, MEASuRE (Metreleptin Efficacy and Safety Registry), a voluntary registry that collects long-term safety and effectiveness data on metreleptin, was developed as a post-authorization requirement by the FDA and EMA. This database contains comprehensive data on long-term adverse effects and drug efficacy in lipodystrophy patients using commercially available metreleptin (278).

Investigational Treatments for Lipodystrophy

Since in the United States partial lipodystrophy has been without medical therapy, several companies with interesting compounds have initiated development of their products for this indication. Current and recently completed investigational treatments with registered studies in ClinicalTrials.gov are presented in Table 4. Data on these trials will be updated as results become available.

The BROADEN study which was the largest global double blinded placebo controlled study published in 2022 revealed that treatment with volanesorsen, an antisense oligonucleotide to apolipoprotein C-III, significantly reduced serum triglyceride levels by over 88% and improved hepatic steatosis in patients with FPLD by 53 % from original level (279, 280). While the exact mechanisms of how volanesorsen led to the effects observed in the FPLD population are unclear, a small scale study showed that hepatic insulin resistance concurrently improved in parallel to an increase in lipoprotein lipase (LPL) activity in a few FPLD patients treated with this drug (281).While Volanesorsen is not approved in the US due to the adverse events of systemic inflammation and thrombocytopenia, this drug has been approved for use in FPLD in Brazil under the name Waylivra, marketed by PTC Therapeutics. The same drug is also available in Canada and EU for treatment of familial hyperchylomicronemia syndrome and can be an off-label option for patients with recurrent pancreatitis and severe hypertriglyceridemia. Currently, second generation anti-sense inhibitors of ApoCIII are under development in the US for severe hypertriglyceridemia and patients with FPLD are not excluded from these studies if they meet the trial population criteria (282-284). We are aware of a few patients with FPLD who are in ongoing studies.

A therapeutic compassionate use trial with the melanocortin-4 receptor agonist setmelanotide was conducted in a patient with atypical partial lipodystrophy, whose metabolic status continued to worsen despite the presence of neutralizing antibodies to metreleptin. The reported findings indicated that the treatment had no improving effect on the lipid profile, insulin resistance, and liver fat percentage (285). The same patient was successfully treated with Mibavademab a monoclonal leptin receptor agonist antibody and remains on long term treatment (286). The promising results obtained from this patient experience led to the development of this therapeutic as an option for patients with generalized lipodystrophy. A small-scale proof of concept study in FPLD patients was also started but very recently discontinued and results are not yet available. Treatment of 16patients with generalized lipodystrophy over a year resulted in meaningful changes in metabolic parameters which are similar to metreleptin effects; but final completion of the study and the definitive dosing schema has not been published so far (287).

Table 4. Ongoing or Recently Completed Investigational Therapies for Lipodystrophy
Investigational agent	Status	Type of lipodystrophy	Primary outcome	Results
Volanesorsen (anti-sense oligonucleotide to apoC-III)	Completed	Familial partial lipodystrophy	Change in fasting triglycerides	88% reduction in triglycerides, 53% reduction in hepatic steatosis
Vupanorsen (Targeting angiopoietin-like 3 “ANGPTL3”) (288)	(Pfizer and Ionis announced discontinuation of vupanorsen clinical development program due to concern for increase in liver fat	Familial partial lipodystrophy	Reduction in fasting triglycerides and free fatty acids	59.9% reduction in triglycerides, 54.7 % reduction in ANGPTL3, 53.5% reduction in VLDL cholesterol, 41.7% reduction in free fatty acids (FFA)
Obeticholic Acid (farnesoid X receptor agonist)	Completed	Familial partial lipodystrophy	Change in liver triglycerides	6.8% reduction in liver triglycerides median value, 16.9 mg/dL reduction in serum triglycerides, 0.5 U/L reduction in serum alanine aminotransferase (ALT) median value
Cholic Acid (primary bile acid)	Completed	Various forms of lipodystrophy	Reduction in liver triglyceride content	7.9% reduction in hepatic triglycerides median value (Fat/Fat+Water)
Setmelanotide (melanocortin-4 receptor agonist) (285)	Expanded access in a single patient	Partial lipodystrophy associated with leptin deficiency	Treatment of refractory hypertriglyceridemia leading to recurrent bouts of pancreatitis	No sustained improvement in glycemic control or hypertriglyceridemia, slight decrease in visceral fat
Gemcabene (monocalcium salt of a dialkyl ether dicarboxylic acid)	Completed	Familial partial lipodystrophy	Change in fasting triglycerides, hepatic steatosis	The mean percentage change in fasting serum triglycerides between weeks 12 and 24 in group 1 (receiving 300 mg Gemcabene daily) was -0.44 (-41.27 to 40.38), and in group 2 (receiving 600 mg Gemcabene daily) was -20.27 (-53.98 to 12.77)
Baricitinib (inhibitor of Janus kinases 1 and 2 “JAK1/2”)	Expanded access available	Autoinflammatory syndromes, familial partial lipodystrophy type 2, Hutchinson-Gilford Progeria Syndrome, and MAD (289)	Clinical benefit from JAK 1/2 inhibition, improves adipogenesis and lipid droplet formation	Increased number of adipocytes and formation of lipid droplets, higher adipocyte differentiation ability, increased lipid droplet size (~76 µm2) in the FPLD2 group
Evinacumab (Anti-ANGPTL3)	Completed	Patients with severe hypertriglyceridemia	Percent lowering of triglycerides	59.9% reduction in mean fasting triglycerides levels from baseline at the end of the treatment (week 27)
Mibavademab	Active, not recruiting	Generalized lipodystrophy	Meaningful improvements in metabolic parameters	Reduction in HbA1c (mean: -1.9%, SD: 2.0) and triglycerides (median: -102.1 mg/dL, IQR: 1355.5 mg/dL, -49.3% [57.2%]) (290) With longer treatment there was a further 0.7% reduction in HbA1c and 42% reduction in fasting triglycerides in patients receiving high dose mibavademab (287)

Emerging Therapeutic Technologies and Gene Replacement Therapy Approaches

Research on novel and emerging technologies is ongoing to broaden therapy options and better understand diseases of complex nature like lipodystrophy. LipocyteProfiler, a sophisticated image-based tool for deep phenotypic analysis, facilitates assessing numerous morphological and cellular profiles that can be methodically associated with genes and genetic variations that have significance in cardiometabolic diseases. LipocyteProfiler is algorithmically generated from over 3,000 morphological and cellular features that map to the cell, cytoplasm, and nucleus across channels differentiating the organelles, namely DNA, mitochondria, AGP (actin, Golgi, plasma membrane), and Lipid. It was observed that LipocyteProfiler was able to detect significant changes in cell profiles during white and brown adipocyte differentiation after genetic and pharmacological manipulations and transcriptional states in adipocytes. Also, profiles associated with the polygenic risk of lipodystrophy confirmed increased mitochondrial activity, reduced actin cytoskeleton remodeling, and reduced lipid accumulation capacity in subcutaneous adipocytes. This tool may shed light on a deeper insight into both known and novel mechanisms by generating cellular profiles that are specific to the processes occurring in response to polygenic metabolic events, particularly in hepatocytes and adipocytes. Analyzing deep phenotypic profiles, especially in lipocytes, can enhance our understanding of lipodystrophy pathophysiology and allow us to develop better therapies (291).

Gene therapy studies conducted in recent years are an emerging and promising approach to treating various genetic lipodystrophy syndromes. A novel study shows that the in vivo embryonic re-expression of human AGPAT2 (hAGPAT2) induces adipocyte differentiation and regenerates 30%–50% of the WAT and BAT depots in Agpat2−/− mice when compared to age-matched wild-type mice. Due to this genetic reorganization in Agpat2-null mice, it was observed that the differentiation of adipocytes, specifically the metabolically active depots (SubQ, Gonadal, and BAT) and dWAT (dermal) was stimulated (292).

An in vivo gene therapy study demonstrated that delivering the human BSCL2 gene using an adeno-associated virus (AAV) in seipin knockout mice resulted in the restoration of adipose tissue, and this led to a significant improvement in metabolic disease (293). Following AAV-mediated gene therapy, it has been documented that there was a reduction in serum triglyceride levels, an improvement in insulin sensitivity and glucose tolerance, and a partial enhancement in the development of visceral WAT depots in seipin knockout mice. However, a dramatic increase in circulating leptin and adiponectin levels could not be achieved. Nevertheless, this study suggests a potential therapeutic approach for treating metabolic conditions related to CGL2 and other lipodystrophy syndromes (293).

Introducing a functional copy of the defective gene associated with the condition or modulating the expression of related genes to restore normal adipose tissue function holds promise for alleviating severe metabolic complications in patients with lipodystrophy. CrispR-cas editing of single nucleotide variants is also rapidly approaching clinical use in all rare diseases. However, further studies are required to move gene therapies from the experimental stage to clinical applications.

CONCLUSION

Lipodystrophy syndromes are a group of fascinating diseases that are caused by mechanisms that disrupt predominantly adipocyte differentiation or lipid droplet formation. LMNA gene defects, the most common single gene defects leading to the development of lipodystrophy syndromes, leads to lipodystrophy possibly due to inducing adipocyte apoptosis or death, but more work is needed on this front. Regardless of the mechanism and whether the diseases present with generalized or partial fat loss, common metabolic complications include severe insulin resistance, hypertriglyceridemia, and ectopic fat deposition, especially hepatic steatosis. This common theme is recapitulated in numerous animal models as well. The diseases are typically progressive and lead to multi-organ involvement and increased mortality. Molecular advances in the understanding of disease mechanisms may lead to better and specific treatments for lipodystrophy syndromes. So far, the most exciting therapeutic development for the treatment of lipodystrophy syndromes has been the approval of leptin replacement therapy for generalized lipodystrophy in the form of metreleptin which started a new era in lipodystrophy research; leading to the launch of registries and natural history studies (e.g. the LD Lync Study-Natural History Study of Lipodystrophy Syndromes (NCT03087253) (294-296), organization of research consortia around the world (e.g., European Consortium of Lipodystrophies (ECLip) (297) and country specific patient advocacy foundations or organizations. All these efforts will contribute to discovery of new disease forms and disease mechanisms, understanding of the natural course of lipodystrophy diseases, development of improved treatment options and possibly cures.

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Pharmacologic Treatment of Overweight and Obesity in Adults

ABSTRACT

Obesity pharmacotherapy has evolved significantly over the past 60 years. Today, six anti-obesity medications (AOMs) are approved by the Federal Drug Administration (FDA) for the long-term treatment of obesity. Similar in approach to other chronic diseases, AOMs are indicated in combination with lifestyle modification for the management of overweight and obesity. Current guidelines recommend that individuals who have attempted lifestyle improvements and continue to have a body mass index (BMI) of ≥ 30 kg/m² or ≥ 27 kg/m² with an obesity-related comorbidity are eligible for weight loss medication treatment. The AOMs reviewed in this chapter include the FDA-approved medicines for chronic weight management, FDA-approved medicines for short-term use of weight management, and off-label use of medicines that have demonstrated benefits for weight control.

INTRODUCTION

Obesity is recognized as a major pandemic of the 21^st century, contributing to increased morbidity, mortality, and the burden of healthcare costs (1). Overweight and obesity are defined by the World Health Organization (WHO) as a BMI of 25-29.9 kg/m² and a BMI ≥ 30 kg/m², respectively (2). In the United States, the prevalence of obesity had risen to 42.4% in 2017-2018 (3) and predictive models now suggest that the prevalence will grow to one in two adults by 2030 (4). Internationally, one in five adults now have obesity (5). The Global Burden of Disease study reports that overweight and obesity are the fourth leading risk for global deaths, and more than 4.7 million adults die each year as a result of overweight or obesity (6). Obesity is a major risk factor in the development of cardiovascular disease (CVD), type 2 diabetes (T2D), musculoskeletal disorders, and several cancers (2). In certain ethnic populations (i.e., East Asian or South Asian), these comorbidities can develop at lower BMIs (7).

The associations between obesity, central obesity (increased waist circumference, especially intra-abdominal/visceral fat) and the risks for cardiometabolic diseases as well as obstructive sleep apnea, asthma, and nonalcoholic fatty liver disease (NAFLD) are well established (8,9). Cytokines secreted from visceral adipocytes, including interleukin-6, tumor necrosis factor alpha, resistin, and plasminogen activation inhibitor-1, have been implicated in the pathogenesis of these diseases, in part by promoting local and systemic states of inflammation and thrombosis (10-12). A reduction in body weight of 5-10% significantly lowers inflammatory and pro-thrombotic makers, as well as chronic disease incidence (13,14).

OBESITY PHARMACOTHERAPY

Principles of Obesity Pharmacotherapy

As with other chronic metabolic diseases, the initial management of overweight and obesity emphasizes sustainable nutritional, physical activity, and behavioral changes that have been shown to reduce weight and lower cardiometabolic risk. However, lifestyle interventions that include caloric restriction and/or portion control alone are insufficient in achieving long-term weight loss maintenance in most patients, with one-third to two-thirds of lost weight regained within one-year following end of treatment, and > 95% weight regained within 5 years (15).

For patients who have failed to achieve clinically significant weight loss, defined as ≥ 5% of baseline weight (16) after 6 months of lifestyle interventions (16-19), professional organizations including The Obesity Society, the Endocrine Society, and the American Association of Clinical Endocrinologists recommend AOMs for individuals with BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with comorbidities.

For health care professionals using pharmacotherapy for weight management, the following basic principles can be kept in mind:

Lifelong treatment: Because obesity is a chronic disease, pharmacotherapy should be prescribed with the intent of lifelong use and as part of a comprehensive management plan that includes nutrition, physical activity, and behavioral counseling. Discontinuation of an AOM often leads to weight regain.
AOMs affect pathophysiological pathways that lead to obesity: Current obesity pharmacotherapy targets the underlying neurohormonal dysregulations that cause weight gain and prevent sustained weight loss. Changes in hormones in response to diet-induced weight loss, such as reduction in the anorexigenic hormone leptin and increase in the orexigenic hormone ghrelin, create a physiologic environment conducive to the body returning to its previously established, higher body weight set point (20,21). Additional adaptation responses to diet-induced weight loss affecting energy expenditure, including reductions in basal metabolic rate, also challenge weight loss maintenance (22,23).
Treatments benefit both weight and comorbidities: The goals of obesity treatment are primary, secondary, and tertiary prevention (17); that is, to prevent the development or exacerbation of obesity and its complications. For example, improvements in cardiometabolic risk factors and reduced diabetes risk have been consistently reported in the Phase 3 trials for AOM’s.
Expect heterogeneity in weight loss response: Phase 3 trials have consistently demonstrated that AOMs achieve significantly greater weight loss than placebo when combined with lifestyle modifications (24-31). The average efficacy in these studies ranges from 5-23% total body weight loss. However, as with any medical therapy, significant inter-individual response variability (32,33) has been reported, including the possibility of no weight loss (non-responders) to 25% or greater weight loss.

History of Anti-Obesity Medications

The development of AOMs dates as far back as the 1940s, predating the standard FDA rules and regulations that are familiar today. Drug approval in the 1940s necessitated only proof of efficacy beyond placebo; evaluation of benefit versus risk with controlled investigations was not a requirement until passage of the Kefauver-Harris amendment in 1962. Approval of the first AOM, desoxyephedrine, in 1947 led to the development of a number of amphetamine derivatives for weight loss that have all since been removed from the market due to this amendment (34). A comprehensive narrative of the history of AOMs covers the development of pharmacotherapy and the FDA’s role in regulation (35). Since the FDA’s adoption of stricter regulations and proof of clinical efficacy, only a couple of AOMs have been removed from the U.S. market for safety concerns (Table 1).

Table 1. Selected Historical Anti-Obesity Medications

Name (Trade Name)

Years Approved

Reason for Removal

Sibutramine (Meridia)

1997-2010

Patients at high risk for CVD were found to have elevated risk of CVD events when given sibutramine (36)

Lorcaserin (Belviq)

2012-2020

Re-analysis of a safety clinical trial showed an increased incidence of certain cancers (37)

Only two AOMs have been removed from the market in recent history. The administration of sibutramine to individuals at high risk of CVD in the SCOUT trial was widely criticized by the medical community as it did not reflect real-life clinical practice; subgroup analysis of patients with T2D without CVD in SCOUT actually showed no increase in CVD events and a decrease in mortality with sibutramine compared to placebo (38). The voluntary recall of lorcaserin in 2020 occurred among significant confusion, as long-term data from the CAMELLIA-TIMI 61 trial did not demonstrate an imbalance in adverse events between treatment groups (39,40). The FDA has clarified their findings that led to this withdrawal recommendation. When all post-randomization adverse events were considered, not just those that occurred “on treatment” (i.e., those that occurred within 30 days of drug discontinuation) as analyzed in CAMELLIA-TIMI 61 (37), even though similar numbers of patients experienced cancers (n=462 out of 6000 on lorcaserin and n=423 out of 6000 on placebo), a greater number of participants who received lorcaserin compared to placebo were reported with multiple primary cancers (n=20 vs. 8), total cancers (n=520 vs. 470), metastases (n=34 vs. 19), and cancer deaths (n=52 vs. 33). The latency period to reach significance for differences in all cancers between the treatment groups was a little over 2 years, and although the overall cancer rates were low, the FDA felt that benefits of lorcaserin could not yet be judged to outweigh this adverse risk.

FDA-Approved Medications for Weight Management

Today, nine FDA-approved AOMs remain on the market, with six approved for long-term weight loss, of which one is indicated for specific monogenic obesity mutations, and one “device” that functions as a medication (Table 2).

Table 2. FDA Approved Anti-Obesity Medications
Name (Trade Names)	Year Approved	Mechanism of Action / Clinical Effect	Average placebo-subtracted weight loss (%)	Achieved ≥5% Weight Loss, Intervention vs. placebo (%)
Approved for short-term use*
Phentermine (Adipex, Lomaira) (41)	1959	Sympathomimetic / Suppresses appetite	4.4 at 28 wks	49 vs.16 at 28 wks
Diethylpropion (42)	197 1979	Sympathomimetic / Suppresses appetite	6.6 at 6 months	67.6 vs. 25.0
Approved for long-term use
Orlistat (Alli, Xenical) (43)	1999	Intestinal lipase inhibitor / Reduces fat absorption by up to 30%	3.8	50.5 vs. 30.7
Phentermine-topiramate (Qsymia) (26)	2012	Combination sympathomimetic and carbonic anhydrase inhibitor / Decreases appetite and binge eating behaviors	8.6	70 vs. 21
Bupropion-naltrexone (Contrave) (44)	2014	Combination of a dopamine and norepinephrine re-uptake inhibitor and mu-opioid receptor antagonist / Decreases appetite and cravings	4.8	48 vs. 16
Liraglutide 3.0mg (Saxenda) (28)	2014	GLP-1 receptor agonist / Decreases appetite, increases fullness, increases satiety	5.4	63.2 vs. 27.1
Gelesis100 (Plenity) (45)	2019	Superabsorbent hydrogel particles of a cellulose-citric acid matrix / Increases fullness. Considered a medical device but functions as a medication.	2.0 at 6 months	58.6 vs. 42.2
Setmelanotide (Imciveree)	2020	Melanocortin-4-receptor agonist / Decreases appetite	Not applicable 12.5-25.6^†	Not applicable 64-90^†
Semaglutide 2.4 mg (Wegovy)	2021	GLP-1 receptor agonist / Decreases appetite, increases fullness, increases satiety	12.4	86.4 vs. 31.5
Tirzepatide (Zepbound)	2023	GLP-1 and GIP receptor agonist / Decreases appetite, increases fullness, increases satiety	17.8	91 vs 35

Weight loss outcomes reported are based on intention-to-treat or intention-to-treat last observation carried forward analyses from RCTs using the maximum doses of medications for 56 weeks unless otherwise stated (17). GLP-1, glucagon-like peptide-1. GIP, glucose-stimulated insulinotropic peptide. *Short-term use is generally accepted as 3 months. ^†Range of weight loss observed in single-arm trial (not placebo-controlled) depended on genetic mutation.

PHENTERMINE AND DIETHYLPROPION

Phentermine (trade name Adipex) was among the first FDA-approved short-term medications for weight loss and remains available today. Phentermine is a sympathomimetic anorexigenic agent. A study from 1968 is the only longer-term controlled trial of phentermine (46). In this 36-week study, 64 patients were randomized to placebo, phentermine 30 mg daily, or intermittent phentermine 30 mg daily (4 weeks on, 4 weeks off). Both phentermine groups lost approximately 13% of their initial weight, while the placebo group lost only 5%. As discussed below, phentermine in combination with topiramate has been approved for long-term use.

Diethylpropion (trade name Tenuate), another sympathomimetic and derivative of bupropion, is also an approved short-term drug for treating obesity. It acts through modulation of norepinephrine action. A 6-month double-blinded placebo-controlled RCT followed by an open-label 6-month extension in 69 adults with obesity demonstrated diethylpropion 50 mg twice a day resulted in average weight loss of 9.8% at 6 months vs. 3.2% with placebo (42).

Phentermine’s and diethylpropion’s main side effects are related to their sympathomimetic properties, including elevation in blood pressure and pulse, insomnia, constipation, and dry mouth (47). Sympathomimetic agents are contraindicated in individuals with uncontrolled hypertension, known CVD (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure), hyperthyroidism, glaucoma, or exposure to monoamine oxidase inhibitors during or within 14 days of administration. Caution should be used in patients with pulmonary hypertension.

ORLISTAT

Orlistat (trade name Xenical) is approved for adult and adolescent obesity (ages 12 to 16) (48). It promotes weight loss by inhibiting gastrointestinal lipases, thereby decreasing the absorption of fat from the gastrointestinal tract. On average, 120 mg of orlistat taken three times per day will decrease fat absorption by 30% (49). Orlistat has been found to be more effective in inhibiting the digestion of fat in solid foods, as opposed to liquids (50). Orlistat at a lower dose of 60 mg 3 times daily (trade name Alli) is approved for over-the-counter use in the United States (51).

Efficacy

Several trials support orlistat’s efficacy for weight loss and maintenance. Rossner et al. found that subjects receiving orlistat lost significantly more weight in the first year of treatment, and fewer regained weight during the second year of treatment, than those taking placebo (52). Subjects taking orlistat had significantly lower serum levels of vitamins D, E, and B-carotene. However, these nutritional deficiencies are easily treated with oral multivitamin supplementation. Trials in Europe demonstrated similar results over a two-year period. Subjects in the orlistat group lost significantly more weight in the first year (10.2 vs. 6.1%) and regained half as much weight during the second year of treatment, as compared to the placebo group (53).

