ABSTRACT

 

Diabetes mellitus is a strong, independent risk factor for the development of atherosclerotic cardiovascular disease (ASCVD) and therefore for atherothrombotic events. Compared to those without diabetes, individuals with diabetes are also at increased risk of cardioembolic stroke in the presence of atrial fibrillation (AF) and of venous thromboembolism. Activation of platelets and the coagulation cascade are the central mechanisms of thrombosis. A range of antiplatelet and anticoagulant drugs are now available. Antithrombotic therapy should be considered in all those with diabetes and established ASCVD or AF. Intensification of antithrombotic therapy is typically indicated during the acute phase of an atherothrombotic event or in those with chronic coronary syndromes who are at high ischemic risk, provided this outweighs bleeding risk. Clinical decisions regarding antithrombotic therapy should be made by assessing an individual’s ischemic and bleeding risks, in consultation with the recipient and reviewed upon any change in circumstances.

 

LIST OF ABBREVIATIONS

 

5HT	5-hydroxytryptamine
ACS	acute coronary syndrome
ADP	adenosine diphosphate
AF	atrial fibrillation
ALI	acute limb ischemia
APT	antiplatelet therapy
ASCVD	atherosclerotic cardiovascular disease
ATP	adenosine triphosphate
ATT	antithrombotic therapy
CAD	coronary artery disease
CCS	chronic coronary syndromes
CI	confidence interval
COX	cyclo-oxygenase
DAPT	dual antiplatelet therapy
DATT	dual antithrombotic therapy
DM	diabetes mellitus
DVT	deep vein thrombosis
GP	glycoprotein
HR	hazard ratio
LEAD	lower extremity artery disease
MACE	major adverse cardiovascular event
MI	myocardial infarction
miR	microribonucleic acid
NOAC	non-vitamin K antagonist oral anticoagulant
OAC	oral anticoagulant
PAD	peripheral artery disease
PAR	protease-activated receptor
PCI	percutaneous coronary intervention
PGI2	prostacyclin
RCTs	randomized controlled trials
RRR	relative risk reduction
SAPT	single antiplatelet therapy
TIMI	thrombolysis in myocardial infarction
TP	thromboprostanoid
TXA2	thromboxane A2
UA	unstable angina
VKA	vitamin K antagonist
vWF	von Willebrand factor

 

INTRODUCTION

 

Despite a century of advances in understanding and management of diabetes mellitus (DM), it continues to increase in prevalence and, furthermore, remains an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), leading to a significant burden of premature mortality and morbidity (1).

 

ASCVD includes a spectrum of clinical syndromes. This can include acute presentations such as acute coronary syndromes (ACS, including myocardial infarction [MI] or unstable angina [UA]), thrombotic stroke, or acute limb ischemia (ALI) (Figure 1). Similarly, ASCVD can lead to chronic conditions such as chronic coronary syndromes (CCS, for example those with stable angina or a history of MI >1 year previously) or chronic lower extremity arterial disease (LEAD) (2).

 

Most acute events in ASCVD are caused by thrombosis. The hemostatic response has an important physiological role in the response to trauma but, if it becomes activated inappropriately, thrombosis can be triggered (3). The clinical effects of thrombosis arise primarily from its location, such as in the coronary arteries leading to acute coronary syndrome (ACS, including myocardial infarction [MI] and unstable angina [UA]), cerebral arteries leading to thrombotic stroke, peripheral arteries leading to acute limb ischemia or deep limb veins leading to deep vein thrombosis (DVT). Alternatively, a thrombus formed at a site can embolize, leading to presentations such as acute pulmonary embolism (typically embolism of a DVT to the pulmonary arteries) or embolic stroke (typically left atrial thrombus to the cerebral arteries) (2,4). In addition to atherosclerotic diseases, individuals with DM who have atrial fibrillation are at higher risk of stroke, secondary to atrial thrombosis and subsequent cardioembolic events (5).