Effect on Metabolic Profile

In addition to promoting weight loss and maintaining lost weight, orlistat has been shown to improve insulin sensitivity and lower serum glucose levels. In a 2-year trial, Davidson et al. reported less weight regain rates and lower levels of serum glucose and insulin in patients maintained on a 120 mg three times per day dose of orlistat, as compared to those on placebo (54). In the 4-year XENDOS study conducted in Sweden, the cumulative incidence of T2D was 9.0% in the placebo plus diet and lifestyle group and 6.2% in the subjects receiving orlistat (24), corresponding to a risk reduction in development of T2D of 37.3%.

In patients with obesity and T2D with or without insulin treatment, orlistat resulted in improved glycemic control, determined via serum blood glucose levels and hemoglobin A1c (HbA1c) measurements, and reduced total cholesterol, low density lipoprotein (LDL) cholesterol, triglyceride, and apolipoprotein B levels (55,56). In subjects with obesity and T2D, hypercholesterolemia, or hypertension, orlistat treatment also led to greater weight loss and reductions in HbA1c, LDL, and total cholesterol (57).

Safety and Side-Effects

The gastrointestinal side effects of orlistat, including fatty/oily stool, fecal urgency, oily spotting, increased defecation, fecal incontinence, flatus with discharge, and oily evacuation (48), are the main reasons for discontinuation of therapy. These symptoms are usually mild to moderate and decrease in frequency the longer the medication is continued. Administration of orlistat with psyllium mucilloid reduced the incidence of GI side effects to 29% with psyllium vs. 71% without psyllium (58). Orlistat may reduce the absorption of fat-soluble vitamins A, D, E, and K, which can be mitigated with separate administration of vitamin supplementation.

PHENTERMINE/TOPIRAMATE

The controlled-release, single-tablet combination phentermine plus topiramate (trade name Qsymia) was approved by the FDA in 2012 as a long-term treatment for obesity for adults with BMI ≥ 30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity. Phentermine is thought to promote weight loss by increasing norepinephrine release and decreasing its uptake in hypothalamic nuclei, leading to a decrease in food intake (59). It also acts as an adrenergic agonist that activates the sympathetic nervous system (60) to possibly increase energy expenditure. Topiramate is an FDA-approved medicine for epilepsy and migraine prophylaxis that has been shown to reduce body weight by promoting taste aversion and decreasing caloric intake (61). A carbonic-anhydrase inhibitor, topiramate was found to stimulate lipolysis in preclinical studies (62). Phentermine/topiramate is available in 4 doses: 3.75/23 mg (starting dose), 7.5/46 mg (lowest treatment dose), 11.25/69 mg or 15/92 mg (maximum treatment dose) daily.

Efficacy

Multiple Phase 1, 2, and 3 studies including more than 5000 subjects have evaluated the efficacy and safety of phentermine/topiramate combination therapy. The one-year EQUIP trial, a phase three 56-week RCT enrolled 1267 patients with obesity (mean BMI of 42.0 kg/m²) and showed 3.5% weight loss in the starting dose group (3.75 mg/23 mg) and 9.3% placebo-subtracted weight loss in the top treatment dose (15 mg/92 mg) group (27). The 52-week CONQUER trial randomized 2487 patients with obesity and a comorbidity (e.g. hypertension, dyslipidemia, prediabetes, diabetes, or abdominal obesity) to placebo, mid-dose treatment dose (7.5mg/46 mg), or maximum treatment dose (15/92 mg) and found 6.6% and 8.6% placebo-subtracted weight loss in the mid and maximum dose arms, respectively (26). A two-year extension of the CONQUER trial was published (SEQUEL) demonstrating mean placebo-subtracted weight loss of 7.5% in the mid-dose group and 8.7% in the maximum-dose group (63).

Effect on Metabolic Profile

Improvements in systolic blood pressure (SBP), diastolic blood pressure (DBP), triglycerides, and high-density lipoprotein (HDL) cholesterol were seen in subjects treated with phentermine plus topiramate compared with placebo in both EQUIP and CONQUER (26,27). Improvements in fasting glucose and insulin levels were seen in the SEQUEL study, and a 54% and 76% reduction in progression to T2D in the two treatment groups was noted in subjects without diabetes at baseline (63).

Safety and Side Effects

Phentermine-topiramate is not recommended for patients with significant cardiac history such as coronary disease and uncontrolled hypertension (64). However, in individuals without coronary disease and with well-controlled hypertension, it is considered safe to use this drug along with regular blood pressure monitoring. Phentermine/topiramate exposure carries an increased risk of cleft lip/palate in infants exposed to the combination drug during the first trimester of pregnancy. Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it. Clinicians who prescribe phentermine-topiramate and pharmacists who dispense it should enroll in a Risk Evaluation and Mitigation Strategy (REMS), which includes education on prescribing information, monitoring during treatment, and side effects. This medication is also contraindicated in patients with hyperthyroidism, glaucoma, and in patients who have taken monoamine oxidase (MAO) inhibitors within 14 days. Topiramate can increase the risk of acidosis and renal stones so should be used cautiously in patients who have had stones previously (65).

In order to mitigate side effects, which include paresthesias, dizziness, dry mouth, constipation, dysgeusia, insomnia, and anxiety, a step-wise dosage titration is recommended. Phentermine-topiramate is initiated at the 3.75/23 mg dose daily for 14 days, followed by 7.5/46 mg daily thereafter. If after 12 weeks, a 3 percent loss in baseline bodyweight is not achieved, the dose can be increased to 11.25/69 mg for 14 days, and then to 15/92 mg daily. If an individual does not lose 5 percent of body weight after 12 weeks on the highest dose, phentermine-topiramate should be discontinued due to lack of response. Discontinuation should be performed gradually because rapid withdrawal of topiramate may provoke seizures.

BUPROPION/NALTREXONE

The combination tablet of bupropion and naltrexone (trade name Contrave) was FDA-approved for weight loss in September 2014. Bupropion is a reuptake inhibitor of dopamine and norepinephrine that promotes activation of the central melanocortin pathways (66). Naltrexone is an opioid receptor antagonist that diminishes the mu-opioid receptor auto-inhibitory feedback loop on anorexigenic hypothalamic neurons activated by bupropion, thereby allowing for sustained weight loss (67). Bupropion/naltrexone comes in tablets containing 90 mg of bupropion HCl sustained-release and 8 mg of naltrexone HCl. The recommended starting dose is 1 tablet daily and increasing by 1 tablet each week until a total dose of 2 tabs twice daily is reached (total daily dose: bupropion 360 mg/naltrexone 32 mg).

Efficacy

Four 56-week multicenter, double-blind, placebo-controlled trials (CONTRAVE Obesity Research: COR-I, COR-II, COR-BMOD, and COR-Diabetes) were conducted to evaluate the effect of bupropion/naltrexone in conjunction with lifestyle modification compared to a placebo-controlled cohort of 4536 patients. The COR-I, COR-II, and COR-BMOD trials enrolled patients with BMI ≥ 30 kg/m² or BMI ≥ 27 kg/m² with at least one comorbidity (25,30,44). The COR-Diabetes trial enrolled patients with BMI greater than 27 kg/m² with T2D with or without hypertension or dyslipidemia (68). The primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight. In the 56-week COR-I trial, significantly greater mean weight loss (6.1%) occurred in patients assigned to naltrexone 32 mg/bupropion 360 mg dose compared with the placebo group (1.3%), and 48% of active treatment group achieved ≥5% weight loss compared to only 16% of placebo group (44). Similar weight loss efficacy was reported in COR-II (25) and COR-Diabetes (68) trials. Bupropion/naltrexone can be combined with intensive behavioral therapy (IBT) to achieve even greater weight loss (5.2% with placebo and 9.3% with bupropion/naltrexone) (30).

Effect on Metabolic Profile

In all of the COR trials, secondary cardiovascular risk endpoints were met, including statistically significant greater improvements in waist circumference (WC), visceral fat, HDL cholesterol, and triglyceride levels in the participants treated with the bupropion 360 mg/naltrexone 32 mg dose compared with placebo-treated participants (25,30,44,68). Participants with diabetes in the COR-Diabetes trial using bupropion/naltrexone also showed a significantly greater 0.6% reduction in HbA1c from baseline, compared to a 0.1% reduction in placebo (68).

Safety and Side Effects

The most common side effects of bupropion/naltrexone include nausea/vomiting, constipation, headache, dizziness, insomnia, and dry mouth. Medication interactions include MAO inhibitors (use during or within 14 days of administration), opioids and opioid agonists (including partial agonists) that are inactive in the presence of naltrexone, and abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs that can increase risk for seizure. Bupropion/naltrexone should be avoided in patients with uncontrolled hypertension, history of seizures, history of bulimia or anorexia nervosa, and in individuals taking narcotics for pain control (69).

The FDA recommends monitoring patients for worsening or emergence of suicidal thoughts or behaviors. Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it.

LIRAGLUTIDE 3.0

Liraglutide 3.0 mg (trade name Saxenda) was approved by the FDA in December 2014 for adult obesity and has proven efficacy in adolescents age 12 to <18 years of age (70). Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that activates the GLP-1 receptor. In animal studies, peripheral administration of liraglutide results in uptake in specific brain regions regulating appetite, including the hypothalamus and brainstem (71). A short-term study (5 weeks) involving individuals with obesity and without diabetes demonstrated that liraglutide 3.0 mg/d suppressed acute food intake, subjective hunger, and delayed gastric emptying (72). Energy expenditure in subjects treated with liraglutide 3.0 mg/d decreased, even when corrected for weight loss (72), which may reflect metabolic adaptation to weight loss.

Efficacy

SCALE Obesity and Prediabetes (n=3731) and SCALE Diabetes (n=846) evaluated the effect of liraglutide 3.0 mg on overweight and obesity with normoglycemia, prediabetes, and diabetes respectively (28,73). Both 56-week, randomized, placebo-controlled, double-blind clinical trials demonstrated significantly greater mean weight loss than placebo (8% vs. 2.6% in SCALE Obesity and Prediabetes (28) and 6.0% vs. 2% in SCALE Diabetes (73). The efficacy of liraglutide 3.0 in maintaining weight loss was examined in the SCALE Maintenance study. Four hundred and twenty-two subjects who lost ≥ 5% of their initial body weight on a low-calorie diet were randomly assigned to liraglutide 3.0 mg daily or placebo for 56 weeks. Mean weight loss on the initial diet was 6.0%. By the end of the study, participants in the liraglutide 3.0 group lost an additional 6.2% compared to 0.2% with placebo (74).

Effect on Metabolic Profile

Secondary endpoints in the SCALE Obesity and Prediabetes included waist circumference, lipids, HbA1c, and blood pressure, all of which showed significantly greater improvement than placebo (28). SBP dropped by 4.2 mmHg vs. 1.5 mmHg in the liraglutide 3.0 mg vs. placebo groups. Diastolic blood pressured was reduced by 2.6 mm Hg vs. 1.9 mm Hg. The most significant change in lipid profile was in the triglycerides that were reduced by 13.0 mg/dl in the liraglutide 3.0 mg group vs. 5.5 mg/dl in the placebo group. Participants assigned to liraglutide 3.0 had a lower frequency of prediabetes and were less likely to develop T2D than those assigned to placebo (28), an outcome that persisted in a 3-year extension analysis (75). For participants with obesity and moderate/severe obstructive sleep apnea, liraglutide 3.0 mg treatment resulted in significantly greater reductions than placebo in apnea-hypopnea index, body weight, SBP, and HbA1c levels (76).

In the SCALE Diabetes study, HbA1c levels were 0.93% lower in the liraglutide 3.0 vs. placebo treated group, and similar significant benefits on triglyceride (lower) and HDL cholesterol (higher) as in the SCALE Obesity study were reported (73).

Although liraglutide 3.0 mg was not evaluated in a cardiovascular outcomes trial (CVOT), the lower dose liraglutide 1.8 mg (Victoza), approved for T2D, was assessed in the LEADER trial (77). The primary outcome was a composite of major adverse cardiovascular events (MACE) including CVD death, nonfatal myocardial infarction (MI), and nonfatal stroke. Adults with T2D and baseline average BMI 32.5 kg/m² were randomized to liraglutide 1.8 mg vs. placebo. Approximately 81% of participants had established CVD. After a median of 3.8 years, individuals on liraglutide 1.8 mg demonstrated a 13% risk reduction in 3-point MACE compared to placebo. Analysis of additional outcomes showed a 22% reduction in CVD death and a 15% reduction in all-cause deaths. This risk reduction was driven primarily by a reduction in death from CV causes (p=0.01 for superiority) and all-cause mortality was reduced by 15%. Statistical significance was not achieved with individual endpoints of nonfatal MI or nonfatal stroke. Liraglutide 1.8 mg is now FDA-approved for secondary CV prevention in adults with T2D (78).

Safety and Side Effects

Gastrointestinal symptoms, such as nausea, vomiting and abdominal pain were the most common reason subjects withdrew from the SCALE trials. In a secondary analysis of these trials, treatment with liraglutide 3.0 resulted in dose-independent, reversible increases in amylase/lipase activity (7% for amylase and 31% for lipase) (79). Thirteen subjects (0.4%) in the liraglutide 3.0 group compared to one (0.1%) with placebo developed pancreatitis, but nearly half of these had evidence for gallstones as well (79). Even though liraglutide treatment showed improvements in blood pressure and lipids, it was found to increase heart rate by an average of 2 beats/min in SCALE Diabetes (73). Animal studies with liraglutide showing an association with medullary thyroid cancer have led to FDA label warnings. Even though the relevance of this observation to humans has not been determined, a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN 2) is considered a contraindication for treatment with this medication (80).

Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it.

SETMELANOTIDE

Setmelanotide (trade name Imcivree) is a melanocortin-4-receptor (MC4R) agonist that was FDA-approved in November 2020 for the treatment of monogenic obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency in individuals ages 6 or older (81). Binding of leptin to its receptor causes intracellular PCSK1 to cleave the POMC peptide into alpha-melanocyte stimulating hormone (ɑMSH), which is the endogenous agonist of MC4R (82). Deficiencies in this pathway manifest clinically as hyperphagia, impaired pubertal development, obesity, and insulin resistance with individuals who are homozygous or compound heterozygous for deleterious mutations in POMC also presenting with adrenal insufficiency and hypopigmentation. Setmelanotide is administered as a once daily subcutaneous injection starting at 2 mg daily in patients age 12 or older and 1 mg daily in patients age 6 to less than 12 years. Dose may be titrated up to a maximum of 3 mg daily depending on tolerance and efficacy.

Efficacy

A single-arm, open-label, multicenter phase 3 trial of 21 participants aged 6 years and older evaluated the efficacy of setmelanotide for weight loss in patients with POMC deficiency (homozygous or compound heterozygous variants in POMC or PCSK1) or LEPR deficiency (83). After 12 weeks of treatment, those who lost at least 5 kg (or 5% if baseline weight was <100 kg) were then continued into an 8-week placebo-controlled withdrawal phase consisting of 4 weeks each of blinded setmelanotide or placebo treatment followed by an additional 32 weeks of open-label treatment. After approximately 1-year, mean weight loss was 25.6% among individuals with POMC deficiency and 12.5% among those with LEPR deficiency. Eight (80%) participants with POMC deficiency and 5 (45%) participants with LEPR deficiency achieved ≥ 10% weight loss.

Effect on Metabolic Profile

Individuals with POMC deficiency experienced an absolute reduction in HbA1c of -0.3%, and those with LEPR deficiency saw a reduction of -0.2%, neither of which were statistically significant. Lipid profiles improved among all participants: HDL increased by 45.0% and 19.6%, LDL decreased by -7.6% and -10.0%, and triglycerides decreased by -36.6% and -7.0% in POMC and LEPR deficiency groups, respectively.

Safety and Side Effects

The most common adverse events were injection site reactions, hyperpigmentation, and nausea. No clinically significant changes in heart rate or blood pressure were observed. Spontaneous penile erections in males have occurred (81). Though the manufacturer warns of suicidal ideation and depression, the phase 3 trial reported one case of suicidal ideation not present at baseline and no treatment-related worsening in depression (83).

SEMAGLUTIDE 2.4

Semaglutide 2.4mg (trade name Wegovy) is FDA-approved for two indications:

To reduce the risk of MACE in adults with established CVD and either obesity or overweight.
To reduce excess body weight and maintain weight reduction long term in (1) adults with obesity or overweight plus at least one weight-related comorbidity and (2) pediatric patients aged 12 years and older with obesity.

Semaglutide is a long-acting GLP-1 analogue administered via weekly subcutaneous injection at doses of 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg (84). It promotes weight loss through multiple mechanisms including slowing gastric emptying, thereby reducing hunger and energy intake, in addition to direct anorexigenic effects on the brain leading to increased satiety (85).

Efficacy

Semaglutide Treatment Effect in People with obesity (STEP) trials 1-4 evaluated the effect of semaglutide 2.4mg once weekly on weight loss in patients with overweight or obesity, with and without T2D (86-89). STEP 1-4 are 68-week, phase 3, double-blind, randomized, multicenter trials. STEP 1 (n=1961) was conducted in adult patients with obesity/overweight without T2D and demonstrated an average placebo-subtracted weight loss of 12.4% with 86.4% achieving ≥ 5% weight loss compared to 31.5% with placebo. STEP 2 (n=1210) was conducted in adults with obesity or overweight and T2D and found an average placebo-subtracted weight loss of 6.2%, with 68.8% achieving ≥ 5% weight loss compared to 28.5% with placebo. STEP 3 (n=611) treated adults with obesity or overweight with semaglutide 2.4 mg as an adjunct to intensive behavioral therapy (IBT) and found an average placebo-subtracted weight loss of 10.3%, with 86.6% achieving ≥ 5% weight loss compared to 47.6% with placebo plus IBT. STEP 4 (n=902) examined the efficacy of semaglutide 2.4mg weekly in maintaining weight loss achieved after a 20-week run-in period (16 weeks of dose escalation; 4 weeks of maintenance dose). Among the 803 patients who completed the run-in period with a mean weight loss of 10.6%, those continued on semaglutide from week 20 to 68 achieved further average weight loss of 7.9% versus an average weight gain of 6.8% in those randomized to placebo after the run-in period. The durability of semaglutide 2.4 mg for weight loss was established by STEP 5 (n=304), which reported mean weight change of -15.2% in the semaglutide group vs -2.6% in the placebo group over a period of 104 weeks (90). Conducted in Japan and South Korea, STEP 6 diversified the eligible population by enrolling adults with BMI ≥ 27 with at least two weight-related comorbidities or BMI ≥35 with at least one weight-related comorbidity. At 68 weeks, mean weight change was -13.2% with semaglutide 2.4 mg, -9.6% with semaglutide 1.7 mg, and -2.1% with placebo (91). STEP TEENS garnered semaglutide’s FDA-approval for treatment of obesity in pediatric and adolescents aged 12 years and older, demonstrating 16.1% weight loss with semaglutide vs 0.6% weight gain with placebo over 68 weeks (92).

Evidence for efficacy compared to similar agents is limited. In a 52-week multicenter phase 2 RCT conducted in adults with obesity and without T2D, semaglutide 0.2-0.4 mg/d demonstrated weight loss superiority compared to liraglutide 3.0 mg/d or placebo (93). The phase 3 RCT, STEP 8, randomized adults with obesity without T2D to liraglutide 3.0 mg/d or semaglutide 2.4 mg/wk or respective placebos (94). After 68 weeks, mean body weight change from baseline was significantly greater with semaglutide: -15.8% with semaglutide vs -6.4% with liraglutide.

In March 2024, semaglutide 2.4 mg received FDA-approval for the treatment of CVD in adults with preexisting CVD and obesity or overweight. In the SELECT trial, adults age 45 years or greater with BMI ≥ 27 and preexisting cardiovascular disease were randomized to semaglutide 2.4 mg vs placebo to investigate the primary endpoint of 3-point MACE: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (95). After a mean follow-up duration of 39.8± 9.4 months, the primary endpoint occurred in 6.5% of participants in the semaglutide group vs 8.0% in the placebo group, resulting in a relative risk reduction of 20%. The SELECT trial builds upon an established body of evidence (e.g., SUSTAIN-6) demonstrating the CV safety and benefits of semaglutide and is groundbreaking as the first CVOT to demonstrate secondary cardiovascular prevention with an anti-obesity medication in a population without T2D.

Effect on Metabolic Profile

Secondary endpoints in the STEP 1 trial included weight circumference, blood pressure, lipids, c-reactive protein, HbA1c, and physical functioning scores (SF-36, IWQOL-Lite-CT), all of which showed significantly greater improvement than placebo (133). SBP was reduced by -6.16 mmHg vs. -1.06 mmHg in the semaglutide 2.4 mg vs. placebo groups. Diastolic blood pressure decreased by -2.83 mmHg vs. -0.42 in the semaglutide 2.4 mg vs. placebo groups. HbA1c decreased by -0.52% vs. -0.17% in semaglutide 2.4 vs. placebo groups, with 84.1% of participants achieving normoglycemia at 68 weeks on semaglutide 2.4 vs. 47.8% of patients on placebo. In the STEP 2 trial, conducted in adults with obesity and T2D, HbA1c levels at 68 weeks were reduced by -1.6% in the semaglutide 2.4 vs. -1.5% in the semaglutide 1.0 vs. -0.4% in the placebo group, and 78.5%, 72.3%, and 26.5% achieved an HbA1c<7.0 (89). There were also significant improvements over placebo in SBP, triglycerides, C-reactive protein and physical functioning scores. A secondary analysis of the SELECT trial demonstrated semaglutide’s potential for the primary prevention of T2D and for the regression of T2D: only 1.5% vs 6.9% with placebo had biochemical diabetes by week 156, establishing a number needed to treat (NNT) of 18.5 to prevent one case of diabetes (96). Furthermore, 69.5% vs 35.8% achieved diabetes regression, defined biochemically as A1c <5.7 (i.e., normoglycemia).

The SELECT trial also examined the pre-specified main composite kidney endpoint of: death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent estimated glomerular filtration rate (eGFR) < 15, persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria) (97). This endpoint was observed in 1.8% of participants on semaglutide 2.4 mg vs 2.2% of participants on placebo, resulting in a relative risk reduction of 22%. No particular subgroup with respect to age, sex, race, ethnicity, baseline eGFR (<60 or ≥60), baseline UACR (<30, 30 to <300, ≥300), baseline body weight, baseline BMI, baseline A1c, or CVD inclusion criteria were found to have a statistically significant interaction with the treatment effect of semaglutide. The FLOW trial established renal benefit with semaglutide 1.0 mg in adults with T2D and CKD (98): after a median of 3.4 years, semaglutide resulted in a 24% relative risk reduction in the primary outcome defined as a composite of the onset of kidney failure (dialysis, transplantation, or eGFR <15 ), ≥50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes.

A dedicated phase 2 trial for the treatment of non-alcoholic steatohepatitis (NASH) involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3 determined semaglutide 0.1 mg/d, 0.2 mg/d, or 0.4 mg/d was more effective than placebo for achieving NASH resolution with no worsening of fibrosis: 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (99). The mean percent weight loss was 13% in the 0.4-mg group vs 1% in the placebo group.

Additional cardiovascular protection has been proven in heart failure with preserved ejection fraction (HFpEF). Semaglutide 2.4 mg was demonstrated in the STEP HFpEF trial to significantly improve the Kansas City Cardiomyopathy Questionnaire clinical summary score by 16.6 points vs 8.7 points with placebo in adults with HFpEF and obesity (BMI ≥ 30) (100). Mean change in body weight was -13.3% with semaglutide and -2.6% with placebo over 52 weeks. The improvement in HFpEF symptoms may be mediated by weight-independent mechanisms and measurable via reductions in N-terminal pro–B-type natriuretic peptide (NT-proBNP)(101).

Safety and Side Effects

The most common side effects in phase 3 RCTs of semaglutide 2.4mg were nausea, diarrhea, vomiting and constipation. In the STEP 1 trial, these gastrointestinal side effects occurred more often in those receiving semaglutide vs. placebo (74.2% vs. 47.9%). However, most of these were mild-moderate in severity; serious adverse events occurred in 9.8% of those receiving semaglutide vs. 6.4% of those on placebo. Serious adverse events included serious gastrointestinal disorders (1.4% with semaglutide vs. 0% with placebo), hepatobiliary disorders (1.3% with semaglutide vs. 0.2% with placebo), gallbladder disorders (2.6% with semaglutide vs. 1.2% with placebo), and mild acute pancreatitis (0.2% with semaglutide vs. 0% placebo). Across all RCTs, participants experienced an average increase in heart rate of 1-4 beats per minute (bpm); 26% of individuals on semaglutide vs. 16% of those on placebo had increased heart rates by 20 bpm or more (84). Among patients with T2D, hypoglycemia occurred in 6.2% of patients treated with semaglutide vs. 2.5% of patients on placebo (89). Psychiatric side effects did not emerge as a treatment-related adverse event, and a real-world cohort study of over 200,000 patients found no evidence for increased risk of suicidal ideation (102).

Like liraglutide, semaglutide is contraindicated in the setting of a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. In rodents, semaglutide was found to cause thyroid C-cell tumors, but no human cases have been linked to semaglutide use. A narrative review of RCT and real-world data found no compelling link between semaglutide and thyroid cancer (103), and a systematic review and meta-analysis further concluded there was no increased risk of any cancer with semaglutide (104). Women of child-bearing age should have a pregnancy test prior to starting the medicine and be using contraception while taking it. Semaglutide 2.4mg should be discontinued at least 2 months prior to conception per manufacturer’s recommendation (84).

TIRZEPATIDE

Tirzepatide (trade name Zepbound) is approved for the treatment of obesity (BMI ≥ 30) or overweight (BMI ≥ 27) with at least one weight-related comorbidity. Tirzepatide is a first-in-class dual agonist at GLP-1 and glucose-dependent insulinotropic peptide (GIP) receptors. It is administered via once weekly subcutaneous injection at doses of 2.5, 5, 7.5, 10, 12.5, and 15 mg. Tirzepatide is biased towards GIP activity, with less GLP1 agonism compared to endogenous GLP1. With respect to potential mechanisms for cardiometabolic protection and weight loss, the actions of GIP may include (105):

Reduction in caloric intake.
Increase in glucose and triglyceride uptake at adipose tissue.
Increase in insulin sensitivity.

Additional mechanisms involving both GIP and GLP1 pathways may also contribute to weight loss (106), though significant nuance exists in understanding their actions as investigated in mouse vs human studies (107).

Efficacy

Tirzepatide has been investigated for the treatment of obesity in four phase 3 RCTs thus far: SURMOUNT-1, SURMOUNT-2, SURMOUNT-3, and SURMOUNT-4.

SURMOUNT-1 enrolled 2539 participants with BMI ≥ 30 or ≥ 27 with at least one weight-related comorbidity who were randomized to 5, 10, or 15 mg of tirzepatide or placebo for 72 weeks (108). Baseline weight was 104.8 kg and baseline BMI was 38.0. The mean weight change was -15.0%, -19.5%, -20.9%, and -3.1% with tirzepatide 5 mg, 10 mg, 15 mg, and placebo, respectively. Categorical weight loss outcomes for tirzepatide 5 mg, 10 mg, 15 mg, and placebo were: 85%, 89%, 91%, and 35%, respectively.

In SURMOUNT-2, adults with BMI ≥ 27 and A1c 7-10% on stable anti-diabetic therapy, either diet and exercise alone or oral antihyperglycemic medication for at least 3 months were randomized to tirzepatide 10 mg, 15 mg, or placebo for 72 weeks (109). Baseline weight was 100.7 kg, BMI 36.1, and A1c 8.02%. On average, duration of diabetes was 8.5 years. Change in weight was -12.8%, -14.7%, and -3.2% with tirzepatide 10 mg, 15 mg, and placebo, respectively. Participants who achieved ≥5% weight loss were 79%, 83%, and 32%, respectively. A1c was equally reduced by 2.1% with both tirzepatide 10 mg and 15 mg vs 0.5% with placebo. A post hoc analysis showed that the proportion of participants who increased anti-diabetic therapy intensity decreased in the tirzepatide arms and increased in the placebo arm.

SURMOUNT-3 investigated the effect of tirzepatide (10 mg or 15 mg) vs placebo after ≥5% weight loss with ILI in adults with BMI ≥ 30 or ≥ 27 and at least one weight-related comorbidity. At baseline, weight was 110.1 kg and BMI was 38.7. After 72 weeks, participants on tirzepatide lost 18.4% of their baseline weight while those on placebo gained 2.5%. Significant more people on tirzepatide than placebo achieved ≥5% weight loss: 87.5% vs 16.5%. The numerically lower average weight loss achieved in SURMOUNT-3 compared to that in SURMOUNT-1 has called into question the role of lifestyle management in the era of highly effective AOMs, but several potential areas of benefit have been identified, outside of weight: body composition and preservation of lean muscle mass, micronutrient adequacy, and cementation of behavior strategies associated with long-term weight loss maintenance (110).

SURMOUNT-4 examined the efficacy of tirzepatide (10 or 15 mg) vs placebo for weight loss maintenance in adults who completed a 36-week lead-in weight loss period. At the end of 36 weeks, average weight loss was 20.9% with tirzepatide vs --- with placebo. From week 36 to week 88, participants lost an addition 5.5% with tirzepatide and gained 14.0% with placebo. Overall, tirzepatide resulted in weight loss maintenance, defined as ≥ 80% of weight lost, for 89.5% of participants compared to only 16.6% of those on placebo. The total mean weight change from week 0 to 88 was -25.3% vs -9.9% in tirzepatide vs placebo arms.

The SURMOUNT trials were notable for a few unique characteristics:

New in-class mechanism of action incorporating GIP agonism.
More balanced male-to-female recruitment approximating 50%, compared to prior obesity clinical trials.
A new threshold achieved for average weight loss, greater than 20%, a milestone approaching and surpassing that of some bariatric surgeries.

Pending SURMOUNT trials include SURMOUNT-5, a head-to-head trial of tirzepatide vs semaglutide for obesity, and SURMOUNT-MMO, tirzepatide’s CVOT.

Effect on Metabolic Profile

The benefits of tirzepatide on cardiometabolic risk factors was consistent across all trials. Participants on tirzepatide experienced significantly greater improvements in SBP, DBP, fasting insulin, fasting glucose, A1c, LDL cholesterol, HDL cholesterol, and triglycerides compared to placebo. In SURMOUNT-1, -2, and -3, SBP decreased by 5 to 7 mmHg with tirzepatide vs no change or increase in placebo groups. In SURMOUNT-4, during the weight loss maintenance phase, SBP increased by 2.1 mmHg with tirzepatide vs 8.4 mmHg with placebo. Insulin sensitivity improved among tirzepatide groups, with fasting insulin reduced by about 40% in SURMOUNT-1, -3, and -4. Among participants with obesity and T2D in SURMOUNT-2, A1c was reduced by about 2% with tirzepatide 10 or 15 mg vs 0.5% with placebo. The most dramatic improvements in lipid profiles remained the reduction of triglycerides of about 25% in SURMOUNT-1, -2, and -3, and up to 33% in SURMOUNT-4.

Tirzepatide has recently been investigated in a phase 3 trial specific for benefits in obstructive sleep apnea (OSA). The SURMOUNT-OSA trial (n=469) assessed the safety and efficacy of tirzepatide 10 or 15mg weekly on adults with moderate-to-severe OSA and a BMI ≥30 (111). At 52 weeks, the trial showed a significant reduction in the apnea-hypopnea index (AHI) both in participants who were and were not receiving positive airway pressure (PAP) at baseline. In participants not receiving PAP therapy, those on tirzepatide had a reduction in AHI by -25.3 events/hr vs, -5.3 events/hr in placebo and a placebo subtracted weight loss of -16.1%. Similarly, in participants receiving PAP therapy at baseline, those on tirzepatide had a reduction in AHI by -29.3 event/hr vs. -5.5 events/hr in placebo and placebo subtracted weight loss of 17.3%.

In a phase 2 study (SYNERGY-NASH) of participants with biopsy-confirmed metabolic-associated steatohepatitis (MASH) and stage F2 or F3 fibrosis, a significantly greater proportion of participants achieved resolution of MASH without worsening of fibrosis in tirzepatide groups compared to placebo after 52 weeks of treatment {Loomba 2024}: 44% (5 mg), 56% (10 mg), 62% (15 mg) vs 10% (placebo).

Safety and Side Effects

Across all four SURMOUNT obesity trials, the most common adverse events were gastrointestinal: nausea, vomiting, diarrhea, constipation. Treatment discontinuation rates due to adverse events were generally low (2-8%). No imbalances were noted for incidence of pancreatitis between tirzepatide groups and placebo. No cases of medullary thyroid carcinoma or pancreatic cancer occurred. In general, the incidence of gallbladder disease was numerically greater in tirzepatide groups compared to placebo though the overall incidences were low (<1%).

While all AOMs are contraindicated in pregnancy, tirzepatide has been observed to affect absorption of estradiol-containing oral contraceptives and potentially reduce their efficacy as birth control, specifically during dose escalation phases of tirzepatide. For this reason, individuals of childbearing potential should be counseled to use a second form of birth control during dose escalation. The purported mechanism for this interference is a reduction in gastrointestinal motility and absorption, which may occur with other incretin therapies (i.e., semaglutide, liraglutide), but such interactions have not been reported.

GELESIS 100

Gelesis100 (Plenity) is the first anti-obesity agent that is FDA-approved for adults with overweight (BMI 25-40 kg/m²) irrespective of comorbidities. Gelesis100 is a hydrogel matrix composed of modified cellulose cross-linked with citric acid. Its mechanism of action is to absorb water to occupy about one-fourth of the average stomach volume, promoting fullness. Because it achieves its primary intended purpose through a mechanical mode of action, it is considered a device rather than a drug and has no systemic effects. One dose is three oral capsules (2.25 g/dose) that is ingested with 500 ml of water 20-30 min prior to lunch and dinner.

Efficacy

The efficacy of Gelesis100 was evaluated in the Gelesis Loss of Weight (GLOW) randomized double-blind placebo-control trial (112). Adults with overweight or obesity with or without comorbidities were randomized to Gelesis100 (n=223) or placebo (n=213) for 6 months, and completers who had lost ≥ 3% of baseline weight after 24 weeks were offered to continue in the 24-week open-label single cross-over extension trial GLOW-EX(112). At 6 months, weight loss was 6.4% vs. 4.4% (p=0.0007) in the Gelesis100 vs. placebo groups, respectively, and 58.6% vs. 42.2% of individuals lost ≥ 5% of baseline weight (p=0.0008). Gelesis100 was not significantly more effective in individuals with prediabetes or drug-naïve T2D with respect to mean percent change in body weight, which had been a notable observation in the pilot study First Loss of Weight (FLOW) (112). However, weight loss of ≥ 10% in this subgroup was achieved by 44% vs. 14% of those on Gelesis100 vs. placebo, respectively. In GLOW-EX (n=39), participants in the Gelesis100 group had achieved at mean of 7.1% weight loss at end of the GLOW trial, and continuation of Gelesis100 resulted in a mean weight loss of 7.6% at 48 weeks, demonstrating weight loss maintenance.

Effect on Metabolic Profile

Overall, there were no significant differences between Gelesis100 or placebo in cardiovascular risk factors of LDL-C, HDL-C, triglycerides, systolic BP, diastolic BP, or HOMA-IR. In a subgroup of individuals with elevated LDL-C, blood pressure, or HOMA-IR, there was a greater reduction in LDL-C, resolution of hypertension, and reduction in HOMA-IR in those treated with Gelesis100.

Safety and Side Effects

Side effects due to Gelesis100 are commonly gastrointestinal, including abdominal distension, infrequent bowel movements, or dyspepsia. There were no significant differences between groups with regards to serum vitamin levels. Gelesis100 is contraindicated in pregnancy or individuals with allergies to cellulose, citric acid, sodium stearyl fumarate, gelatin, or titanium oxide (45). It should be avoided in patients with esophageal anatomic anomalies, suspected strictures, or post-operative complications that affect gastrointestinal transit and motility. The manufacturer recommends caution in patients with active gastrointestinal reflux diseases. The impact of Gelesis100 on the absorption of other medications was investigated only with metformin. Concurrent administration of Gelesis100 with metformin in the fasting state reduced the median area-under-the-curve (AUC) for metformin but had no effect on metformin AUC when administered during a meal. It is recommended that Gelesis100 be considered “food” when counseling patients on administration of other medications that require ingestion “on an empty stomach” vs. “with food.”

NON-FDA APPROVED (OFF-LABEL) MEDICATIONS THAT CAUSE WEIGHT LOSS

Several medications prescribed for conditions other than obesity have been found to be effective weight loss drugs in patients with obesity. If used for weight loss, the prescribed use of these medications would be off-label.

Bupropion

Bupropion (trade name Wellbutrin or Zyban) is used for depression and smoking cessation and can cause weight loss as a side effect. While the mean weight loss seen with bupropion is small, it is a preferred alternative to most antidepressants, which commonly cause weight gain.

A 48-week randomized placebo-controlled trial randomized individuals with obesity to placebo, 300 mg, or 400 mg of bupropion sustained release (SR). Percentage losses of initial body weight for subjects completing 24 weeks were 5.0%, 7.2%, and 10.1% for placebo, bupropion SR 300, and 400 mg/d, respectively (113). In subjects with obesity and depressive symptoms, bupropion SR was more effective than placebo in achieving weight-loss when combined with a 500 kcal deficit diet (4.6% vs.1.8% loss of baseline body weight, P<0.001) (114). Bupropion is contraindicated in patients with seizures, current or prior diagnosis of bulimia or anorexia nervosa, and concurrent use with MAOs (115). Caution should be used in patients with hypertension, mania/hypomania, psychosis, and angle-closure glaucoma.

Metformin

Metformin (trade name Glucophage) is an antihyperglycemic agent that acts by suppressing gluconeogenesis and increasing peripheral insulin sensitivity (116). Potential weight loss mechanisms include:

Activation of AMP-activated protein kinase (AMPK) to mimic an “energy deficient” state (117,118).
Increasing anorexigenic hormones GLP-1 (119), growth/differentiation factor-15 (GDF-15) (120), neuropeptide Y (NPY), and agouti-related protein (AgRP) (121).
Increasing leptin sensitivity (122).

In the landmark Diabetes Prevention Program (DPP), 3234 participants without T2D but with fasting and post-prandial hyperglycemia were randomized to intensive lifestyle intervention (ILI), metformin, or placebo (14). ILI consisted of a 7% weight loss goal, 150 minutes per week of physical activity, and a low-fat diet. The mean age was 51 years and mean BMI was 34.0 kg/m². The metformin group was not offered ILI and was assigned to metformin 850 mg twice a day. After an average follow-up of 2.8 years, patients in the metformin group achieved greater weight loss than placebo but less than the ILI group. The average weight loss was 0.1 kg, 2.1 kg, and 5.6 kg in the placebo, metformin, and ILI groups, respectively (P<0.001, cross-group comparison) (14). The extended observational trial DPP Observation Study showed that the group on metformin maintained 3% weight reduction compared to placebo for 6-15 years after DPP ended (123). Short-term studies and meta-analyses in individuals with obesity and without prediabetes/diabetes consistently demonstrate ~2% weight loss beyond placebo, with a greater response in those with more insulin resistance (124). Metformin is therefore considered a first line drug in treating patients with T2D and obesity. The most common side effects of metformin are nausea, flatulence, diarrhea, and bloating (125). The most serious side effect is lactic acidosis, but this is rare (<1/100,000) (126). Monitoring for vitamin B12 deficiency is recommend as long-term use of metformin has been associated with low vitamin B12 levels and neuropathy (127).

Pramlintide

Pramlintide acetate (trade name Symlin) is an injectable agent that is FDA-approved for the treatment of type 1 and T2D. Pramlintide mimics the action of the pancreatic hormone amylin, which along with insulin regulates postprandial glucose control. Its effect on weight loss is thought to be mediated through central (brain) receptors (128) that improve appetite control (129). In a pooled, post-hoc analysis of overweight and obese insulin-treated patients with T2D, pramlintide-treated patients (receiving 120 ug twice daily) had a body weight reduction of -1.8 kg (P<0.0001) compared with placebo-treated patients (130). In this study, pramlintide-treated patients experienced a 3-fold increase in successfully achieving a total body weight loss of ≥ 5%, when compared to those who received placebo. Subsequently, randomized trials combining pramlintide or placebo with a lifestyle intervention were undertaken in obese participants without diabetes. Treatment with pramlintide (up to 240 ug three time daily) for 16 weeks resulted in a placebo-corrected reduction in body weight of 3.7% (P<0.001) and 31% of pramlintide-treated subjects achieved ≥5% weight loss vs. 2% with placebo (P<0.001) (131). In another study with one year follow-up, placebo-corrected weight loss in those taking 120 g three time daily and 360 ug twice daily averaged 5.6% and 6.8% (132). Nausea is the most common adverse event with pramlintide treatment in these studies.

Sodium-Glucose Transporter-2 Inhibitors

Sodium-glucose transport-2 (SLGT2) inhibitors are a class of medications used for the treatment of T2D. Inhibition of SGLT2 in the kidney lowers the renal threshold for glucose reabsorption, resulting in glucosuria and improved plasma glucose levels. As of 2024, there are five SLGT2 inhibitors approved in the U.S.: canagliflozin (Invokana), dapagliflozin (Farxiga), ertugliflozin (Steglatro), empagliflozin (Jardiance), and bexagliflozin (Brenzavvy). Pooled analyses of four phase 3 trials in adults with T2D showed about 2-3% placebo-subtracted weight loss with canagliflozin 100-300 mg/d at 26 weeks (133). Dapagliflozin on a background of metformin was found to result in a placebo-subtracted weight loss of 2.42kg at 102 weeks in adults with T2D and obesity (134). In the landmark EMPA-REG CVOT, average placebo-subtracted weight loss of about 2 kg was maintained out to 220 weeks with empagliflozin 25 mg (135). The fourth SGLT2 inhibitor, ertugliflozin, also resulted in about 2kg weight loss over placebo in adults with T2D treated for 26 weeks (136). A meta-analysis of EMPA-REG, CANVAS (137,138), and DECLARE-TIMI 58 (139) found that SGLT2 inhibitors were associated with a 24% reduction in hospitalization for heart failure and CVD death in individuals with T2D and established CVD (140). This same meta-analysis concluded that SGLT2 inhibitors were also associated with nearly a 50% reduction in the composite outcome of end-stage renal disease, renal worsening, or renal failure in individuals with T2D and CVD or CVD risk factors. The reno-protective effect may be independent of baseline A1c given attenuated eGFR declines observed in CREDENCE and DAPA-HF trials with little change in A1c (141,142), suggesting a role of SGLT2 inhibitors in individuals with nephropathy without T2D. Dapagliflozin was recently approved by the FDA for the treatment of heart failure in individuals with or without T2D based on the results of the DAPA-HF trial (142). EMPEROR-Preserved and EMPEROR-Reduced established similar benefits of empagliflozin in heart failure irrespective of ejection fraction (143).

DAPA-CKD and EMPA-KIDNEY evaluated the effect of SGLT2 inhibitors in the broader CKD population (144,145). In DAPA-CKD, adults with eGFR 25-75 and urinary albumin-to-creatinine ratio (UACR) of 200-5000 were randomized to dapagliflozin 10 mg or placebo (146). The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. After a median of 2.4 years, the primary outcome occurred in 9.2% vs 14.5% in the dapagliflozin vs placebo groups, respectively, representing a 39% relative risk reduction. In EMPA-KIDNEY, adults with eGFR 20-45 or eGFR 45-90 with UACR ≥200 were randomized to empagliflozin 10 mg or placebo (147). The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. After a median of 2.0 years, the primary outcome occurred in 13.1% vs 16.9% in the empagliflozin and placebo groups, respectively, representing a 28% relative risk reduction.

Data for bexagliflozin is comparatively scarce to other members of its class. In a phase 3 RCT of adults with T2D and stage 3a/3b CKD, bexagliflozin resulted in A1c reduction of 0.59-0.65% vs 0.16-0.34% with placebo, depending on eGFR (148).

Due to the mechanism of action, all SGLT2 inhibitors may cause urinary tract infections, genital mycotic infections, and dehydration. They are contraindicated in end-stage renal disease and dialysis (149-152).

Topiramate

Topiramate (trade name Topamax) is an antiepileptic agent that has been found to reduce body weight in patients with a variety of disorders including epilepsy, bipolar disorder, and binge eating disorder (153). Randomized controlled trials have shown that topiramate is both tolerable and effective in promoting weight loss (61). In addition to use for epilepsy, topiramate has received FDA approval for the prevention of migraine headaches. Topiramate can cause paresthesias and cognitive side effects, such as word-finding difficulty and memory loss. Caution should be taken if used in patients predisposed to renal stones, acute angle glaucoma, or metabolic acidosis (154).