 

There are clear links between pathological processes associated with DM and those responsible for atherogenesis and thrombosis, including inflammation, platelet activation, and coagulation (6,7). Alongside control of glucose levels and optimization of other risk factors, such as dyslipidemia, hypertension, and smoking cessation, antithrombotic therapy (ATT), including antiplatelet therapy (APT) and oral anticoagulation (OAC), has become a key component of the treatment and prevention of atherothrombotic and cardioembolic events. ATT has evolved greatly in the last decades, both in terms of the range of drugs available but also our understanding of how best to deploy them (8).

 

Whilst ATT reduces thrombotic risk, in particular reducing the composite of major adverse cardiovascular events (MACE, typically defined as cardiovascular death, stroke or MI), it also leads to an increased risk of bleeding. Balancing these risks is central to interpretation of clinical trial data and development of treatment recommendations, including in those with DM (9).

 

In this chapter, we will review the underlying pathophysiological mechanisms of thrombosis and the pharmacology of commonly prescribed drugs during ATT. With specific reference to individuals with DM, we will appraise evidence for ATT in a broad range of clinical settings, highlighting current treatment recommendations and particular areas in which more data are needed.

THE THROMBOTIC RESPONSE AND ITS PHARMACOLOGY

 

As described in Virchow’s triad, prothrombotic changes in the blood flow, constituents and/or vessel wall can trigger thrombosis (10). Broadly, thrombosis involves the activation of platelets and the coagulation cascade (Figure 2). Understanding these processes provides insights into how pharmacological modulation may improve ischemic risk and increase bleeding risk as well as how the individual components of combination ATT interact, including in those with DM.

 

Platelet Activation

 

Platelet activation typically occurs upon endothelial injury and atherosclerotic plaque rupture or erosion, resulting in exposure of blood constituents to prothrombotic substances such as collagen. Collagen exposure leads to platelets adhering to the vessel wall via the glycoprotein (GP) Ia receptor and activation via GPVI (11,12). GPIb forms a complex with clotting factors IX, V and von Willebrand Factor (vWF), strengthening adhesion (13).

 

Platelet activation involves several key processes. Alterations in the cytoskeleton lead to shape change with the formation of filopodia, which increase surface area to volume ratio and may facilitate mechanical adhesion to the vessel wall, other platelets and fibrin strands (14). Platelet activation also involves the release of arachidonic acid from the cell membrane, which is then locally converted to thromboxane A₂ (TXA₂) by cyclo-oxygenase (COX) 1 and TXA₂synthase. TXA₂, via the platelet TP-α receptor, contributes further to platelet activation (15). Aspirin (acetylsalicylic acid) irreversibly inhibits COX1, thereby blocking the downstream release of TXA₂ for the platelet’s lifespan (around 8-10 days in healthy individuals) as, unlike nucleated cells, platelets cannot regenerate the enzyme (8). Endothelial COX1 and 2 generate the antiplatelet and vasodilatory substance prostacyclin (PGI₂). The facts that aspirin is short-lived in the systemic circulation, that platelets are exposed to higher levels of aspirin than endothelium, due to travel through the portal circulation, and that aspirin has relative selectivity for COX1 over COX2 leads to aspirin’s net antiplatelet effect at low doses (16).

 

Platelets also undergo degranulation on activation; a granules contain procoagulant and proinflammatory factors, including platelet P-selectin (also known as CD62P), the surface expression of which is therefore increased. P-selectin mediates platelet-leukocyte aggregation and therefore contributes to an associated inflammatory response (17). Dense granules contain adenosine triphosphate (ATP), adenosine diphosphate (ADP) and 5-hydroxytryptamine (5HT, also known as serotonin). In particular, ADP stimulates platelet activation via P2Y₁ and, most significantly, P2Y₁₂ receptors (18,19).

 

Stimulation of the P2Y₁₂ receptor leads to central amplification of the response to a range of agonists and contributes significantly to activation of platelet surface GPIIb/IIIa receptors, the final pathway of platelet aggregation (20). Via vWF and fibrinogen bridges, GPIIb/IIIa mediates platelet-platelet interaction (21).