Zonisamide

Zonisamide (trade name Zonegran) is another antiepileptic medication that has also been found to reduce body weight in patients. Short (16 weeks) and longer (one year) randomized-controlled studies in patients with obesity have shown that 400 mg of zonisamide daily is effective in promoting modest weight loss (~5 kg placebo-subtracted weight) (155,156). The most commonly reported side effects compared to placebo were gastrointestinal (nausea/vomiting), nervous system (headaches), and cognitive (anxiety, impaired memory, language problems) (156). Zonisamide should not be given to patients hypersensitive to sulfonamides (157).

Metreleptin

Metreleptin (trade name Myalept) is a leptin analog approved to treat the complications of leptin deficiency in individuals with congenital or acquired generalized lipodystrophy (158). It has been used off-label for the treatment of obesity and other endocrine complications in people with congenital leptin deficiency and hypothalamic amenorrhea (159). Metreleptin is administered as a once daily subcutaneous injection with dosages ranging from 0.06 mg/kg/d to 10 mg/d, depending on body weight and sex. Additional precautions should be implemented if it is being considered for individuals with T-cell lymphoma or autoimmune disorders. During therapy, patients should be tested for neutralizing anti-metreleptin antibodies if they develop severe infections or loss of efficacy. Common side effects include headache, hypoglycemia, decreased weight, and abdominal pain.

MEDICATION-INDUCED OBESITY

The role of medications as a factor that can induce weight gain is often overlooked. Several commonly prescribed medications as well as over-the-counter medications are associated with significant weight gain. This includes medications used to treat T2D, hypertension, depression, schizophrenia, and insomnia (160-162). When evaluating a patient with obesity for the first time, the clinician should perform a thorough review of all current prescription and over-the-counter medications to investigate for potential weight-gaining medications. Whenever possible, the clinician should consider alternatives to medications known to cause weight gain (163), or should consider measures that would ameliorate the weight-gaining effect of the prescribed drug.

FUTURE DIRECTIONS FOR WEIGHT-LOSS MEDICATIONS

Medical providers, policy makers, and pharmaceutical industries have increasingly recognized the need for safe and effective pharmacotherapy for patients with overweight or obesity. With the advent of highly effective nutrient-stimulated hormone therapies (NuSH) (e.g., semaglutide, tirzepatide) achieving weight loss thresholds of ≥15% necessary to resolve comorbid diseases, a new generation of AOMs have arrived to significantly shift the trajectory of the obesity epidemic. Several AOMs are currently in various stages of development and are increasingly focused on multi-target strategies. Retatrutide is a triple agonist at GLP-1, GIP, and glucagon receptors that has been shown to have a 100% response rate for clinically significant weight loss and an average weight loss of 24% in a phase 2 trial (164). Semaglutide 2.4 mg in combination with cagrilintide, an amylin analog, has been shown to cause 15% weight loss in a phase 2 trial (165). Interest is also burgeoning into increasing scalability and accessibility. Small molecule oral AOMs are potential solutions. Orforglipron is a small molecule GLP-1RA that has also demonstrated about 15% weight loss in a phase 2 trial (166). Innovators are also exploring peripheral targets outside of NuSH mechanisms that do not rely on anorexigenic effects to mediate weight loss. Bimagrumab is a first-in-class novel AOM that is a monoclonal antibody against activin type 2 receptors on skeletal myoblasts; its phase 2 trial focused on the unique endpoint of fat mass loss rather than total body weight loss (167). With the advent of highly effective AOMs and newer agents targeted specifically at fat mass loss, pharmacotherapy is likely to become more acceptable by society and the medical community to treat obesity as a disease.

IMPLICATIONS FOR PRACTICE

The plethora of on- and off-label AOMs creates the unique challenge for physicians to decide which medication may be most appropriate for the individual patient. Akin to management of other chronic diseases, selection of an AOM should be based on safety and tolerability, comorbidities, and accessibility.

The following principles could serve as a guide the physician in choice of AOM:

Safety and tolerability: Avoid medications for which the patient has contraindications or is at risk of intolerability due to the medications side effect profile. A patient with HTN and lower extremity edema may be better treated with a diuretic rather than amlodipine, which may have the side effect of leg swelling. Analogously, in a patient with obesity and HTN or anxiety, sympathomimetics like phentermine and bupropion/naltrexone should be avoided or used with caution due to potential side effects of these AOMs.

Comorbidities: Target treatment to multiple comorbidities when possible, taking advantage of medications that have dual indications. A patient with HTN and T2D complicated by microalbuminuria would be recommended for an angiotensin converting enzyme inhibitor (ACEi) or aldosterone receptor blocker (ARB) instead of a calcium channel blocker because of the dual benefits of ACEi’s or ARBs. Analogously, in obesity and T2D, semaglutide or tirzepatide would be preferred due to their dual indications and additional cardiovascular benefit in those with preexisting cardiovascular disease. Selection of an AOM may also depend on the degree of weight loss desired and associated health goal. For example, resolution of OSA is likely to require ≥15% weight loss, which is more likely to be achieved with semaglutide or tirzepatide; whereas a patient with prediabetes seeking diabetes prevention can be effectively protected with just 5% weight loss, achievable with most on- and off-label AOMs.

Combinations of AOMs: Combining medications with complementary mechanisms of action is a rational management strategy to target the pathophysiology of obesity and metabolic adaptation. For example, a patient who has lost weight with metformin and reached a weight loss plateau may experience increased hunger due to higher levels of ghrelin, a mechanism that has been reported after diet-induced weight loss; an appetite suppressant such as phentermine or phentermine/topiramate may be helpful to mitigate this compensatory mechanism. While some of these combinations have been investigated (168,169), most AOM permutations have not been tested in RCTs, and the “how” and “when” of AOM combinatorial approaches remains in the realm of clinical judgement and future research. Combinations of off-label AOMs have been associated with significant long-term weight loss and may be a pragmatic approach to increase access to evidence-based obesity care in an era when on-label AOMs are poorly covered by insurance {Weintraub 2023}.

Overall, the approach to obesity management should adopt a comprehensive, multidisciplinary approach to address the root cause (i.e., obesity) as well as its downstream consequences. The decision to pursue obesity pharmacotherapy and the choice of AOM should be made in conjunction with an engaged care team and relevant specialists especially if specific populations are being managed (Table 3).

Table 3. Choice of AOM in Special Populations
Special Population	Care Team	Specific Considerations
Post-bariatric surgery weight regain	Bariatric surgeon, registered dietitian-nutritionist	Absorption of oral medications may be affected by specific surgeries {Angeles 2019} Moderate evidence exists to treat post-bariatric surgery weight gain with AOMs {Barenbaum 2022}
Depression, anxiety, severe mental illness	Psychiatrist, psychologist	Some psychotropic medications are associated with weight gain {Apovian 2014}
Eating disorder (e.g., atypical anorexia, avoidant/restrictive food intake disorder, bulimia nervosa, binge eating)	Psychiatrist, psychologist	Screen for disordered eating at initial visit {Freshwater 2022}
Individuals of child-bearing potential	Obstetrician-gynecologist	All AOMs are contraindicated in pregnancy, and some are suspected to affect contraception efficacy
Elderly	Geriatrician, exercise physiologist	Excess weight loss without sufficient physical activity may predispose individual to sarcopenic obesity and frailty {Prado 2024}

CONCLUSION

The obesity pandemic continues to grow at an alarming rate. Because lifestyle modifications have been limited in their success in weight loss maintenance, pharmacotherapy plays an important role in achieving clinically significant weight loss and preventing the development or exacerbation of comorbid conditions. As society and the scientific community furthers our understanding of obesity, obesity management will evolve to match the standard of care of other chronic conditions, recognizing polypharmacotherapy as a vital component of comprehensive care.

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Prolactinoma Management

ABSTRACT

Prolactinomas comprise nearly 40% of all pituitary tumors. Patients with prolactinomas usually come to medical attention as a result of symptoms caused by elevated prolactin levels, such as hypogonadism, menstrual irregularities, infertility or galactorrhea, or due to mass effects. Sometimes these patients can present as an emergency, either due to a visual field defect or loss of vision, or due to acute severe headache caused by pituitary apoplexy associated with hypopituitarism. Most patients with hyperprolactinemia do not have prolactinomas. A number of physiological conditions as well as several medications can also cause prolactin elevations; in these instances, prolactin levels are usually < 150 ng/mL (3000 mIU/L). Hyperprolactinemia can also result from reduced dopamine reaching the lactotrophs due to stalk compression. Furthermore, when evaluating patients with only modestly elevated prolactin levels and large macroadenomas, one should be aware of the “hook effect”, caused by saturation of antibodies of a two-site immunoassay by very high prolactin levels. A dopamine agonist is the treatment of choice in the vast majority of cases. Dopamine agonists can normalize prolactin levels, restore the function of the gonadal axis, stop galactorrhea, and significantly decrease tumor size in most of the patients, with cabergoline generally being more efficacious and better tolerated than bromocriptine. Indeed, cabergoline is first-line therapy even in patients with visual field defects, as long as visual acuity is not threatened by rapid progression or recent tumor hemorrhage. Cerebrospinal fluid leakage is a rare complication of dopamine agonists if they cause rapid tumor shrinkage and there is disruption of the sellar floor by the tumor. Transsphenoidal surgery is an alternative treatment in cases of dopamine agonist resistance or intolerance. Radiation therapy is reserved for those rare patients with macroadenomas not responding to either medical or surgical treatment. Symptomatic growth during pregnancy may occur in about 20-25% of macroprolactinomas, and therefore visual field testing is indicated each trimester in such patients. MRI scans (without gadolinium) are done in those patients who develop visual field defects or severe headaches when a therapeutic intervention is contemplated. Prolactinoma is the most common pituitary tumor subtype in children and adolescents and macroprolactinomas are more frequent in this age group compared to adults. In addition to typical symptoms of hyperprolactinemia, pediatric patients may present with delayed or arrested puberty, growth failure, and weight gain. Many aspects of the care for children and adolescents with prolactinomas are similar to that in adults; however, key differences exist, particularly in presentation and etiology. For that reason, children and adolescents with pituitary adenomas, including prolactinomas, should be treated by a pituitary specific multidisciplinary team.

CLINICAL RECOGNITION

Patients with prolactinomas come to clinical recognition because of the effects of elevated prolactin levels or tumor mass effects. The most typical symptoms of hyperprolactinemia in premenopausal women are oligo/amenorrhea (approximately 90%) and galactorrhea (approximately 80%) (1). Hyperprolactinemia is a cause of amenorrhea in 10%-20% of nonpregnant women (2), while non-puerperal galactorrhea may occur in 5-10% of normally menstruating, normoprolactinemic women, and therefore is suggestive, but not definitive, of hyperprolactinemia. However, when oligo/amenorrhea is associated with galactorrhea, about 75% of women will be found to have hyperprolactinemia. Galactorrhea is reported in ~10% of cases in men with prolactinomas and is virtually pathognomonic of a prolactinoma. Hyperprolactinemia inhibits the pulsatile secretion of gonadotropin releasing hormone via interfering with hypothalamic kisspeptin-secreting cells via the prolactin receptor, and may involve an opioid link (3).

Table 1. Etiology of Hyperprolactinemia

Pituitary Disease

Prolactinomas

Acromegaly

Clinically nonfunctioning pituitary adenomas

Empty Sella syndrome

Hypophysitis

Rathke’s pouch cyst

Metastases (breast, lung)

Hypothalamic Disease

Craniopharyngiomas

Meningiomas

Germinomas

Other tumors

Sarcoidosis

Langerhans cell histiocytosis

Neuroaxis irradiation

Vascular

Tuberculosis

Pituitary Stalk Section

Medications

Phenothiazines

Butyrophenones

Atypical Antipsychotics

Tricyclic Antidepressants

Serotonin Reuptake Inhibitors

Serotonin Noradrenaline Reuptake inhibitors

Sibutramine

MAO inhibitors

Reserpine

Methyldopa

Verapamil

Metoclopramide

Domperidone

Opioids

Estrogens

GnRH agonists

Other

Neurogenic

Chest wall/Breast lesions

Spinal Cord lesions

Other

Pregnancy

Breast-feeding

Hypothyroidism

Renal Insufficiency

Severe liver disease

Adrenal Insufficiency

Polycystic ovary syndrome

Ectopic prolactin production

Familial hyperprolactinemia (mutated prolactin receptor)

Untreated phenylketonuria and tetrahydrobiopterin deficiencies

Idiopathic

EPIDEMIOLOGY

Prolactinomas comprise 25 to 50% of all pituitary adenomas (4). Prolactinomas are roughly three times more common in women than in men; prior to menopause, prolactinomas predominantly affect women in a ratio of 5:1 to 10:1, while the ratio equalizes afterwards, mainly reflecting the decline in circulating estrogen levels. Microprolactinomas (<10 mm in maximal diameter) are the most frequent type and very rarely grow into macroprolactinomas (≥ 10 mm in maximal diameter). Macroprolactinomas, on the other hand, have a different clinical prognosis (higher risk of invasiveness, higher rates of resistance to medical therapy as well as a higher frequency of other anterior pituitary hormone deficiencies) and require closer follow-up, particularly in men (5). Prolactinomas measuring > 40 mm in diameter are named giant prolactinomas.

PATHOPHYSIOLOGY

The vast majority of prolactinomas are sporadic. Familial cases of prolactinomas are very rare and occur usually in association with Multiple Endocrine Neoplasia type 1 or the Familial Isolated Pituitary Adenoma (FIPA) syndrome and more rarely due to MEN4, MEN5 or associated with paragangliomas (6-8). Genetic testing for young-onset macroprolactinomas should include the MEN1 and AIP genes. Similar to other types of pituitary adenomas, prolactinomas arise from a single transformed cell (lactotroph) with monoclonal proliferation.

A number of candidate somatic genetic alterations involved in the genesis and progression of prolactinomas have been investigated, among which a somatic mutation in the splicing factor 3 subunit B1 (SF3B1) gene stands out. A mutational hotspot (SF3B1R625H) was described in approximately 20% of over 200 surgically resected prolactinomas from a cohort of Chinese patients (9). A recent study by the same group suggests that the SF3B1R625H allele, by promoting aberrant splicing and suppression of Human Disc Large (DLG1), a tumor suppressor protein, may stimulate cell migration, invasion, and epithelial-mesenchymal transition (10). A recent retrospective, multicenter study involving 282 patients from 8 European centers detected SF3B1 variants (including a new variant SF3B1R625C) in seven patients with lactotroph tumors, including 3 metastatic and 3 aggressive tumors (11). The overall prevalence of likely pathogenic SF3B1 variants in lactotroph tumors was 2.5%, but when considering only metastatic cases, it reached the 50%. Furthermore, SF3B1 variants correlated with significantly larger tumor size, higher Ki67 proliferation index, multiple treatments, including radiotherapy and chemotherapy, increased disease-specific death, and shorter postoperative survival.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

The majority of patients with hyperprolactinemia do not actually have prolactinomas (Table 1) (2,12,13). Drug-induced hyperprolactinemia is the most common cause, and a number of physiological conditions, including stress (psychological or associated with acute illness), exercise and sleep can also cause prolactin elevation. The hyperprolactinemia caused by drugs and other non-prolactinoma causes is usually <150 ng/mL (3000 mIU/L). Many medications block dopamine release or action, the most common being antipsychotic medications, verapamil, and metoclopramide (14,15). The best way to determine whether hyperprolactinemia is drug-induced or not is to discontinue the drug or switch to another drug in a similar class that is not known to cause hyperprolactinemia and see if the prolactin levels return to normal within 72 hours. The best example is the partial dopamine receptor agonist aripiprazole, which has been shown to be effective in attenuating antipsychotic medication-induced hyperprolactinemia (16).

A variety of suprasellar lesions cause hyperprolactinemia because of compression of the hypothalamus or pituitary stalk with decreased dopamine reaching the lactotrophs. These can be mass lesions, such as craniopharyngiomas or meningiomas, or infiltrative disease, such as sarcoidosis and Langerhans cell histiocytosis. Cystic prolactinomas, which are prolactin secreting tumors in which the cystic component accounts for more than 50% of the tumor volume, may offer a diagnostic challenge since the prolactin levels are usually lower (50-150 ng/mL) than their solid counterparts. The diagnostic evaluation should exclude other pituitary cystic lesions with hyperprolactinemia caused by stalk compression, such as cystic non-functioning pituitary adenomas (NFPAs), craniopharyngiomas, and Rathke's cleft cysts. It should be noted that cystic prolactinomas might respond to dopamine agonist therapy, which should be considered a viable option, particularly in patients without urgent need of optic chiasm decompression (5). The rapidity and degree of response to dopamine agonist therapy could be a possible way to differentiate the two scenarios with the idea that hyperprolactinemia due to lack of dopamine release would respond more rapidly and markedly to dopamine agonist therapy than prolactinomas. Nevertheless, a recent descriptive study on 68 prolactinomas presenting with prolactin levels between 50 and 200 ng/mL described a median prolactin percent change of 87% by 2 months with more than 25% of the patients having a percent drop >95% (17).

The high estrogen levels of pregnancy cause lactotroph hyperplasia and hyperprolactinemia, so pregnancy must always be excluded. The estrogen levels produced by oral contraceptives or post-menopausal hormonal replacement therapy generally do not cause hyperprolactinemia. The prevalence of hyperprolactinemia in patients with polycystic ovary syndrome is variable and should be a diagnosis of exclusion. Notably, prolactin values above 60-80 ng/mL suggest another underlying cause of hyperprolactinemia that should be actively investigated (2,18). Hypothyroidism and renal failure (serum creatinine >2 mg/dL (176 µmol/L) can also cause hyperprolactinemia (19). Thus, the initial laboratory evaluation involves repeat measurement of prolactin, a TSH, a serum creatinine, and a pregnancy test. Unless there is very good evidence for these conditions or drug-induced hyperprolactinemia, even patients with mild hyperprolactinemia should be evaluated with radiological methods, preferably MRI, to distinguish among idiopathic hyperprolactinemia, microprolactinomas, and large mass lesions. Measurement of IGF-1 is recommended for patients presenting with hyperprolactinemia and pituitary adenomas (19,20) as prolactin may be elevated in up to 50% of patients with GH-secreting tumors (21).

Special caution is needed when two-site (‘sandwich’) prolactin assays are used, as patients with large prolactinomas and very high prolactin levels may appear to have prolactin levels that are normal or only modestly elevated, thus mimicking a large NFPA. This “hook effect” is due to saturation of the assay antibodies and prolactin levels should always be remeasured at 1:10 or 1:100 dilution in patients with larger macroadenomas (> 2-3 cm) and normal to modestly elevated prolactin levels (20,22-24).

Sometimes prolactin levels are elevated due to increased amounts of macroprolactin. Macroprolactin consists of high molecular weight prolactin variants that are either aggregates with immunoglobulins or dimers, and have diminished biologic potency. Macroprolactin can be detected in the serum by precipitating the complex with polyethylene glycol. In normal individuals, macroprolactin comprises < 30% of circulating prolactin; therefore, if after precipitation with polyethylene glycol the prolactin levels in the supernatant are > 70% of the upper limit of normal for the assay, the patient can be assumed to have true hyperprolactinemia and not an elevation due simply to macroprolactin. Macroprolactinemia has usually been found in patients with equivocal symptoms and not those typically due to hyperprolactinemia. A lack of recognition of the presence of macroprolactin can lead to unnecessary laboratory investigations, imaging, and pharmacologic or surgical treatment.

When no pituitary lesions are seen by radiological studies and other known causes have been excluded, the diagnosis of idiopathic hyperprolactinemia is made; in long term follow-up, although prolactin levels may rise to over 50% of the baseline in 10-15% of the patients, only about 10% develop detectable microadenomas, one-third resolve their hyperprolactinemia without specific intervention and prolactin levels remain stable in most patients (25).

TREATMENT

Figure 1. Serum prolactin measurement is required in all patients presenting with hypothalamic-pituitary lesions before surgery (Figure courtesy of D. Korbonits)

Not all patients require treatment. If a patient with a microadenoma or idiopathic hyperprolactinemia presents with non-bothersome galactorrhea and has normal estrogen/testosterone levels, they can simply be followed with periodic prolactin levels. Similar patients who may have amenorrhea but are not interested in fertility may be treated with estrogen replacement. However, for most symptomatic patients, a dopamine agonist is the therapy of choice. Dopamine agonists normalize prolactin levels, correct amenorrhea-galactorrhea, and decrease tumor size by more than 50% in 80-90% of patients, with cabergoline generally being more efficacious and better tolerated than bromocriptine (19,26). Thus, defining whether a pituitary tumor is a prolactinoma is crucial for optimal patient management since it is reasonable to use cabergoline as first-line therapy even in patients with visual field defects, unless visual acuity is threatened by rapid progression or recent tumor hemorrhage, in which cases, surgery is indicated (Figure 2). Starting dose in patients with large tumors threatening vision could be somewhat higher than usual, as illustrated by a retrospective case series of 14 patients with giant prolactinomas and visual field defects who received cabergoline starting doses of 0.5 mg twice or three times a week with visual improvement in 85% of the cases (27). Rapid escalation of cabergoline dose seems to be safe but not more effective than conventional treatment for the achievement of normoprolactinemia and significant tumor shrinkage as shown by a prospective randomized trial including 38 newly diagnosed patients with macroprolactinomas, 68% of them presenting with visual field defects (28). The drop in prolactin levels may be seen as early as 24 hours after initiation of medical treatment, as illustrated by the case of a 16-year old male patient presenting with a giant invasive prolactinoma whose prolactin levels fell from 1,238,960 mIU/L (58,441 ng/mL) to 307,500 mIU/L (14,505 ng/mL) after a single dose of cabergoline 0.25 mg (29,30). Vision often starts to improve within days after the initiation of dopamine agonist therapy and should be preferentially monitored with serial Goldman perimetry tests.

Figure 2. Suggested management in patients presenting with a pituitary mass and new onset compressive symptoms.

In non-emergent situations cabergoline is usually initiated at 0.25-0.5 mg/week (taken initially carefully with meal just before bedtime, to reduce nausea and improve compliance), whereas the initial dose of bromocriptine is 1.25 mg/day. About 40-50% of patients, whose prolactin levels normalize and tumors shrink to the point of non-visualization, can be tapered off cabergoline after 1-2 years without tumor re-expansion. Favorable predictors of successful withdrawal include low maintenance doses of cabergoline, treatment duration >2 years, and substantial adenoma size reduction (5) Factors associated with greater risk of recurrence are the presence of pituitary deficits at diagnosis and higher prolactin levels, at diagnosis and before withdrawal (31)

A rare but significant side-effect of dopamine agonist treatment is cerebrospinal fluid leakage (CSF) leak, due to the rapid shrinkage of a large prolactinoma allowing CSF to escape if significant damage is present at the fossa floor (32). According to a retrospective series of 38 patients with medically induced CSF leaks (97% of them associated with dopamine agonists), the average time from initialization of medical treatment to onset of rhinorrhea was 3.3 months (range 3 days-17 months), but this adverse effect can also occur during long term treatment (33). Patients should be advised to seek medical assistance if clear fluid appears and this should be tested for beta-2 transferrin (20,34) or beta-trace-protein (35), If positive, patients need urgent neurosurgical input. Discontinuing dopamine agonist therapy is not usually recommended as it may cause recurrence of the tumor (36).

Dopamine agonist therapy has been implicated as a precipitating factor for pituitary apoplexy in patients with prolactinomas (37,38). Nonetheless, prolactinomas are, by themselves, more prone to bleeding, and the reported prevalence of pituitary apoplexy in macroprolactinomas treated with dopamine agonists, ranging from 1% to 6%, is not significantly different from the rate recorded in untreated prolactinomas (39). As opposed to the normal pituitary, the vascularization of pituitary adenomas is predominantly supported by a direct arterial blood supply rather than the portal system (40). Indeed, abnormal terminal arterioles have been described in prolactinomas suggesting reduced blood supply (41). Further precipitating factors which have been associated with pituitary apoplexy are cerebral angiography, surgical procedures, head trauma, dynamic tests, anticoagulation therapy, and pregnancy (40,42).

Pituitary apoplexy is a medical emergency and treatment must be tailored to each patient after a thorough evaluation by a multidisciplinary team, including an endocrinologist, a neuroradiologist, an ophthalmologist, and a neurosurgeon with expertise in pituitary pathology. The optimal management of pituitary apoplexy is still controversial, as some patients recover normal visual and endocrine function after conservative steroid-based management. However, prolactinomas with an important bleeding component may not significantly shrink under conservative management and close surveillance is mandatory. Surgical decompression is the most rapid treatment to improve symptoms and relieve compression of local structures and is indicated in case of significant neuro-ophthalmic signs or reduced levels of consciousness (43).

Rarely, vision deterioration may occur during dopamine agonist treatment despite normalization of prolactin levels and tumor shrinkage. An under recognized complication of dopamine agonist therapy in macroprolactinomas is optic chiasm herniation (the optic chiasm which is pulled down into a partially empty sella) which can be diagnosed by MRI (44,45). Multidisciplinary team evaluation is indicated, and treatment approaches include reduction/interruption of dopamine agonist therapy or neurosurgery (chiasmopexy).

A well-described side-effects of dopamine agonists include psychiatric complications, such as depression, anxiety, insomnia, hallucinations, and mania. More recently impulse control disorders have also been described in pituitary adenoma patients (20,46-49). The underlying mechanism is related to an interaction between the dopamine agonists and the D3 receptor in the mesolymbic system (50). Impulse control disorders can manifest as hypersexualism, gambling, compulsive eating, compulsive shopping, and “punding” (compulsive performance of and fascination with repetitive mechanical tasks, for example assembling and disassembling household objects or collecting or sorting various items) (48), with hypersexualism and gambling being the most commonly observed in pituitary patients. Hypersexualism has also been described in teenage children (30). Although impulse control disorders are infrequent, they have the potential to cause devastating consequences on patients’ life and clinicians should be sensitive to these potential side-effects discussing it with the patient and patient´s partner and/or family members at the start of treatment and during long-term follow-up (48). Discontinuation of the dopamine agonists usually reverses these side-effects (47).

In some cases, prolactinomas appear to be resistant to a dopamine agonist, but it is important to ensure compliance and to be certain that the underlying lesion is a prolactinoma and not some other cause of hyperprolactinemia. About 50% of patients resistant to bromocriptine will then respond to cabergoline. Most patients resistant to standard doses of cabergoline respond to larger doses (51). T2-weighted MRI intensity may aid as a tool for predicting response to dopamine agonists. Prolactinomas showing T2-weighted MRI signal heterogeneity are more common in males, are usually larger, more secreting, and may show poorer hormonal response to dopamine agonists as compared with homogeneous prolactinomas (52). In females, T2-weighted MRI tumor hypointensity has been associated with higher prolactin levels at diagnosis and dopamine agonists resistance (53).

Previous reports in patients taking cabergoline for Parkinson’s disease have shown that doses >3 mg/day may be associated with cardiac valvular abnormalities. Whether similar valvular changes occur in patients receiving low-dose cabergoline for treatment of hyperprolactinemia is still debatable; common practice has been to perform periodic echocardiograms every 12 to 24 months in patients taking >2 mg/week (54). However, a clinically significant association between low-dose cabergoline and cardiac valvulopathy is not supported by a large multicenter follow-up study (55). A meta-analysis of case-control studies evaluating patients who had received ³6 months cabergoline treatment for hyperprolactinemia reported an increased risk of mild tricuspid regurgitation in the cabergoline-treated patients compared to controls (56). Nevertheless, these results were mainly influenced by the results from a single center (57)and in the majority of the reviewed studies there were no cases of moderate-severe tricuspid regurgitation in either group. Furthermore, neither cumulative dose nor treatment duration was associated with an increased risk of moderate-severe valve lesions (56) and none of these lesions were found as a result of cardiac symptoms.

According to the cross-sectional CATCH study conducted among 174 community-based adults (mean age of 49 years) receiving dopamine agonists for >12 months for hyperprolactinemia and no cardiac-related symptoms, cabergoline use and greater cumulative cabergoline exposure (>115 mg) were associated with a higher prevalence of valvular regurgitation, i.e., ≥2 valves with grade 2+ regurgitation, compared with bromocriptine (58). According to a joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology (59), a standard transthoracic echocardiogram should be performed before a patient starts dopamine agonist therapy for hyperprolactinemia in order to detect any pre-existing valve alterations. Repeat transthoracic echocardiography should then be performed at 5 years after starting cabergoline in patients taking a total weekly dose less than or equal to 2 mg. If there has been no change on the 5-year scan, repeat echocardiography could continue at 5-yearly intervals. If a patient is taking more than a total weekly dose of 2 mg, then annual echocardiography is recommended. Patients treated with ≤2.0 mg/week of cabergoline who develop clinical signs or symptoms potentially suggestive of valvular abnormalities should undergo annual echocardiography if treatment is continued. Decisions regarding discontinuation of dopamine agonist therapy should only be made after review of serial imaging by a cardiologist experienced in analyzing drug induced valvopathy or carcinoid heart disease. These recommendations diverge to some extent from a recently published international consensus statement of the Pituitary Society (5) which recommends baseline echocardiography only if long-term treatment with a weekly dose > 2 mg is anticipated, echocardiographic monitoring every 2-3 years in patients taking more than a total weekly dose of 2 mg, instead of annual cardiac examination, and, in patients treated with < 1 mg per weak who have no clinical signs of valvular dysfunction, some experts suggested repeated examinations would not be necessary.

An alternative approach is transsphenoidal surgery, which has initial remission rates of approximately 75% for microprolactinomas and 40% for macroadenomas, and long-term recurrence rates of nearly 20% and 35%, respectively, when performed by expert neurosurgeons (60). Transsphenoidal surgery has been usually reserved for patients with resistance or intolerance to dopamine agonists, macroprolactinomas with chiasmal compression and visual deficits without rapid improvement on medical treatment, or with acute tumor complications, such as symptomatic apoplexy or cerebrospinal fluid leakage (20). Complications of hypopituitarism, infections, and bleeding are minimal, but increase proportionately with tumor size. Nevertheless, reappraisal of the position of surgery as a viable first line option alongside dopamine agonists in the treatment algorithm of adult patients with microprolactinomas and well circumscribed macroprolactinomas (Knosp grade 0 and 1) has been recently advocated by some experts (5) based on the advance of surgical techniques over the years, improved remission and low complication rates of current transsphenoidal surgery performed by experienced neurosurgeons (61,62). Craniotomy for large tumors is rarely curative and is fraught with much higher complication rates. Radiation therapy is reserved for those patients with macroadenomas not responding to either medical or surgical treatment. Radiation therapy in all forms is associated with a high rate of hypopituitarism that develops gradually over many years. Temozolomide, an orally-active alkylating chemotherapeutic agent, is reserved for the treatment of aggressive prolactinomas refractory to other treatment modalities (63). Despite current limited experience, alternative medical approaches for uncontrolled patients with aggressive tumors include cytotoxic drugs, mTOR/Akt inhibitors, tyrosine kinase inhibitors, anti-VEGF monoclonal antibody, peptide receptor radionuclide therapy, and immunotherapy (64).

FOLLOW-UP

The goals of treatment are to normalize prolactin levels or at least bring them to levels at which gonadal/reproductive/sexual function is normalized and to decrease tumor size. As noted, according to different series, nearly 80% of patients treated with dopamine agonists will reach these prolactin goals and achieve significant tumor size reduction (65-67). Once prolactin levels have reached normal or near-normal level, they can just be monitored every 3-6 months for the first year and then every 6-12 months thereafter. Macroadenoma tumor size can be monitored by serial MRI scans and once maximal size reduction has been documented, further scans may not be necessary as long as prolactin levels are being monitored. Whether a second MRI scan is necessary in patient with microadenomas is debatable if prolactin levels are regularly monitored. It is extremely rare for a tumor to increase in size without there being a significant increase in prolactin levels. Visual field testing should be repeated until the visual fields normalize or remain stable and then do not need to be repeated.

PREGNANCY

Dopamine agonists have to be given to allow ovulation to occur and then are usually stopped once pregnancy is diagnosed. In this fashion, the developing fetus has been exposed to the drug for about 4-6 weeks. There do not appear to be any risks for fetal malformations or other adverse pregnancy outcomes with either bromocriptine or cabergoline. A comprehensive review confirms no impairments in maternal–fetal outcomes in bromocriptine-induced pregnancies (6272 cases) as well as in cabergoline-induced pregnancies (1061 cases) regarding premature labor, abortions, and fetal malformations (68). In a recent multicenter study including 194 women (233 pregnancies) with prolactinomas the miscarriage rate among women who discontinued cabergoline shortly after pregnancy diagnosis was lower (7.5%) than in those who maintained the medication by medical advice or inadvertently (38%) (69). Despite the potential effect of cabergoline on abortion rates, no associations were observed between maintaining cabergoline after the first trimester and preterm birth, congenital malformations, or neurodevelopmental changes. Dopamine agonists should be reinstituted when breast-feeding is completed.

Pregnancy is a risk factor for prolactinoma enlargement, especially for macroprolactinomas, and risk is increased in patients without prior surgery (5). Symptomatic growth occurs in about 23% of macroprolactinomas and about 3% of microprolactinomas in the second or third trimester due both to the stimulatory effect of the high estrogen levels of pregnancy and the withdrawal of the dopamine agonist that may have been restraining tumor growth. In patients with growing or invasive macroadenomas, pregnancy can be recommended once the gonadotrophic axis is restored and the tumor is reduced within the sellar boundaries (68). Maintenance of dopamine agonist therapy during pregnancy is an option, particularly in patients who have not had prior surgical or radiation therapy of if the tumor is abutting the optic chiasm (5,19).

A recent joint position statement from the Brazilian Societies of Endocrinology and Gynecology recommends dopamine agonists for at least one year to reduce tumor dimension to less than 10 mm in patients with macroprolactinomas who wish to become pregnant. If the tumor reduces in size, discontinuation of the medication once pregnancy is confirmed may be discussed (45). Otherwise, pituitary surgery should be considered. Pre-pregnancy adenoma debulking could increase the chance to avoid symptoms from tumor enlargement during pregnancy. If transsphenoidal surgery is performed prior to pregnancy, the risk of symptomatic macroprolactinoma enlargement is reduced from 21% to 4.7% (5,70).Nevertheless, patients undergoing pituitary surgery before pregnancy should be informed of the potential risk of hypopituitarism and its impact on fertility. Most experts recommend surgery in women with macroprolactinomas who wish to become pregnant if the tumor is close to optic structures and do not experience pituitary tumor shrinkage during dopamine agonist therapy or who cannot tolerate dopamine agonist therapy (5,19).

Visual field testing should be carried out each trimester in patients with macroadenomas but in those with microadenomas only when they develop visual symptoms or progressive headaches. MRI scans (without gadolinium) are done in those patients who develop visual field defects or severe headaches when a therapeutic intervention is contemplated. Prolactin levels may rise during pregnancy when there is no tumor size change and some tumors enlarge without an associated rise in prolactin; therefore, measurement of prolactin during pregnancy need not be carried out, as the results can be misleading. When there is evidence of significant symptoms and tumor growth, the patient should be restarted on the dopamine agonist that was discontinued at conception (71). Again, there are fewer data with cabergoline than bromocriptine but there is no particular reason to favor one versus the other in this context. Transsphenoidal surgical decompression can be performed if there is an unsatisfactory response to the dopamine agonist. Delivery of the baby and placenta can also be initiated if the pregnancy is sufficiently advanced.

Pituitary apoplexy during pregnancy is a rare event, estimated to occur in about 1 in 10,000 term pregnancies and, on numerous occasions, it can be the first clinical manifestation of a pituitary tumor (43). The pathogenesis of pituitary apoplexy during pregnancy is suggested to include compromised blood supply to the pituitary gland due to the physiological gestational growth of the lactotroph cells and the compression of blood vessels which, in combination with a prothrombotic state of pregnancy may predispose to infarction or hemorrhage. According to a recent review of 25 cases of prolactinomas complicated by apoplexy during pregnancy (72), pituitary apoplexy mostly occurred during the second or third trimester. The main presenting symptom was sudden severe headache, followed by visual disturbances. Dopamine agonists had been discontinued at the diagnosis of pregnancy in all cases. Microadenomas accounted for 9 out of 25 cases. Half of the prolactinomas, whether microprolactinomas or not, were managed conservatively, with dopamine agonist therapy and hormone replacement when necessary. In the other half of patients, surgery was performed. Healthy babies were born at term in most of the cases.

CHILDREN AND ADOLESCENTS

Despite the rarity of pituitary adenomas in this age group, prolactinoma is the most common adenoma type in children and adolescents, affecting approximately 100,000 patients every year (73). Although prolactinomas may be diagnosed before puberty, an adolescent presentation is more typical (74). Many aspects of the care for children and adolescents with prolactinomas are similar to those in adults; however, key differences exist, particularly in presentation and etiology. For that reason, children and adolescents with pituitary adenomas, including prolactinomas, should be treated by a pituitary specific multidisciplinary team, with experts from both pediatric and adult practice aiming to achieve optimal care, improved quality of live and reducing potentially serious life-changing and life-limiting sequelae (15,75).

Pediatric patients with hyperprolactinemia may display delayed or arrested puberty, growth failure, menstrual disturbances, including primary or secondary amenorrhea (in post-menarche girls), galactorrhea, and gynecomastia (in boys). Of course, gynecomastia is very common in adolescent boys even in the absence of hyperprolactinemia. Of note, up to 50% of children or adolescents with macroprolactinomas may present with overweight or obesity at diagnosis and weight gain may be the main complaint in some patients (76). As macroprolactinomas, including giant prolactinomas, are more common in this age group compared to adults (77), mass effects, such as headaches and visual field loss, are frequently observed and are more common in boys than in girls. Visual assessment in children and adolescents should be done with age-specific tests, including assessment of visual acuity (ideally with logarithm of the minimum angle of resolution measurement), visual fields (ideally Goldmann perimetry), fundoscopy (with or without color vision) and, in patients with potentially severe deficits, optical coherence tomography (75). Pituitary hemorrhage resulting in apoplexy seems to be more common within prolactinomas in children than in adults. (78). Therefore, the level of suspicion for potential apoplexy in children with prolactinoma and new headache, visual loss or other sudden symptoms should be high.

Genetic testing should be offered to all children and adolescents with prolactinomas. In a retrospective series of 77 patients with macroprolactinomas diagnosed before the age of 20, 14% had a genetic etiology (5% MEN 1 and 9% AIP) (76). Further rare germline abnormalities described include MEN-1 like due to MAX variants and pheochromocytoma-paraganglioma gene related pituitary disease (3PA) due to SDHx variants, as previously mentioned. In regards to biochemical evaluation, serum prolactin concentrations need to be interpreted according to pubertal status and sex. Pediatric cohort studies of prolactinomas report diagnostic serum PRL concentrations above 4,000 mIU/L (188 mcg/L), although lower levels may be seen in patients with microprolactinomas (74,76). As in adults, IGF-1 should be also evaluated to rule out mixed GH and prolactin hypersecretion and should be interpreted according to age and sex-specific reference ranges. Few cases of macroprolactinemia have been reported in the pediatric population (79,80), so assessment of baseline macroprolactin levels should be performed where serum prolactin is found to mildly or incidentally elevated. As with the adult population, serial dilutions of serum for prolactin measurement should be ordered in patients with large lesions and normal or mildly elevated PRL levels to exclude a “high dose hook-effect”.

Medical treatment with a dopamine agonist is first line treatment in children and adolescents with prolactinomas. Several studies conducted in the pediatric population have shown that dopamine agonists reduce clinical symptoms and prolactin levels as well as induce tumor shrinkage (73,81). Cabergoline is the agonist of choice due to its superior effectiveness and lower adverse effect profile, even in the presence of visual disturbance and pituitary apoplexy, while carefully monitoring for any deterioration in vision, pituitary function, or general status. Dopamine agonist therapy is initiated at low doses (for example, 0.25 mg per week of cabergoline), with slow dose increases due to increased probability of adverse effects in children. The frequency of dose-independent psychological intolerance, including mental disorders and behavioral problems, seems to be higher in children and adolescents than in adults (82). Maintenance doses do not differ from the adult population, with most patients achieving treatment goals with conventional doses (up to 2 mg/week). For resistant cases, the dose may be increased to 3.5 mg/week or up to 7 mg in exceptional cases. Although successful dopamine agonist discontinuation has been achieved in children and adolescents, younger patients and those with high serum prolactin concentrations at diagnosis are less likely to achieve complete remission (81). To date, cardiac valvopathy in children and adolescents treated with dopamine agonists for hyperprolactinemia has not been reported. Nevertheless, considering potential longer treatment duration and larger cumulative doses in the pediatric population, surveillance for cardiac valvopathy with echocardiography is recommended such as in the adult population.

In children and adolescents with prolactinomas, neurosurgical intervention should be considered if vision deteriorates or does not improve on medical therapy or if dopamine agonist resistance, escape or intolerance occurs. Pediatric series report lower surgical remission rates than in adults, most likely due to the higher incidence of proportionately larger prolactinomas in children and adolescents, as well as a possible higher frequency of new and permanent pituitary hormone deficiencies after surgery (83,84). If surgery is indicated, it should be performed by experienced pituitary surgeons in age-appropriate neurosurgical units. Endoscopic rather than microscopic transsphenoidal surgery should be considered for its potentially superior efficacy in preserving pituitary function in this age group (85,86). Radiotherapy is reserved for exceptional patients who need control of tumor growth where other treatment modalities are not available or have been exhausted (75).

For follow-up imaging, particularly in macroadenomas, gadolinium-containing contrast agents should be used judiciously since low-level gadolinium deposits in the dentate nucleus and globus pallidus have unknown neurological impact. Unenhanced T1-weighted and T2-weighted MRI sequences should be considered during follow-up in pediatric patients, especially if good quality enhanced images have been obtained at diagnosis (87,88). If gadolinium-containing contrast agents are necessary, macrocyclic or newer linear contrast agents are preferred until further studies clarify possible long-term retention risks.

GUIDELINES

Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 1, general recommendations. Nat Rev Endocrinol. 2024 Feb 9. doi: 10.1038/s41574-023-00948-8. Epub ahead of print. PMID: 38336897.

Korbonits M, Blair JC, Boguslawska A, Ayuk J, Davies JH, Druce MR, Evanson J, Flanagan D, Glynn N, Higham CE, Jacques TS, Sinha S, Simmons I, Thorp N, Swords FM, Storr HL, Spoudeas HA. Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 2, specific diseases. Nat Rev Endocrinol. 2024 Feb 9. doi: 10.1038/s41574-023-00949-7. Epub ahead of print. PMID: 38336898.

Treatment of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM). Benetti-Pinto CL, Prestes Nácul A, Rosa-E-Silva ACJS, Maciel GAR, Dos Santos Nunes Nogueira V, Condé Lamparelli Elias P, Martins M, Kasuki L, Mendes Garmes H, Glezer A.Arch Endocrinol Metab. 2024 Apr 5;68:e230504. doi: 10.20945/2359-4292-2023-0504.PMID: 38578473.

Diagnosis of hyperprolactinemia in women: A Position Statement from the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and the Brazilian Society of Endocrinology and Metabolism (SBEM). Glezer A, Mendes Garmes H, Kasuki L, Martins M, Condé Lamparelli Elias P, Dos Santos Nunes Nogueira V, Rosa-E-Silva ACJS, Maciel GAR, Benetti-Pinto CL, Prestes Nácul A.Arch Endocrinol Metab. 2024 Apr 5;68:e230502. doi: 10.20945/2359-4292-2023-0502.PMID: 38578472.

Petersenn, S., Fleseriu, M., Casanueva, F.F.et al. Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society International Consensus Statement. Nat Rev Endocrinol 19, 722–740 (2023).

Shlomo Melmed, Felipe F. Casanueva, Andrew R. Hoffman, David L. Kleinberg, Victor M. Montori, Janet A. Schlechte, John A. H. Wass. Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism, 2011;96(2): 273–288.

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Hypopituitarism Following Cranial Radiotherapy

ABSTRACT

Radiation treatment is used for patients with secreting and non-secreting pituitary adenomas, with residual pituitary adenomas, or recurrent pituitary adenomas with the aim to achieve long term disease control. Radiotherapy is an integral component of the management of other tumors in the sellar region (craniopharyngiomas) and for certain types of cancers and lymphomas. Pituitary hormone deficiencies are the commonest late complication of radiotherapy, which usually occurs after several years. The development of hormone deficiencies with time varies in the published literature. Predictors for the development of hypopituitarism are the dose of radiation and the age at time of treatment. Different pituitary axes appear to have different radio-sensitivity with the somatotrophic axis being the most sensitive. Long-term endocrine evaluations are recommended in patients after cranial radiotherapy to identify new pituitary hormone deficiencies and introduce appropriate hormone replacement therapy. Clinical evaluation, baseline pituitary hormone assessment, and dynamic testing for growth hormone and adrenocorticotropic hormone (ACTH) deficiency should begin one year after cranial radiotherapy. Compared with conventional radiotherapy, advanced radiation technologies (stereotactic radiosurgery, cyber knife, fractionated stereotactic radiotherapy, proton beam therapy) are presumed to have the ability to deliver radiation to the tumor with remarkable precision minimizing its effects on healthy tissues. Results from larger series with longer length of follow-up are needed to help clinicians identify who will benefit most from advanced radiation techniques.