Several oral platelet P2Y₁₂ receptor antagonists (‘P2Y₁₂ inhibitors’) are currently available (23). Clopidogrel and prasugrel are irreversibly-binding thienopyridines (8). As pro-drugs, they require hepatic metabolism to be activated. In the case of prasugrel this pathway is reliable, whereas there is interindividual variation in the metabolism of clopidogrel meaning around one-third of recipients have poor response when assessed using aggregometry (22). Ticagrelor is a reversibly-binding cyclopentyl-triazolopyrimidine that does not require metabolism to be active. Prasugrel or ticagrelor provide more potent and reliable platelet inhibition compared with clopidogrel (24).

 

Parenterally administered P2Y₁₂ inhibitors have also been developed. Cangrelor is a reversibly-binding ATP analogue that is potent and has rapid onset and offset (25). Selatogrel is a novel, parenterally-active, reversibly-binding P2Y₁₂ inhibitor formulated for subcutaneous administration, but has not yet completed phase III trials and is yet to be marketed (26).

 

Activation of the Coagulation Cascade

 

Although likely an oversimplification of the in vivo state, the coagulation cascade can be summarized as two key pathways made up of factors that converge on a final pathway (27).

 

Loss of endothelium leads to exposure of subendothelial extracellular matrix and contact activation of factor XII, triggering the chain of clotting factor activation known as the intrinsic pathway (28). Tissue factor, expressed on subendothelial cells and released in microparticles from atheromatous plaques, can activate factor IX when in a complex with factor VII: this is the extrinsic pathway (29).

 

Initiation of either pathway can lead to activation of factor X, which associates with activated factor V, calcium (released from damaged tissue) and phospholipids to form the prothrombinase complex (30). Prothrombin (II) is thus broken down to thrombin (IIa), which completes the process through cleavage of fibrinogen to fibrin, the latter being insoluble and forming strands. Tissue factor pathway inhibitor and antithrombin limit this response, but, as recruitment of activated platelets contributes to higher levels of thrombin generation, this endogenous inhibition is quickly overwhelmed (31). Once fibrin is formed, factor XIIIa, activated by thrombin, stabilizes the structure of clot by forming crosslinks between strands and by crosslinking anti-fibrinolytic proteins into the clot (32).

 

Fibrin is lysed by plasmin, a proteolytic enzyme that degrades into variously termed fragments (33). Plasmin is cleaved from its precursor, plasminogen, by tissue plasminogen activator, and is endogenously inhibited by antiplasmin.

 

A number of drugs target the coagulation cascade. During chronic administration, vitamin K antagonists (VKA) such as warfarin reduce the biological activity of prothrombotic vitamin-K-dependent factors (II, VII, IX, X) more than antithrombotic factors (e.g., proteins C and S) (34). Non-vitamin K antagonist oral anticoagulants (NOACs) include the Xa inhibitors apixaban, edoxaban and rivaroxaban and the thrombin inhibitor dabigatran (35).

 

Crosstalk Between Platelets and the Coagulation Cascade

 

Despite the fact that platelets and coagulation are often considered separately when discussing physiology and pharmacology, there is significant crosstalk between the two. Thrombin is generated upon activation of coagulation, and is able to stimulate platelet activation via action on protease-activated receptor (PAR) 1 and, at higher concentrations, PAR4 (36). Conversely platelets can contribute to thrombin generation, increasing coagulability, via scramblase activity that leads to greater surface expression of phosphatidylserine, supporting the assembly of prothrombinase complex on the activated platelet surface, which potentiates thrombin generation (37).

 

SPECIAL PATHOPHYSIOLOGICAL CONSIDERATIONS IN DIABETES

 

DM is an independent risk factor for atherothrombosis and also thrombosis after vascular interventions (38).  Individuals with DM have greater average atherosclerotic plaque burden than those without (39), and onset is at an earlier age (40). There is also some evidence that atherosclerosis in people with DM is more likely to involve distal vessels than those without DM (41). The reasons for this are not completely understood and are likely multifactorial, but a number of relevant pathological processes such as hyperglycemia, chronic inflammation, and oxidative stress are prominent in DM. These contribute to both endothelial injury/dysfunction and increased platelet reactivity, resulting in a prothrombotic milieu (42-44).

 

Platelet activation markers are enhanced in people with DM (45). Effects of hyperglycemia on platelets include increased expression of GPIba, GPIIb/IIIa, and P2Y₁₂, and reduced platelet membrane fluidity (46,47).Hyperglycemia-induced changes in intracellular magnesium and calcium signaling increase sensitivity of platelets to agonists such as ADP, epinephrine and thrombin (48). TXA₂ and F2-isoprostane synthesis is increased, the latter via oxidative stress, leading to increased TPa receptor stimulation (49). Reduced sensitivity to PGI₂, nitric oxide and insulin, which inhibit platelet activation, also contributes to hyper-reactivity (50,51).

 

Platelet turnover is accelerated in those with DM compared to those without (52). This increased activity in the creation and destruction of circulating platelets means a higher proportion of immature platelets, which are hyper-reactive, are present at any time (53). As well as increasing baseline platelet reactivity, the more frequent appearance of aspirin-naïve platelets in the circulation means more have uninhibited COX1 between doses (54).

 

There is also evidence that DM affects expression of platelet-associated microRNAs (miR-223, miR-26b, miR-126, miR-140), which play a role in the expression in a wide range of genes including those encoding the P2Y₁₂ receptor and P-selectin, though the significance of this remains to be fully established (55,56).

 

As well as platelet activation, DM may affect coagulation and fibrinolysis (57). Changes include increased levels of tissue factor, prothrombin, factor VII and fibrinogen leading to impaired anticoagulant and fibrinolytic activity (58). Increased levels of fibrinogen and its levels of glycation and oxidation lead to more compact, densely-packed fibrin networks and reduced fibrinolysis (59). Hyperglycemia inhibits the fibrinolytic activity of plasminogen through inducing qualitative changes (60). Fibrinolysis is further impaired by elevated levels of plasminogen activator inhibitor 1 and thrombin-activatable fibrinolysis inhibitor as well as incorporation into clot of complement C3 and plasmin inhibitor (59,61).

 

DM also appears to enhance the crosstalk between platelets and clotting factors, leading to tendency to more externalization of phosphatidylserine in the outer platelet membrane, promoting clotting factor assembly and tissue factor activation (62).

 

Finally, individuals with DM frequently have other metabolic conditions such as obesity, dyslipidemia, and increased systemic inflammation. These may interact with diabetes to further enhance platelet reactivity and impair fibrinolysis (59).

 

CURRENT EVIDENCE AND TREATMENT RECOMMENDATIONS FOR ANTITHROMBOTIC THERAPY IN DIABETES

 

The Need for Therapeutic Oral Anticoagulation

 

Broadly, when considering the need for antithrombotic therapy (ATT), including in people with DM, it is helpful to make first a distinction between those with an indication for therapeutic anticoagulation and those without. The most common indication is for prevention of cardioembolic stroke in those with current or previous atrial fibrillation (AF). Individuals with atrial flutter are typically regarded as having similar thrombotic risk to those with AF so similar recommendations are followed (63).

 

DM increases the risk of developing AF by around 40% (64,65). Whilst difficult to completely exclude the effects of confounders such as obesity and hypertension, epidemiological data suggest a causal association between DM and AF, including that poor glycemic control and longer diabetes duration increase AF risk (66). A raised level of HbA1c is also associated with a higher chance of AF recurrence after catheter ablation (67). Hyperglycemia and glycemic fluctuations may contribute to the development of AF though exact mechanisms remain to be determined. Disappointingly, however, there is no clear evidence that intensive glycemic control reduces AF risk, though prospective trials are lacking (66). Treatment with metformin, thiazolidinediones, or dapagliflozin is associated with lower AF risk, suggesting that hypoglycemia avoidance may play a role but adequately designed studies to investigate this possibility are lacking (68-71). AF is often clinically silent and screening with simple pulse checking or using wearable devices should be considered in those over 65 years old (72).