INTRODUCTION

In the past few decades, the survival of patients with brain tumors, including malignant tumors has improved greatly. However, these patients tend to develop acute and late complications of tumor treatment, which includes cranial irradiation.

The rationale for radiotherapy is to achieve excellent long-term tumor control after partial surgical excision and published 10-year tumor control rates are reported to be high. The following diseases are treated with radiotherapy: pituitary adenomas or other sellar tumors not derived from pituitary tissue (craniopharyngioma, meningioma, germinoma), brain cancers, head and neck tumors, and acute lymphoblastic leukemia (ALL) (Table 1).

Table 1. Diseases Treated with Cranial Irradiation
PITUITARY
· Acromegaly, Cushing disease, prolactinoma, nonfunctioning pituitary adenoma
OTHER SELLAR TUMORS
· Craniopharyngioma, meningioma, germinoma
NONPITUITARY BRAIN TUMORS
· Meningioma, metastases, neuroblastoma, lymphoma
HEAD AND NECK TUMORS
· Nasopharyngeal carcinoma, rhabdomyosarcoma, retinoblastoma, skull-based tumors
HEMATOLOGICAL MALIGNANCIES
· Acute lymphoblastic leukemia, lymphoma
OTHER DISEASES REQUIRING HEMATOPOIETIC STEM-CELL TRANSPLANTATION (after conditioning with total body irradiation)

Following radiotherapy, the side effects of radiotherapy may be acute toxicity (within weeks of completion of therapy) and late toxicity which occur years after treatment. The risk of toxicity depends on the total radiation dose. Doses are divided into fractions and the duration of cranial radiotherapy varies from one or a few days in short courses to several weeks of daily radiations in long courses. Higher doses (up to 60Gy) are used for pituitary tumors, non-pituitary brain tumors, head and neck tumors (nasopharyngeal cancer, rhabdomyosarcoma) and skull-base tumors, while lower doses are used in patients with ALL and total body irradiation as preconditioning before bone or stem cell transplantation (1-14).

Radiotherapy has greatly evolved over the past few decades. Conventional radiotherapy has been used for the longest period of time. Conventional radiotherapy is administered by a linear accelerator, with a total dose of 40-45Gy, in at least 20 sessions. A single beam of high-energy radiation is focused onto a small treatment area, but the radiation also includes healthy surrounding tissue. In photon-based radiotherapy, photons interact with the electrons and deposit energy, causing DNA damage. Maximum dose deposition occurs shortly after entering the body, decreasing then until the exit the body. Standard photon-beam radiotherapy (conventional fractionated photon-based) is administered by a linear accelerator and deliver 1.8-2Gy fractions of radiation dose 5 days a week for 4-6 weeks. 3D conformal radiation therapy, including whole brain and total body radiotherapy have been widely used for years but with little possibility of organ at-risk sparing. It involves the use of CT scans and manual optimization of the shaped dose to the tumor.

Technical advances in radiotherapy refer to high precision treatment (stereotactic) and they include radiosurgery (gamma knife), robotic arm mounted linear accelerator (cyber knife), and proton beam therapy (Table 2) (15).

Stereotactic radiosurgery (SRS) delivers a single fraction of high dose radiation focused on the tumor. SRS uses photons (gamma knife, LINAC, cyber knife) or heavy particles (protons). SRS delivers multiple beams stereotactically with high-dose gradients allowing good organ at-risk sparing. Stereotactic radiosurgery uses precise immobilization techniques, CT/MRI and multiple intersecting beams. With this approach it is possible to deliver a single large radiation dose to a tumor volume, with reduced dose to surrounding healthy tissue.

Fractionated stereotactic radiotherapy (FRST) uses a linear accelerator (LINAC) to deliver photon radiotherapy. Tumor targeting and radiation planning are better with the use of computer assisted program. The patient is immobilized for precise delivery of radiation. The treatment is delivered by intensity-modulated radiotherapy or by volumetric-modulated arc radiotherapy. Intensity-modulated radiotherapy (IMRT) as an advanced method of delivering conventional radiotherapy, has been used since the 2000s. IMRT relies on several beams, normo-fractioned (with 1-2 Gy fractions), with focus on tumor volume and clear delineation of surrounding healthy tissues. IMRT uses a CT scan and a computer algorithm for automatic planning of radiotherapy. This radiation technique allows dose escalation to the tumor tissue with sparring normal tissues. The photon radiotherapy has further improved over the next decades and new techniques were introduced: an image-guided radiotherapy (IGRT), volumetric-modulated arc therapy (VMAT) and helical tomo-therapy (16). In VMAT treatment is delivered using multiple arcs or beams shaped with multi-leaf collimators to the tumor’s geometry.

Proton beam therapy uses the delivery of proton particles for the radiation treatment. Protons travel through tissue in a straight line, with more rapid fall-off of radiation with distance from the tumor and the absence of an exit dose (Bragg peak effect). Proton therapy is further indicated in order to spare healthy tissues from radiation due to lack of diffusion of the radiation.

Initial data suggest that the radiation-associated endocrine dysfunctions may be reduced with these new radiation techniques. However, further clinical studies with more patients, longer follow-up, control group, randomized prospective studies are needed to better define the consequences of these new radiation methods.

Table 2. Radiation Techniques
Type	Characteristics	Number of sessions
CONVENTIONAL	The fractionation allows normal tissue to recover, while tumorous tissue is destroyed + extra tumoral side effects	several
STEREOTACTIC	Higher accuracy, fewer side effects
	· Gamma knife radiosurgery	Single
	· Fractionated stereotactic radiotherapy	several
	· Cyber Knife	Single or 3-5 fractions (hypofractionated SRS)
PROTON BEAM	Lack of diffusion of the radiation + lack of extra tumoral side effects

SRS: stereotactic radiosurgery

ACUTE AND CHRONIC COMPLICATIONS OF CRANIAL RADIOTHERAPY

Acute toxic effects of radiation include skin erythema, hair loss, tiredness, nausea, headache, and hearing problems. These short-term complications resolve spontaneously within days to weeks after radiotherapy. Long-term complications of pituitary irradiation include hypothalamic-pituitary dysfunction (hypopituitarism, hyperprolactinemia, central precocious puberty), optic neuropathy, cranial neuropathies (II, III, IV, V and VI cranial nerve injury), brain radio-necrosis (neurocognitive dysfunction, focal neurologic signs, seizures), carotid artery stenosis, cerebrovascular accidents, and second brain tumors (most commonly meningioma and glioma) (Table 3) (17-26). The risk of hypopituitarism varies, depending on the radiation technique, the radiation dose, and increases with the duration of follow-up. After conventional radiotherapy in patients with a pituitary adenoma, the incidence of hypopituitarism occurs in 30-60% of patients 5-10 years after irradiation. The risk for other radiation-induced chronic complications is usually low (< 5% for new visual deficits, cranial neuropathies, or brain radio-necrosis, and < 1% for secondary brain tumors) (27).

Table 3. Complications of Cranial Radiotherapy
ACUTE	CHRONIC
Skin erythema	Hypothalamic-pituitary dysfunction · GH deficiency · FSH/LH deficiency · TSH deficiency · ACTH deficiency · Hyperprolactinemia · Central precocious puberty
Hair loss	Neuropathy · Optic · Cranial (II, III, IV, V, VI)
Headache	Brain radionecrosis Neurocognitive dysfunction Focal neurological signs · Seizures
Hearing impairment	Carotid artery stenosis
Nausea	Cerebrovascular insult (stroke)
Tiredness	Second brain tumor

INCIDENCE OF RADIATION-INDUCED NEUROENDOCRINE DYSFUNCTION

A number of studies reported very different incidences of radiation-induced hypopituitarism, central precocious puberty, or hyperprolactinemia, depending on indications for radiotherapy, radiation technique, radiation dose, and duration of follow-up.

Pituitary Adenomas and Craniopharyngiomas

The incidence rate of new onset hypopituitarism after conventional radiotherapy in patients with recurrent or residual functioning or nonfunctioning pituitary adenoma reaches 30-100% after follow-up of 10 years (28-31). According to the data from one of the largest cohorts of 4110 patients with adult-onset growth hormone (GH) deficiency (Pfizer International Metabolic Database, KIMS), 36% of patients with isolated GH deficiency and 37% of patients with multiple pituitary hormone deficiencies had a history of cranial radiotherapy (32).

New data indicate that modern radiation techniques, such as stereotactic radiosurgery or fractionated radiotherapy, can achieve long-term control with lower incidence of radiation-induced hypopituitarism (10-40% of patients at 5 years) compared with conventional radiation techniques (33, 34). A systematic review and meta-analysis of 24 studies with 1381 patients with pituitary adenomas treated with gamma knife radiosurgery (median marginal dose 22.6 Gy, maximum dose 50 Gy, and isodose line 50%) reported that 11.4% experienced endocrinopathies at a median of 45 months after radiotherapy, with pooled 5-year rates of 8% (35). Panhypopituitarism was reported in 19.6% of cases, secondary hypothyroidism in 42.4% and hypogonadotropic hypogonadism in 33.5% of cases.

A large multicenter international study followed 1023 patients with a median follow-up 51 months after gamma knife radiosurgery for pituitary adenoma and 24.2% of patients developed new anterior pituitary hormone deficiency (36). The median time to hypopituitarism was 39 months. Sixty percent of patients had single and 39.5% patients had multiple hormone deficiencies. ACTH deficiency developed in 21.6% patients, TSH deficiency in 35.6%, gonadotropin deficiency in 24.3%, GH deficiency in 15.6% and AVP deficiency in 2.9% patients. The 5-year rate of hypopituitarism was 22.4%, and 10-year rate of hypopituitarism was 31.3% Prognostic factors for hypopituitarism were: a lower isodose line, whole sella targeting and treatment of a functional pituitary adenoma (36). The authors concluded that the majority of hypopituitarism occurred within the first 1-5 years after radiotherapy, but delayed hypopituitarism can occur even beyond 10 years.

In patients with Cushing´s disease treated with conventional radiotherapy, hypopituitarism occurred in 50% of patients, with at least 5 years of follow-up (37). In a review of 1318 patients with Cushing´s disease treated with SRS, with a mean follow-up of 5 years, new anterior pituitary hormone deficiency developed in 20-30% of patients, usually within 2 years from radiotherapy (38). The use of intensity-modulated radiotherapy for Cushing´ disease reported 22.9% of hypopituitarism after a median follow-up time of 36.8 months (39).

The prevalence of at least one anterior-pituitary deficit after surgery and radiotherapy for a craniopharyngioma varies between 60% and 100% (40). A nationwide retrospective study included 145 patients with childhood-onset craniopharyngioma (mean age at diagnosis 8.4 years), with cranial radiotherapy in 39% of cases after surgery. All patients but one presented with at least one hormone pituitary deficiency. TSH deficiency was most frequent (98.3%), followed by ACTH (96.8%), arginine vasopressin (91.1%), and growth hormone deficiency (77.4%) (40).

Recently published study followed 101 children and adolescents with craniopharyngioma after treatment with photon-based conformal and intensity-modulated radiation therapy for 10 years (41). The 10-year cumulative incidence of growth hormone deficiency (GHD) was 68.42% for black patients and 94.23% for white patients. Cumulative incidence of TSH deficiency was 70.94% at 10 years for non-shunted patients, 91.67% at 6 years for shunted patients, 100% at 4 years for those with diabetes insipidus and 71.36% at 10 years for those without diabetes insipidus. The 10-year cumulative incidence of ACTH deficiency was 70.00% for those with diabetes insipidus and 48.39% for those without diabetes insipidus. The 10-year cumulative incidence LH/FSH deficiency was 43.33% age < 7 years, 61.29% aged 7-10 years, and 78.95% age ≥10 years. Predictive factors for the occurrence of hypopituitarism were hydrocephalus, host (race) and vasopressin deficiency (41).

Skull Base Meningioma

Patients with skull base meningioma underwent radiotherapy either as first-line treatment of following initial surgery (partial or total). Little information is available regarding the prevalence of hypopituitarism in patients irradiated for skull base meningioma. A study of 48 patients with a skull base meningioma, treated with radiotherapy, reported that complete hypopituitarism was present in 13% of patients, while at least one pituitary hormone deficit was present in 38% of patients after a median follow-up period of 7.5 years (42). The growth hormone and TSH deficiencies were the most prevalent deficiencies (35% and 32%, respectively), followed by FSH/LH deficiency (28%) and ACTH deficiency (13%). Several risk factors for radiation-induced hypopituitarism were identified: localization of meningioma, radio-sensitivity of meningioma (regression after radiotherapy), treatment duration and radiation dose (42). Another study with 52 adult patients receiving photon-beam therapy for skull base meningiomas reported up to 60.1% of patients who had 2 or more pituitary deficiencies 10 years after radiotherapy (43). The gonadotroph deficiency (37%) was the most prevalent abnormality, followed by thyrotroph (28%), corticotroph (18%) and somatotroph (15%) deficiencies. Hypopituitarism could appear very early, within the first year after radiotherapy, with increasing incidence of hypopituitarism later, during the follow-up. Large meningioma (more than 4cm) or a radiation dose of more than 50Gy were predictive factors for hypopituitarism (43).

Brain Tumors Distant from the Hypothalamus and Pituitary

Studies with shorter follow-up showed that 41% of patients irradiated for brain tumors distant from the hypothalamus and pituitary region developed hypopituitarism, 16% with isolated pituitary hormone deficiency and 25% with multiple pituitary hormone deficiencies (44). The largest study with long follow-up (median 8 years) showed a higher prevalence of pituitary dysfunction (88.8%) after cranial radiotherapy for adult-onset non-pituitary brain tumors (45). GH deficiency was the most frequent neuroendocrine abnormality (86.9% of patients), followed by gonadotrophin deficiency (34.6%), ACTH deficiency (23.4%) and TSH deficiency (11.2%). Hyperprolactinemia was reported in 15% of patients. Single pituitary axis dysfunction was reported in 41.1% of patients, while multiple pituitary hormone deficits were present in 47.7% of patients (45).

Conventional fractionated radiotherapy in adults with gliomas found a high prevalence of hypopituitarism in these patients (84.5%) after a follow-up of 8.2 ± 5.2 years (46). The mean radiation dose to the glioma was 53.9 Gy and to the hypothalamo-pituitary axis was 35.9 Gy. The most prevalent deficiency was growth hormone deficiency (82.8%), followed by central hypogonadism (20.7%), central hypocortisolism (19%) and central hypothyroidism (6.9%). Multiple pituitary hormone deficits were observed in almost 40% of patients. Hyperprolactinemia was present in 10.3% of patients, all females, and was transient in the majority of patients. The hypothalamo-pituitary radiation dose thresholds for the growth hormone deficiency, hypogonadism, hypocortisolism and hypothyroidism were 10, 30, 32 and 40.8Gy, respectively. Neuroendocrine dysfunction following cranial radiotherapy correlated with the radiotherapy dose delivered to the hypothalamo-pituitary axis and duration of follow-up (46).

A meta-analysis of 18 studies with a total of 813 patients showed that approximately two thirds of all adults previously treated with cranial radiotherapy for an intracranial tumor or nasopharyngeal cancer developed some degree of hypopituitarism (47). Growth hormone deficiency was the most prevalent (45%), followed by gonadotropin deficiency (30%), TSH deficiency (25%) and ACTH deficiency (22%).

Recently published analysis of 45 studies from 2000 to 2022 of adult patients undergoing radiotherapy for pituitary adenoma, brain tumors, head and neck tumors showed that endocrine deficiencies occurred in about 40% of patients within a median follow-up of 5.6 years, without a clear difference between radiotherapy modalities (48). In this review, somatotropic axis was the most radiosensitive, while the thyrotropic axis was the least radiosensitive.

Systematic search of the literature showed that hypopituitarism can occur within the first year after radiotherapy (range 3 months-25.6 years) in 20-93% of adult cancer patients treated with cranial radiotherapy (49). It is important to notice early onset of hypopituitarism (within the first year after cranial radiotherapy) and to start replacement therapy (glucocorticoids, thyroxin) in patients with brain metastases or other malignancies treated with cranial radiotherapy (nasopharyngeal cancer, non-pituitary brain tumor, head and neck cancer), and in patients with small cell lung cancer treated with prophylactic cranial irradiation. Modern radiotherapeutic technique with a sparing approach of the hypothalamo-pituitary axis might be a promising option for these patients (50).

Childhood-Onset Brain Tumors

Cranial radiotherapy in childhood often affects growth causing growth retardation and affects sexual development causing early or delayed puberty (9, 51-55). ACTH deficiency may develop many years after the cranial irradiation, especially in childhood cancer survivors who had tumors located and/or had surgery near the hypothalamo-pituitary axis and who received radiotherapy dose of over 30Gy to the hypothalamo-pituitary region (56). Children treated with radiotherapy for brain tumors had decreased pituitary height and endocrine deficiencies at 2, 5, and 10 years post-diagnosis (57). In the largest cohort of childhood-onset brain tumors (Childhood Cancer Survivor Study, CCSS), 43% of 1607 children who survived their disease for 5 or more years developed one or more anterior pituitary hormone deficiencies (51). A retrospective clinical study reported the prevalence of hypopituitarism in a large cohort of 748 adult survivors in the USA treated with cranial radiotherapy in childhood (CCSS), among them 72% with a leukemia diagnosis (9). After a long duration of follow-up (mean 27.3 years, range 10-47 years), the prevalence of GH deficiency was 46.5%, gonadotropin deficiency 10.8%, TSH deficiency 7.5% and ACTH deficiency 4%. The same population of patients were investigated in 2019, when the authors compared the prevalence of neuroendocrine deficiency in irradiated and non-irradiated childhood cancer survivors (58). In the 1086 irradiated children 40.2% had GH deficiency, 11.1% had TSH deficiency, 10.6% had FSH/LH deficiency, and 3.2% had ACTH deficiency, after a median follow-up time of 24.1 years, higher than in non-irradiated children (only 6.2% had GH deficiency and less than 1% had other endocrinopathies) (58). Similar results were published in 2022, when the authors investigated the neuroendocrine dysfunction in 355 children and adolescents who were treated with conformal radiation therapy for central nervous system tumors (low-grade glioma or ependymoma) at median age of 6.4 at radiotherapy and after the median follow-up of 10.1 years (59). The prevalence of GH deficiency was 37.2%, gonadotropin deficiency 17.7%, TSH deficiency 14.9%, ACTH deficiency 10.3% Hypothalamus mean dose ≥ 36 Gy was associated with higher odds of any deficiency (59). Recently published study on 41 adult survivors of childhood brain tumors treated with proton and photon irradiation showed that 63% of patients had GH deficiency after 14.8 years of follow-up (60).

A retrospective analysis of 102 children treated for brain, head and neck, and hematological malignancies with photon beam radiotherapy followed for 5.7 years showed that the majority (62.7%) developed pituitary insufficiency (61). Forty-one percent had one and 38% had two hormone deficiencies. Growth hormone deficiency was the most common (56.9%), followed with TSH deficiency (31.4%). Patients who developed pituitary insufficiency received higher maximum pituitary dose (median dose 44Gy). Doses of 40-49 Gy or more than 50 Gy led to a higher cumulative incidence rate of hypopituitarism compared with radiotherapy dose less of 20 Gy. However, even at lower dose of radiotherapy (less than 20 and 20-29 Gy), a five-year cumulative incidence of GH and TSH deficiency was about 30%.

It has been shown that large proportion (85.4%) of childhood nasopharyngeal carcinoma patients had reduced pituitary heights three months after radiotherapy (62). Some patients even had empty sella after radiotherapy. These changes of pituitary volume had long term side effects on the linear growth of these children (62). In addition, some childhood cancer survivors develop overweight or obesity (due to hypothalamic damage), dyslipidemia, metabolic syndrome and low bone mineral density (53).

Guidelines of the Endocrine Society addresses the diagnosis and treatment of hypothalamic-pituitary and growth disorders encountered in childhood cancer survivors (63).

THE PATHOPHYSIOLOGICAL MECHANISMS OF RADIATION-INDUCED NEUROENDOCRINE DYSFUNCTION

Cranial irradiation causes irreversible and progressive damage to the hypothalamic-pituitary region. There are several pathophysiological mechanisms of the radiation-induced hypopituitarism including direct hypothalamic neuronal and vascular injury, with secondary pituitary atrophy being the most common mechanism. Female acute lymphoblastic leukemia (ALL) survivors treated with cranial radiotherapy had smaller hypothalamic volume (measured on T1-weighed MRI images), compared to gender matched controls (64).

The integrity of the microstructure of the hypothalamus can be examined in vivo using the MRI technique diffusion tensor imaging (DTI), based on the direction and degree of the diffusion of water molecules. This MRI technique shows brain tissue microstructure alterations and provides information about brain white matter organization by assessing the restriction of randomly moving water molecules. Recently, this new technique of in vivo brain damage investigation was used in cranially irradiated patients (ALL and childhood craniopharyngioma survivors) (65). Important microstructure alterations in the hypothalamus were detected in ALL survivors, with worse alterations in overweight survivors compared to survivors with normal weight. These microstructure alterations suggest demyelination and axonal loss the hypothalamus and were not found in childhood onset craniopharyngioma survivors without hypothalamic involvement (65).

White matter lesions are pathological changes caused by obstruction of small cerebral vessels resulting in hypo-perfusion of the brain. These lesions can be visualized on T2-weighted MRI and correspond to myelin loss and mild gliosis (66). In patients with childhood-onset craniopharyngioma after photon cranial radiotherapy (with 3-field technique) an increase in white matter lesions volume was found, as well as reduced hypothalamic volume (67). The exact time when white matter lesions started to develop seemed to be around 20 years after cranial radiotherapy. The authors reported that having received cranial radiotherapy in childhood-onset craniopharyngioma patients corresponded to the similar effect as being 18 years older. Patients with more white matter lesions had higher cardiovascular risk (67). Animal studies using radiation-induced brain injury with a total dose of 30Gy (15 Gy with 2 fractions) showed also deficits in axonal transport as a result of multiple factors, such as decline in motor proteins kinesin-1 and cytoplasmic dynein, neuronal apoptosis, synaptic damage and energy metabolism dysfunction (decline in expression of the energy metabolism-related proteins) (68).

The third mechanism of radiation-induced hypothalamic dysfunction is the alteration of the neurotransmitters in the hypothalamus and other brain regions which regulate hypothalamic function (69-71). Animal studies showed that whole brain irradiation (11Gy) decreased levels of inhibitory neurotransmitters (GABA, glycine, taurine, aspartate) and receptors (GABAa receptor) in the hypothalamus, causing a neurochemical imbalance and neuroendocrine disturbances (72).

Direct pituitary damage may also occur, as it is the case in patients after stereotactic radiosurgery for pituitary adenomas. Animal studies using transcriptomics reported also that irradiation significantly changed pituitary transcriptome (73). These authors found reduced cell proliferation and activation of apoptosis related-p53 signaling pathway in the pituitary gland after cranial irradiation. Also, irradiation increased the expression of pro-inflammatory genes, decreased the expression of anti-inflammatory genes and activated the TNF inflammatory signaling pathway in the pituitary gland, leading to persistent inflammation (73). These findings could be used to develop new strategies (for example, anti-inflammatory interventions) for reducing radiotherapy-induced side effects.

It is also proposed that immune system may be a potential mediator of neuroendocrine dysfunction after cranial radiotherapy. The presence of anti-hypothalamic and anti-pituitary antibodies were found in 47.8% of irradiated children with craniopharyngioma, germinoma or gliomas and none in the healthy controls (74).

The posterior pituitary gland is less sensitive to radiation injury.

NEUROENDOCRINE DYSFUNCTION AFTER CRANIAL IRRADIATION

The incidence and severity of radiation-induced neuroendocrine dysfunction depends on radiation dose, radiation schedule, and duration of follow-up.

Radiation Dose

The severity and frequency of pituitary hormone deficiencies, hyperprolactinemia, or central precocious puberty as a complication of cranial radiotherapy correlates with the total radiation dose (Table 4).

Table 4. Hypothalamic-Pituitary Dysfunction After Cranial Radiotherapy
DYSFUNCTION	HYPOTHALAMIC-PITUITARY DOSE OF IRRADIATION
GH deficiency	≥ 18 Gy
Central precocious puberty	≥ 18 Gy
FSH/LH deficiency	≥ 30 Gy
TSH deficiency	≥ 30 Gy
ACTH deficiency	≥ 30 Gy
Hyperprolactinemia	≥ 50 Gy

The somatotroph axis is the most vulnerable and isolated growth hormone deficiency (GHD) may occur with a low radiation dose of 18 Gy (75, 76). If the radiation dose is less than 30 Gy, isolated GHD is present in 30% of patients (4, 28, 77). The incidence of GHD increases to 45-100% of patients if the radiation dose is 30-50Gy (47, 77-80).

If radiation dose is less than 18 Gy, central precocious puberty is a potential complication (with lower effective dose in girls compared with boys), while TSH and ACTH deficiencies are uncommon (13, 47, 81). A large retrospective study reported that the prevalence of central precocious puberty following the treatment of 80 patients with pediatric cancer and CNS tumors was 15.2% overall (29.2% for tumors in the hypothalamic-pituitary region and 6.6% for other CNS tumors) (82).

With an increase of radiation dose, GHD is followed by other pituitary hormone deficiencies: gonadotropin deficiency (30% of patients), TSH deficiency (6-25% of patients) and ACTH deficiency (22% of patients) (47, 83).

Radiotherapy Schedule

The severity of neuroendocrine dysfunction after cranial radiotherapy also depends on the radiotherapy schedule. If the total radiation dose is administered over a short period, it will induce more hypothalamic-pituitary damage than if the same dose is administered over a longer period.

Follow-Up Period

The incidence of radiation-induced hypopituitarism correlates also with the time elapsed since treatment (30, 31). Hormone deficits accumulate throughout the follow-up period, with the majority of hormone deficits developing during the first 5 years post-radiotherapy. In a large study of the effect of cranial radiotherapy in patients with non-pituitary brain tumors, the incidence of all pituitary deficiencies almost doubled between years 2 and 7 of follow-up (45).

GH deficiency occurred the earliest (mean of 2.6 years), followed by gonadotropin deficiency and hyperprolactinemia (after 3.8 years), ACTH deficiency (after 6 years) and TSH deficiency (after 11 years) (74). After a follow-up period of 10 years, multiple pituitary hormone deficiencies occurred in 30-60% of patients (77, 79).

NEW RADIATION TECHNIQUES AND HYPOTHALAMIC-PITUITARY DYSFUNCTION

New stereotactic radiation techniques (stereotactic radiosurgery with a Leksell gamma knife, a stereotactic linear accelerator, a Cyber Knife, or proton beam therapy) have been developed with the aim to improve effectiveness, to irradiate less normal tissue, and to reduce toxic effects (17). The stereotactic radiation techniques involve photon energy from multiple ⁶⁰Cobalt radiation sources (gamma knife) or a modified linear accelerator (LINAC). It can be delivered as a single fraction stereotactic radiosurgery or as a fractionated stereotactic radiotherapy. Stereotactic radiosurgery is a single dose radiation technique at doses of 16-25 Gy used in patients with small and medium-sized pituitary adenoma at least 2-4mm from the optic chiasm, whereas fractionated stereotactic radiotherapy is used in patients with large (>2.5-3cm) pituitary adenoma, frequently involving the optic chiasm (84).

Gamma Knife Stereotactic Radiosurgery

Gamma knife stereotactic radiosurgery delivers in a single session a highly collimated dose of ionizing radiation (⁶⁰Cobalt) conformed to the shape of the target and sparing normal tissue, in contrast to conventional radiotherapy, which covers the tumor and the surrounding structures with a fractionated dose gradient of radio-toxicity between target cells and normal tissue. As already mentioned, gamma knife stereotactic radiosurgery is usually used in patients with relatively small tumors not in close proximity of the optic apparatus (at least 2-4mm away from the optic chiasm). The patient wears a rigid metal helmet fixed on the scull. The dose is usually prescribed at the 50% isodose, ensuring maximum dose at the isocenter and prescribed dose at tumor margins. The radiation is delivered in one session and the dose delivered to the tumor margin are higher for functioning pituitary adenomas (18-35 Gy), compared with nonfunctioning pituitary adenomas (10-20Gy) (84). The studies on long-term follow-up results of gamma knife stereotactic radiosurgery in patients with pituitary adenoma reported radiation-induced hypopituitarism in up to 50% of patients (25, 27, 85-92). Data published in last four years and meta-analysis of outcomes and toxicities following stereotactic radiosurgery for nonfunctioning pituitary adenomas showed lower incidence (15-28%) of radiotherapy-induced hypopituitarism (93-96). The retrospective study of long-term results (median of 64.5 months, range 14.5 – 236 months of follow-up) of gamma knife radiosurgery (median tumor margin dose 14 Gy, range 9-20 Gy) for postsurgical residual or recurrent nonfunctioning pituitary adenomas showed new hypopituitarism in 27.5% of patients, hypocortisolism being the most common deficiency (15 out of 80 patients) (93). The cumulative rates of developing new hypopituitarism at 1, 3, 5 and 10 years was 4%, 21%, 30% and 57%, respectively (93). Similar rates of new hypopituitarism (17.3% and 28%, respectively) after gamma-knife radiosurgery for functioning and nonfunctioning pituitary adenoma were also reported (95, 96). Pituitary deficits occurred after a median time of 22 months (96). Four percent of patients developed panhypopituitarism, while isolated hypocortisolism was observed in 16%, hypothyroidism in 14%, hypogonadism in 14% and growth hormone deficiency in 4% of patients (96). These authors tested biological effective dose (BED) as a possible predicting factor for tumor remission and radiation-induced hypopituitarism (96, 97). BED is defined as a dosimetric parameter that incorporates correction factors for both the slow and fast components of DNA repair which is activated by neoplasm during the radiotherapy (98). A shorter treatment time allows less opportunity for DNA repair and more efficient therapy. This dosimetric variable may be used for optimization of radiotherapy planning, rather than mean pituitary gland dose, for increased rate of remission and reduced rate of radiation-induced hypopituitarism. It was shown that BED above 45 Gy_2.47 was associated with a 14-fold increase in risk of hypopituitarism, while mean pituitary gland dose above 10 Gy was associated with a 12-fold increase in risk of hypopituitarism (97).

A study with long-term endocrine and radiographic follow-up of patients with acromegaly or Cushing’s disease treated with gamma knife radiosurgery showed more than a half of patients (58.3%) had new pituitary deficiencies after the median time of 61 months (range 12-160) (99). GH deficiency was the most common deficiency (28.3%) and the rate of hypopituitarism gradually increased with time of follow up (10% at 3 years, 21.7% after 5 years and 53.3% at 10 years of follow-up) (99). Recently published study of gamma knife radiosurgery for acromegaly showed lower incidence (29%) of post-radiotherapy hypopituitarism at a median 29.5 months (range 6-143 months) (97). This rate of radiotherapy-induced hypopituitarism in patients with acromegaly after stereotactic radiosurgery is lower compared with fractionated radiotherapy (100). Another study showed the that 19.6% of patients with acromegaly and Cushing´s disease developed radiation-induced hypopituitarism after a median follow-up time of 39 months (range 6-106 months) and the median margin dose of 30Gy (range 16-35 Gy) (101). In this study, the most common pituitary axis deficiency was hypothyroidism, in combination with other deficiencies - hypogonadism and growth hormone deficiency (in patients with Cushing´s disease), or hypocorticism (in patients with acromegaly) (101).

Gamma knife radiosurgery is also an option in patients with medically and surgically refractory prolactinomas, in whom hypopituitarism was reported in 30.3% of patients after median follow-up od 42 months (range 6-207.9) (90). Also, gamma knife radiosurgery may be the initial option for elderly patients with nonfunctioning pituitary adenoma (102). New-onset hypopituitarism was reported in 19.4% of these patients after the median time of 23.1 months.

Some predictors of hypopituitarism following gamma knife stereotactic radiosurgery have been identified and include margin dose to the tumor, supra-sellar extension, the radiation dose to the distal infundibulum (maximum safe dose of 17 Gy), cavernous sinus invasion of the tumor, male sex, smaller pituitary gland volume, tumor volume, mean gland dose, biological effective dose and the amount of healthy tissue within the high dose region (87, 89, 94-96, 99-104). Data referring to the development of hypopituitarism related to gamma knife radiosurgery shows that keeping the mean radiation dose to the pituitary under 15 Gy and the dose to the distal infundibulum under 17 Gy may prevent the development of radiation-induced hypopituitarism (103). Decompression of pituitary gland by surgical resection and dose reduction in pituitary gland may reduce the rate of new hypopituitarism after gamma knife radiosurgery for patients with pituitary adenoma (93).

Gamma knife radiosurgery might be a precipitating factor of new or worsened pituitary hemorrhage (95, 105). Pituitary apoplexy (clinical and subclinical) is not a rare phenomenon and could compromise the results of gamma knife radiosurgery. The mechanism of pituitary apoplexy after radiation may include vascular changes and chronic hypo-perfusion of the pituitary gland, associated with tumor infarction, necrosis and hemorrhage. In a study which investigated the incidence, risk factors and prognosis of pituitary hemorrhage in pituitary adenomas treated with gamma knife radiosurgery, 7.3% patients developed new or worsened pituitary hemorrhage after median time of 18.9 months following radiotherapy (range 3.1-70.7 months) (105). Some of these patients developed new hypopituitarism. Nonfunctioning pituitary adenoma was independent risk factor of new or worsened pituitary hemorrhage after gamma knife radiosurgery and some of patients received surgical resection for clinical pituitary apoplexy (105). On the other hand, tumor shrinkage might be accelerated by hemorrhage due to radiotherapy. Pituitary tumor volume (above 10cm³) was significantly associated with new apoplexy after gamma knife radiosurgery (95).

Fractionated Stereotactic Radiotherapy

Stereotactic radiosurgery is a convenient radio-therapeutic approach for patients with small either secreting or nonfunctioning pituitary tumors, but caution should be used in patients with moderate or large-sized tumors (>3 cm) in close proximity to critical structures (optic chiasm and brainstem). For these patients, fractionated stereotactic radiotherapy (FSRT) may be a safer treatment option because of advantages of dose fractionation. This therapy is used at doses of 45-54Gy delivered in 25-30 daily fractions in patients with pituitary adenomas. In a study on the efficacy and safety of FRST in patients with large and invasive nonfunctioning pituitary tumors, the incidence of new anterior pituitary deficits was 40% at 5 years and 72% at 10 years, while no other radiation-induced complications occurred (106). Meta-analysis with more than 600 patients with pituitary adenomas showed that both stereotactic radiosurgery and fractionated stereotactic radiotherapy have comparable efficacy and safety (107). A recently published meta-analysis of 10 studies analyzed effects of fractionated stereotactic radiotherapy of 256 craniopharyngioma patients and found the new-onset hypopituitarism in 5% of cases (108).

In patients with tumors located near the optic structures, hypo-fractionated radiotherapy may be used, because of lower toxicity for the optic nerves compared with single-dose radiosurgery. Cyber knife uses a linear accelerator mounted on a mobile robotic arm and an image-guided robotic system and it delivers a radiation in 1 or few (2-5) sessions (hypo-fractionated SRS). The patient is immobilized with a thermoplastic masc. Recently published study analyzed 31 acromegaly patients treated with Cyber Knife stereotactic hypo-fractionated radiotherapy after 62 months of follow-up and reported endocrine remission in 86.7% of patients, with 22.4% cured disease rate at five years (109). Hypopituitarism was reported in 32.3% patients and no cases of radiation-induced optic neuropathy were reported.

Proton Radiotherapy

Pediatric diencephalic tumors, such as optic pathway/hypothalamic glioma, craniopharyngioma, germ cell tumors, Langerhans cell histiocytosis, and pituitary adenomas, have excellent survival outcomes and the focus in therapy has shifted toward methods which may reduce long-term morbidity and mortality (110, 111). One of the possibilities is the use of proton radiotherapy, as the preferred choice for children with diencephalic tumors, especially craniopharyngioma, low grade glioma and optic pathway glioma (110, 112).

Proton radiotherapy is the conformal technique used for certain types of cancer and lymphomas, with precise delivery of radiation to a tumor and decreased radiation dose to normal brain because of lower entrance dose and elimination of exit dose compared with photon beams. Less normal brain is irradiated at low or intermediate doses, and this could decrease the risk of late effects of radiation, such as endocrinopathy, second malignancy, or neurocognitive deficits (113). After the calculation of the expected costs and effectiveness regarding growth hormone deficiency for a specific mean radiation dose to the hypothalamus, it has been demonstrated that proton radiotherapy may be more cost effective (compared with photon radiotherapy) for children in which radiation dose to the hypothalamus can be spared, for tumors not originating in or not directly involving the hypothalamus (114). Initial studies suggest lower rates of endocrine complications in children treated with proton radiation for medulloblastoma and low-grade glioma, with increased sparing of normal tissues (115, 116). The comparison between photon radiotherapy and proton radiotherapy for medulloblastoma showed that newer proton radiotherapy may reduce the risk of some radiation-associated endocrine complications (hypothyroidism and gonadotropin deficiency), but not all complications (the incidence of GH and ACTH deficiency, or precocious puberty was not changed) (116, 117). In a study of 118 patients with medulloblastoma (the mean age at diagnosis was 7.6 years, followed for a median of 5.6 years after the radiotherapy) 66% of patients developed growth hormone deficiency, 31% developed hypothyroidism, and 18% developed adrenal insufficiency (117). Primary hypothyroidism occurred less often after proton cranio-spinal radiotherapy (6%) compared to photon cranio-spinal radiotherapy (28%), while central hypothyroidism, growth hormone deficiency and adrenal insufficiency incidence rates were similar between the groups (117).

It seems that proton conformal radiotherapy has advantages over conventional photon therapy for children with gliomas. Depending on the tumor location, it can spare the hypothalamic-pituitary axis. There was only 1 patient with endocrinopathy in the 14 irradiated children in the low (radiation dose less than 12 Gy) or intermediate endocrine risk groups (radiation dose 12-40Gy) (115).

A study on the effects of proton radiotherapy in a large group of 189 pediatric and young adult patients treated for brain tumors showed that the rate of any pituitary hormone deficiency at four years was 48.8% (118). The incidence of hormone deficiencies was strongly associated with the dose of radiation and the age at time of treatment, with children being especially sensitive. The most frequent endocrine disorders according to the level of irradiation (< 20 Gy, 20-40 Gy, and 40 Gy) were as follows: GH deficiency (9%, 40%, and 79%), followed by TSH deficiency (4%, 25%, and 43%), ACTH deficiency (4%, 4%, and 18%), and gonadotropin deficiency (0%, 3%, and 14%) (118).

Children with brain tumors treated with combined conventional plus proton beam radiotherapy received a higher radiation dose and developed neuroendocrine dysfunction sooner (47% of patients after mean time of 0.33 year), compared with children treating with proton beam radiotherapy only (33% of patients after mean time of 1.17 years) (119).

In the future the late consequences of new radiation techniques should be more completely defined. Further studies are needed to investigate longer-term side effects of proton radiotherapy and confirm whether this technique of radiation and lower radiation doses with proton radiotherapy will change the risk for neuroendocrine dysfunction and secondary malignancy.

New Planning and Dose Delivery Techniques

Cranial radiotherapy has evolved with the development of new planning and dose delivery techniques of photons (intensity-modulated radiotherapy, volumetric-modulated arc radiotherapy) and proton beam radiotherapy (16, 120). These new planning and dose delivery techniques allow increasingly precise delivery of irradiation with reduction of the dose to surrounding neurovascular and brain structures, especially hypothalamic-pituitary axis and hippocampus (34, 120-122). Modern techniques of intensity-modulated proton therapy are able to produce acceptable cranio-spinal irradiation plans, avoid important intracranial structures (hypothalamus, pituitary and hippocampus receive 50% reduced dose of irradiation) and improve patient quality of life (122).

Patients with somatotroph adenoma that had not achieved complete remission after surgery and medical therapy, treated with fractionated intensity-modulated radiotherapy, developed hypopituitarism in 28.3% of cases, after the median follow-up time of 36 months (range, 6-105.5 months), similar to stereotactic radiosurgery (121). In this study, only age below 33 years was a significant predictor of radiation-induced hypopituitarism.

Modern radiotherapeutic technique such as volumetric-modulated arc therapy, with a sparing approach of both hippocampus and hypothalamus-pituitary axis might be a promising option for the patients undergoing whole-brain radiotherapy (50). The aim of this approach is to reduce dose application to these brain areas and to reduce common side effects (cognitive impairment and neuroendocrine dysfunction). A combined sparing approach involving both hippocampus and hypothalamo-pituitary axis using volumetric modulated arc therapy allows simultaneous dose reduction (less than 50% of the prescribed dose to the target) to these functional brain areas without compromised target coverage (50). Even in patients with brain metastasis requiring whole brain radiotherapy (WBRT), protection of the hypothalamo-pituitary axis during WBRT may be unlikely to compromise the tumor recurrence rate, because the rarity of brain metastasis in the hypothalamo-pituitary area (123).

The selection of the radio-therapeutic method is based on the tumor size, distance from the optic structures and local invasion (124). SRS is reserved for tumors less than 3cm or small remnants in the cavernous sinus, located more than 3-5 mm away from the optic structures and the dose to the optic chiasm should not exceed 8 Gy. Fractionated radio-therapeutic methods are used for large pituitary tumors, or those which invade the optic nerves. Hypo-fractionated SRS (in 2-5 sessions) has been used for perioptic tumors.

New radiation technology including intensity-modulated proton therapy (IMPT), proton-based stereotactic radiosurgery, and FLASH-proton therapy (delivery of very high doses of radiation in fractions of a second), may provide in the future efficient control of the primary tumor with decrease of long-term complications (110). Prospective studies on endocrine and neurologic outcome are required to establish the long-term morbidity, neuroendocrine and cognitive sequelae.

Strategies for Precise Radioprotection

It is still a challenge how to protect the normal tissue from radiation-induced damage. There are studies on several agents which could protect the normal cells from radiation-induced damage with no affecting the radiation-induced killing of the tumor cells (memantine hydrochloride, amifosine, antioxidants). Recently published study on MitoQ, a mitochondria-targeted antioxidant, showed a good neuro-protective effect of this antioxidant in preclinical studies (125). MitoQ is absorbed to the inner mitochondrial membrane, affects mitochondrial respiration and induces selective protective autophagy among radiated normal cells (125). Tumor cells rely on aerobic glycolysis, mitochondria-independent energy supply pathway and are not protected due to the absence of autophagy.

SCREENING FOR NEUROENDOCRINE DYSFUNCTION FOLLOWING CRANIAL RADIOTHERAPY

Recently, recommendations for screening for hypopituitarism after cranial radiotherapy were suggested (13, 63, 112, 126, 127). According to this approach, clinical evaluation, baseline pituitary hormone assessment, and dynamic testing for GH and ACTH deficiency should begin one year after cranial radiotherapy (Table 5). Clinical examination of children (including linear growth and pubertal staging) should be done every 6 to 12 months until final height is attained, and then yearly thereafter (13, 63). In patients at risk for central precocious puberty, pubertal development should be monitored every 6 months until age 9 years in girls and 10 years in boys (13).

If results of the assessment are normal, reassessment should be done every 2-4 years until at least 10 years following radiation. GH testing should be done only in patients who are good candidates for GH replacement therapy (keeping in mind the safety in underlying malignancy). It is also recommended to perform an endocrine assessment at 1 year after radiotherapy in patients treated for non-pituitary intracranial neoplasms, since they also may develop hypothalamic-pituitary dysfunctions (128).

Table 5. Screening for Hypothalamic-Pituitary Dysfunction
DYSFUNCTION	Clinical data	Basal analysis	Dynamic test
GH deficiency	Growth velocity (children)	IGF-I	ITT, glucagon, clonidine (children)
FSH/LH deficiency	Pubertal staging	FSH, LH, estradiol (female), testosterone (male)	GnRH
TSH deficiency	Clinical examination	TSH, FT4	TRH
ACTH deficiency	Clinical examination	Cortisol	ITT, Synacthen
Hyperprolactinemia		PRL
Precocious puberty	Pubertal stage	FSH, LH, estradiol (female), testosterone (male)

Somatotroph Axis

Two stimulation tests for estimating GH secretion are required in the case of isolated GHD, while in patients with multiple pituitary hormone deficiencies there is no need for formal testing to establish a diagnosis of GH deficiency. Interpretation of results for the GH stimulatory tests following cranial radiation may be complicated because of the different mechanisms governing GH release during the gold standard, the insulin tolerance test (ITT), and other tests (arginine+GHRH and GHRH+GHRP-6 test in the past). In some cases, the results of different GH stimulatory tests may be discordant (75, 129, 130). The hypothalamus is more sensitive to radiation-induced injury compared with pituitary. Provocative tests which directly stimulate the somatotrophs (GHRH) may give false negative results in the early years after radiotherapy (131). Failing to pass the hypoglycemia test (ITT) is more common after radiation than to other stimulatory tests but may not necessarily reflect GH deficiency (132-135). It has been suggested that lower radiation doses (<40 Gy) predominantly cause hypothalamic damage with GHRH deficiency and subsequent somatotroph atrophy. In cases with robust response to ITT it is suggested to repeat screening at four years, while in cases with borderline response to this test, it should be repeated at two years (126).

IGF-1 levels may be useful in screening for severe GH deficiency in children and adults (63). However, in childhood cancer survivors exposed to cranial radiotherapy, it is recommended against relying solely on serum IGF-I levels to make the diagnosis of GH deficiency (52, 60, 63, 136). Recently published study of 41 survivors of childhood brain tumors treated with proton and photon irradiation and followed for 14.8 years showed low diagnostic value of IGF-1 and high prevalence of undiagnosed GH deficiency (50%) (60). Meta analysis of 15 studies with 477 childhood cancer survivors showed the same diagnostic accuracy of various dynamic tests (ITT, GHRH, GHRH plus arginine, levodopa, clonidine) for GH deficiency in childhood cancer survivors as in other causes of GH deficiency (52).

In children with growth failure, risk factors and comorbidities, in which the GH stimulatory test may be uncomfortable, an evidence-based prediction model to diagnose GH deficiency was proposed (137). In the large cohort of 770 children the authors identified clinically relevant risk factors for GH deficiency (among them cranial radiotherapy ≥18 Gy), to build a clinical prediction model for GH deficiency, a mathematical and machine-learning approach to avoid GH stimulatory testing in children with growth failure and comorbidities (137). The specificity of their prediction rule for GH deficiency without need for pharmacological stimulation tests in children with risk factors was 99.2%.

Hypothalamic-Pituitary-Gonadal Axis

Low radiation dose (˂ 18Gy) in pre-pubertal children may cause premature activation of hypothalamic-pituitary-gonadal axis leading to central precocious puberty, mostly in girls, due to loss of neurons with inhibitory γ-aminobutyric acid (30, 31, 81, 138, 139). Higher radiation doses may cause central hypogonadism with a cumulative incidence of 20-50% on long-term follow-up (4, 28, 44, 47, 77, 78, 83). Gonadotroph deficiency is defined as low or normal gonadotropin levels and low plasma testosterone in men and amenorrhea with low plasma estradiol in premenopausal women (˂50 years old).

Hyperprolactinemia

Hyperprolactinemia may develop after cranial radiotherapy in 20-50% of patients and indicates hypothalamic damage and reduced inhibitory dopamine activity (4, 30, 31, 134). Elevated prolactin level is mostly seen in young females after high dose cranial irradiation (> 50Gy) (13, 44, 47, 77, 78, 140). Elevated prolactin levels may be asymptomatic, without clinical significance or may cause central hypogonadism (78). Elevated prolactin levels may decline and normalize during follow-up due to radiation-induced reduction of the pituitary lactotroph cells (28).

Hypothalamic-Pituitary-Adrenal Axis and Hypothalamic-Pituitary-Thyroid Axis

The hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-thyroid axis are more radioresistant than the GH and gonadotropin axes. Corticotroph deficiency is defined as low morning serum cortisol (normal range for morning serum cortisol, 7– 25 mg/dl; for evening serum cortisol, 2–14 mg/dl) and a normal or low serum ACTH level. Thyrotroph deficiency is based on a low free T4 with normal or decreased TSH. ACTH and TSH deficiency may occur after a large dose of cranial radiation (>50 Gy) used for nasopharyngeal cancer and skull base tumor, in 30-60% of patients after long-term follow-up (4, 28, 30, 31, 47, 77, 80). Central hypocorticism and hypothyroidism may be subclinical and diagnosed by stimulatory tests (ITT, glucagon, Synacthen test and TRH test).

OTHER CHRONIC COMPLICATIONS OF CRANIAL IRRADIATION

Cerebrovascular Insult (Stroke)

The large Dutch study which included 806 patients with nonfunctioning pituitary adenomas (456 treated with cranial radiotherapy) reported the increased incidence of cerebrovascular events in men treated with cranial radiotherapy (hazard ratio 2.99, 95% CI 1.31-6.79) (20).

Radiation-Induced Ocular Complications

Radiation-induced ocular complications include cataract, dry eye syndrome, corneal erosions, perforations and scarring, as well as radiation retinopathy, neuropathy and neo-vascular glaucoma (141). The use of fractionated robotic radiotherapy (Cyber Knife system) on benign para-sellar tumor located close to the optic pathway is safe and does not impair the structure and function of the anterior and posterior segments of the eye during the 24-month observation (142). Only the thinning of the retinal nerve fiber layer (RNFL) was described, but it did not impair visual function and it did not correlate with the dose delivered to the optic pathway. Single doses lower than 8–10 Gy are considered safe in patients undergoing single and multi-fraction stereotactic radiotherapy (143). The dose per fraction received seems to be the most important factor and should not exceed 1.9 Gy.

Second CNS Tumor

The occurrence of a second intracranial neoplasm is a rare complication after radiotherapy, including the development of radiation-associated intracranial neoplasm and malignant transformation of a benign lesion (22, 23, 144, 145). Tumors such as meningioma, glioma or sarcoma are the most prevalent secondary neoplasms after cranial irradiation. The systematic review of 21 studies in children and adults who received cranial radiation for prophylactic or therapeutic purposes showed a 7-10-fold increase in subsequent CNS tumors in children, with a latency period ranging from 5.5 to 30 years (glioma developed 5-10 years and meningioma around 15 years after radiation) (22). Additional investigation is needed on the risk of radiation-induced secondary tumors in adults, because some studies showed no increased risk, while other studies reported a higher risk for secondary CNS tumors with a latency period from 5 to 34 years (22). A large study that included 8917 patients from the Pfizer International Metabolic Database (KIMS) reported an increased incidence for de novo brain tumors in patients treated for pituitary/sellar lesions (23). The risk of developing a malignant brain tumor increased by 2-4-fold and meningioma by 1.6-fold with every 10 years of younger age at radiotherapy, irrespectively of the type of radiotherapy (conventional vs stereotactic) (23).

Recently published retrospective, multicenter study of 3679 patients with long-term follow-up after radiotherapy (recipients of proton beam or stereotactic radiotherapy were excluded) for pituitary adenoma and craniopharyngioma reported the cumulative probability of second brain tumor of 0.9% after 10-years follow-up and 4% after 20-year follow-up (146). Medial latency period for secondary malignant tumor (glioblastoma, astrocytoma) was 8.3 years, and for secondary benign tumor (meningioma, acoustic neuroma, neurocytoma, low-grade glioma) was 17.7 years. The authors reported that older age at pituitary tumor detection was a predictor of developing a second brain tumor. Patients with second malignancy in the region of previous radiotherapy often present with aggressive clinical course and disease resistant to various treatment modalities several years after radiotherapy (145). Sarcoma of the sellar region is a rare malignant complication after radiotherapy of the pituitary tumor. In a systematic review of 94 sarcoma of the sellar region, one third was associated with radiotherapy and developed after median time of 10.5 years and mean radiation dose 47.5 ± 5.05 Gy (147). Ionizing radiation is a known risk factor for sarcomatous transformation of fibrous dysplasia of the bone in patients with McCune-Albright syndrome.

It is important to differentiate correctly radionecrotic lesion on contrast MRI from brain neoplasia (148). Brain radionecrosis is a neuronal death, vascular endothelial damage and demyelination lesions after high-dose radiotherapy and it can be differentiated from a tumor by molecular imaging techniques (18-FDG PET/CT, 11C-acetate PET/CT) (148).

There are some data that the risk for secondary malignancy is lower with stereotactic radiosurgery, in comparison with conventional radiotherapy (144). A large multicenter study of 4905 patients with gamma knife radiosurgery for arteriovenous malformation, trigeminal neuralgia, or benign intracranial tumors (including pituitary adenomas) reported the overall incidence of 6.8 per 100 000 patients-years, or a cumulative incidence of 0.00045% over 10 years, similar to the risk of developing a primary CNS tumor in the general population (144). Long-term follow-up for patients treated with new radiation techniques (stereotactic radiosurgery and proton beam therapy) are needed.

CONCLUSION

Hypothalamic-pituitary dysfunction is among the most common late effect of cranial radiotherapy. Radiation causes irreversible and progressive damage to the hypothalamic-pituitary region. The pathophysiology of the radiation-induced damage includes direct neuronal and vascular injury and fibrosis. The incidence and severity of hypopituitarism correlate with the total radiation dose delivered to the hypothalamic-pituitary region, the fraction size, the time between fractions, and the duration of follow-up. Periodical life-long endocrine assessment is recommended in all long-term survivors of childhood or adulthood tumors who were treated with cranial radiotherapy or with total body irradiation. With newer radiation techniques the dose and volume of normal tissue irradiated are reduced. Further analysis of new radiation techniques (stereotactic radiosurgery and proton beam therapy) and long-term hypothalamic-pituitary dysfunctions are needed.

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Pituitary Diseases in the Tropics

ABSTRACT

The pituitary gland is the master controller of the hormonal axes in the body and modulates its hormonal output based on the information received from the hypothalamus and the peripheral target organs. The traditional feedback hormonal loop involving the central and peripheral organs is termed the hypothalamo-pituitary-target organ axis. Pituitary disorders may present either due to the structural or hormonal manifestations. Pituitary disorders often have a long gestation period before their clinical identification. The commonest pituitary disorders include functional and non-functional adenomas and hypopituitarism. In this chapter, we shall discuss the pituitary disorders encountered in the tropical countries along with their unique features and management.

INTRODUCTION

The pituitary gland is the fulcrum of the entire hormonal axes in the human body and is located in the sella turcica of the temporal bone. The pituitary gland is divided into anterior and posterior portions connected by an intermediary lobe. The anterior pituitary secretes growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotrophic hormone (ACTH), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin. Vasopressin and oxytocin are the two hormones released from the posterior pituitary. The common pituitary disorders in endocrine practice include prolactinoma, acromegaly, Cushing’s disease, non-functional pituitary adenoma (NFPA), and hypopituitarism. Hypopituitarism denotes either complete or partial deficiency of pituitary hormones. The etiologies that lead to hypopituitarism are classified as congenital, neoplastic, and inflammatory diseases (1). Pituitary dysfunction in tropical countries is observed due to specific etiologies as shown in table 1. In the subsequent sections, we shall discuss the individual disorders.

Table 1. Pituitary Diseases of the Tropics

Gynecological- Sheehan’s syndrome, Pseudocyesis

Environmental- Snake envenomation, Heat stroke, Traumatic brain injury

Infections- Tuberculosis, Toxoplasmosis, Pneumocystis, Cytomegalovirus, Aspergillosis, Candida

Miscellaneous- Hemochromatosis, Steroid abuse

SHEEHAN’S SYNDROME

Harold Sheehan described this syndrome in 1937 as post-partum pituitary necrosis (2). It is a common cause of pituitary insufficiency in tropical countries where obstetric care is not well advanced. In a study from India, the prevalence of Sheehan’s syndrome (SS) is reported to be 3% in women above 20 years of age and according to this study two third of SS patients had undergone home delivery (3). This might be a tip of the iceberg as the majority of cases go unrecognized because of the long lag period between the primary insult and clinical presentation and the significant number of unreported home deliveries (4). Post-partum hemorrhage (PPH) is the initiating event which triggers the cascade of pituitary necrosis as shown in the figure 1.

Figure 1. Etiopathogenesis of Sheehan’s Syndrome

Pathogenesis

The pituitary is a highly vascularized organ and is very vulnerable to ischemic insults secondary to a fall in mean arterial pressure. PPH is the primary insult which leads to hypotension and compromised blood flow to pituitary, leading to irreversible necrosis and deficiencies of various pituitary hormones. The pituitary gland increases in size during pregnancy and its location inside the sellar compartment makes it susceptible to ischemic insults. Other factors which aid in the progression of SS are disseminated intravascular coagulation, mutation in various coagulant factors like factor II and V, vasospasm, multiparity, advanced maternal age, and autoimmunity. Lactotrophs and somatotrophs are located laterally and are commonly affected in comparison to medially located corticotrophs and thyrotrophs (4). Anti-pituitary (APA) and anti-hypothalamus antibodies (AHA) are seen in patients with SS even many years after the primary insult. It is postulated that necrosed pituitary cells exposes various antigens to which these antibodies develop and subsequently leads to autoimmune damage (5). The various risk factors for the development of SS are summarized in the table 2.

Table 2. Predisposing Factors for Sheehan’s Syndrome

Anatomical

Physiological

Obstetrical

Miscellaneous

Small sella turcica

Pituitary enlargement

Coagulation disorders

Prothrombotic states

Vasospasm

Postpartum bleed

Home deliveries

Advanced age

Multiparity

Autoimmunity

Clinical Presentation

Patients with SS can have an acute, subacute, or chronic presentation and symptoms in SS are related to the underlying pituitary hormone deficiencies. Usually a lag period between the primary insult to first presentation is in the range of 7-19 years. However, SS may present as an acute catastrophic event immediately after delivery which can be associated with a high mortality. Acute SS may present as emergency in the form of myxedema coma, severe hyponatremia, adrenal crisis, and hypoglycemia coma. Failure of lactation, inability to resume menstrual cycles, and loss of secondary sexual characteristics in the background of PPH should raise suspicion of SS. Figure 2 summarizes various clinical features of SS. It is also important to understand that about 10% of patients with SS may remain asymptomatic and about 50% of patients may have nonspecific signs and symptoms eluding clinical diagnosis. Diabetes Insipidus is a rare phenomenon in SS. In chronic SS, clinical examination reveals the loss of axillary and pubic hair, breast atrophy, wrinkling around the eyes and mouth, and features of hypothyroidism (4).

Figure 2. Clinical Features of Sheehan’s Syndrome (SS)

In appropriate clinical settings, SS syndrome is diagnosed by detecting variable degrees of pituitary hormone deficiencies. Dynamic stimulation testing might be required for diagnosing SS. Hyponatremia is commonly seen in SS and its occurrence is explained by multiple factors like hypothyroidism, hypocortisolemia, and increased anti-diuretic hormone secretion as a result of decreased mean arterial pressure. On sellar imaging an empty sella is a hallmark finding in SS. Complete and partial empty sellars is seen in about 70-75% and 20 – 25% of patients with SS respectively. In acute SS, pituitary might be enlarged with features suggestive of necrosis on neuroimaging. Rarely, patients with SS can have a normal pituitary on imaging (6). Lymphocytic hypophysitis may present similarly and the differentiating features between the two conditions are summarized in table 3.

Table 3. Differences Between Sheehan’s Syndrome and Lymphocytic Hypophysitis
Sheehan’s syndrome	Lymphocytic hypophysitis
Women in postpartum period affected	Women, men, & children can be affected
Post-partum hemorrhage common hence seen in developing countries	Common in affluent nations
Lactation failure present	No lactation failure
Other autoimmune disorders not common	Can be associated with other autoimmune disorders
PRL, TSH, GH ACTH, FSH, LH are affected late	ACTH, TSH, PRL Normal GH, FSH, LH
DI rare	DI common
Empty sella on imaging	Enhancing pituitary mass may progress to empty sella, thick stalk

PRL, prolactin; TSH, thyroid stimulating hormone; GH, growth hormone; ACTH, adrenocorticotrophic hormone; FSH, follicular stimulating hormone; LH, luteinizing hormone; DI, diabetes insipidus

Management

In acute SS syndrome, intravenous glucocorticoids, thyroid hormone replacement, and fluid resuscitation constitutes the main treatment. It is important to keep in mind that thyroid hormone replacement should not be done without testing for the adequacy of the pituitary adrenal axis. Long term management is guided by diagnosing the specific endocrine deficits and replacement for these abnormalities. Besides glucocorticoid and thyroxine, the patient may require sex steroids, growth hormone, and desmopressin therapy. At appropriate intervals, patients should be screened for malignancies and bone health (7).

SNAKE ENVENOMATION AND PITUITARY DYSFUNCTION

The World Health Organization (WHO) has included snake bite in the priority list of neglected tropical diseases. About 85,000–138,000 deaths occur per year all over the world as a result of snake envenomation and more than 75 percent of these deaths happen in tropical countries. About 10 percent of people who survive snake envenomation develop pituitary dysfunction. Pituitary dysfunction is more common with vasculotoxic snakes like Russel’s viper (8). The exact prevalence of hypopituitarism following snake bite is not known because the majority of these bites occur in countries where the reporting system of snake bite is not robust. Somatotrophs and corticotrophs are frequently affected and patients may present in an acute or chronic stage with various signs and symptoms of hypopituitarism. Kidney injury and disseminated intravascular coagulation (DIC) are postulated to be predictors of hypopituitarism following snake bite. Pituitary imaging may show a spectrum of findings ranging between a completely normal pituitary to an empty sella (9).

Figure 3 illustrates the pathophysiology of hypopituitarism in snake bites. Vasculotoxic snake bites lead to a capillary leak syndrome which causes pituitary swelling and initiation of DIC. Increased capillary permeability also exposes various pituitary antigens and leads to the development of various antibodies which further damages pituitary cells. Vasculotoxic snake venom also has a direct stimulatory effect on pituitary cells and can result in damage. Circulatory collapse further leads to pituitary ischemia and finally hypopituitarism (10).

Figure 3. Pathogenesis of Hypopituitarism in Snake Bites

Hypopituitarism following snake bites can present as early as 24 hrs to as late as 24 years. Patients may present acutely with adrenal crisis or chronically with non-specific signs and symptoms. Deficiency of growth hormone and cortisol are common and central diabetes insipidus is rare after snake bite induced hypopituitarism (11). Appropriate hormonal replacement remains the mainstay of treatment.

POST TRAUMATIC PITUTARY DYSFUNCTION

In India it is reported that about 405 deaths and 1290 injuries happen as a result of road traffic accidents every day. Out of these accidents, two thirds occur in individuals between 15-44 years of age and a significant number of these patients are left with various disabilities (12). Post traumatic hypopituitarism is described after various injuries ranging from mild to severe or even with repeated injuries. Post traumatic hypopituitarism is believed to be responsible for about 7.2% of all causes of hypopituitarism and can develop after road traffic accidents, sports injuries, blast injuries, and other trauma. In the acute phase of post traumatic brain injury, pituitary dysfunction is seen in as high as two thirds of patients (13).

Events and pathogenesis of post traumatic hypopituitarism is described in figure 4. As described in the pathogenesis of SS, pituitary vasculature has a unique propensity for ischemic insult. Autoimmunity is also postulated to play a part in the pathogenesis of post traumatic hypopituitarism. It is believed that as a result of trauma there is disruptions of the blood brain barrier and there is exposure to various hypothalamic and pituitary antigens. Anti-pituitary antibodies and anti-hypothalamic antibodies have been demonstrated by various authors many years after the primary injury. It has also been reported that patients who does not have anti-pituitary antibodies have a higher chance of recovery of pituitary functions within 5 years (14). The role of varied expression of miRNA and the protective role of apolipoprotein E3 have also been described. Somatotrophs and gonadotrophs are first affected by ischemic damage and centrally located corticotrophs and thyrotropes are preserved (13).

Figure 4. Pathogenesis of Post Traumatic Hypopituitarism

The diagnosis of post traumatic hypopituitarism can be difficult because of the non-specific signs and symptoms, impaired cognition, and difficulty to carry out dynamic tests. Patients may have varied presentations like neuropsychiatric manifestations, dementia, altered body fat distribution, and altered metabolic profile. Neuroimaging may show brain contusions, skull fractures, diffuse axonal injuries, diffuse brain swelling, decreased pituitary volume, and even empty sella. Various authors have reported that diffuse brain swelling, skull fractures, axonal injury are predictors of post traumatic hypopituitarism (13). Appropriate hormonal replacement is the mainstay of treatment and pituitary functions revert back to normal within 5 years in a significant number of patients (15).

PITUITARY INFECTIONS

Pituitary infections are considered to be a rare in usual practice. However, in tropical countries it can pose a great challenge especially when there is no clinical suspicion. Of all the infections, mycobacterium tuberculosis is a frontrunner in causing pituitary dysfunction. Pituitary insufficiency is reported in children with tubercular meningitis and hyperprolactinemia and adrenal insufficiency was common abnormalities (16). There are a large number of people living with human immunodeficiency virus (HIV) and pituitary infections with cytomegalovirus and toxoplasma gondii can be seen in some of these patients. Immunocompromised patients can also develop pituitary abscesses and the posterior pituitary is commonly affected as it receives its blood supply directly from the systemic circulation. Aspergillus, candida albicans, and pneumocystis jiroveci are common organisms incriminated in pituitary abscesses. The endocrine abnormalities seen most often are DI, hyperprolactinemia, and hypogonadism. On neuroimaging a pituitary abscess may present as parasellar mass (17). Tertiary syphilis can rarely infect the pituitary. The infected pituitary can develop pituitary dysfunction as result of chronic ischemia which leads to necrosis (1).

MISCELLANEOUS CONDITIONS

Pseudocyesis describes a clinical condition in which a woman who is not pregnant, presents with a strong conviction of being pregnant along with the associated signs and symptoms mimicking a true pregnancy state. Though pseudocyesis has been recognized since antiquity, the hormonal changes have been studied in the recent decades. The disease is rarely reported in developed countries but is fairly common in tropical countries, especially Africa, where childbearing is considered as essential for women to live with respect. A notable example of this condition was Mary Tudor, the first queen of England, who believed that God did not bless her with a child because of the harsh punishments given by her to the protestants. In this disorder women of child bearing age develops raised prolactin and LH levels (16). Quack therapies are commonly practiced in tropical countries and steroids are the main constituents of such forms of therapies which leads to suppression of the hypothalamic pituitary axis (18). Heat injuries are common in tropical countries and pituitary dysfunction has been reported in heat related injuries. Heat stress is considered to damage somatotrophs and corticotrophs (19). Hemochromatosis is a condition with excess deposition of iron in tissues leading to functional consequences. Hypopituitarism has been reported frequently in patients with hemochromatosis and this is often exaggerated in tropical countries due to poor chelation therapy (20).

CONCLUSION

Pituitary disorders in the tropics have certain unique etiologies that include Sheehan’s syndrome, snake-bite, and certain infectious disorders. A high index of clinical suspicion is required to identify the underlying condition in the absence of typical clinical features. The evaluation and management of the hypopituitarism is akin to other etiologies. Improved obstetric care has resulted in a reduced prevalence of Sheehan’s syndrome. Close monitoring and lifelong hormone replacement therapy as deemed necessary are the cornerstones of the therapy to reduce the associated morbidity and mortality.

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