 

Presence of DM is incorporated into the CHA₂DS₂VASc score used to assess stroke risk when determining whether to recommend oral anticoagulation in people with AF (Table 1 and 2) (73). Long-term oral anticoagulation is strongly recommended in those with AF/atrial flutter and a CHA₂DS₂VASc score of ³2 (if male) or ³3 (if female), and should be considered when the score is 1 (male) or 2 (female). Individuals with DM, technically defined for the purposes of calculating the score as treatment with oral hypoglycemic drugs and/or insulin or fasting blood glucose >7.0 mmol/L (126 mg/dL), will have a score of at least 1 (males) or 2 (females), therefore OAC should be considered in all people with DM and concurrent AF (63). Bleeding risk should also be considered when weighing the benefits and risks of OAC, but there is no concrete evidence that DM itself increases this, including in those with complications such as retinopathy (74). For people with non-valvular AF (i.e., those without at least moderate mitral valve stenosis or a mechanical valve prothesis), there is now good evidence that, unless contraindicated, a NOAC should be preferred over a VKA, offering better stroke prevention whilst leading to less bleeding, including in individuals with DM (75).

 

Components of the CHA2DS2VASc score are shown in Table 1 and the relation of the score with stroke risk is shown in table 2 (76-78).

 

Table 1. Components of the CHA2DS2VASc Score
Abbreviation	Criterion	Contribution to score	Details
C	Congestive heart failure	1	LVEF £40%
H	Hypertension	1	Includes patients receiving antihypertensive medication
A	Age ³75 years	2
D	Diabetes	1	Treatment with oral hypoglycemic drugs and/or insulin or fasting blood glucose >7.0 mmol/L (126 mg/dL)
S	Stroke/TIA/thromboembolism	2
V	Vascular disease	1	Atherosclerotic disease e.g., prior MI, PAD or aortic plaque
A	Age 65-74	1
Sc	Sex category female	1

LVEF, left ventricular ejection fraction; MI, myocardial infarction; PAD, peripheral artery disease; TIA, transient ischemic attack.

 

Table 2. Relation of CHA2DS2VASc Score with Stroke Risk
Total CHA2DS2VASc score	Adjusted stroke risk (% per year)
0	<1
1	1.3
2	2.2
3	3.2
4	4.0
5	6.7
6	9.8
7	9.6
8	6.7
9	15.2

 

When choosing between individual non-vitamin K antagonist oral anticoagulants (NOACs), beyond considering specific drug interactions, there is little evidence to support the use of one agent over another as these have never undergone head-to-head clinical outcome-driven randomized controlled trials (RCTs), although observational data have emerged to provide some insights. In a large retrospective observational study of 434,046 participants with non-valvular AF comparing treatment with apixaban, dabigatran, rivaroxaban and warfarin, apixaban led to a lower risk of stroke against both dabigatran (HR 0.72 [ 95% CI 0.60-0.85]) and rivaroxaban (0.80 [0.73-0.89]), whilst also leading to less bleeding (major bleeding: vs. dabigatran 0.78 [0.70-0.87]; vs. rivaroxaban 0.80 [0.55-0.59]) (79). These findings remain hypothesis-generating, however, and prospective trials would clarify this issue more definitively.

 

Although not discussed in detail in this chapter, OAC may also be indicated for the treatment and prevention of venous thromboembolism. Whilst DM is regarded as a weak risk factor for VTE, beyond this there are no particular considerations relating to DM and usual clinical guidelines as for non-DM individuals should generally be followed (4). Of specific note, however, is that people with DM who are experiencing hyperosmolar states such as ketoacidosis or hyperosmolar hyperglycemic syndrome are at particular risk of VTE. There is ongoing debate around the intensity of anticoagulation that is appropriate for thromboprophylaxis in this group. Consensus is that at least prophylactic doses of low molecular weight heparin, for example, are warranted, with others advocate therapeutic doses (80,81). A robustly-powered clinical outcomes-driven RCT would be welcome to definitively address this issue.

 

Where indications for both anti-platelet therapy (APT) and therapeutic levels of oral anticoagulant therapy (OAC) exist, the general principle is to prioritize continuation of OAC. Co-prescription of APT and OAC should in general be reserved for those with acute coronary syndrome (ACS), recent percutaneous coronary intervention (PCI) or indication for long-term therapy in selected individuals with chronic coronary syndromes (CCS) where ischemic risk is felt to significantly outweigh bleeding risk (22).

 

Treating Acute Atherothrombotic Events

 

ACUTE CORONARY SYNDROMES (ACS)

 

Current guidelines recommend 12 months of dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ inhibitor, including in those with DM, as the default antithrombotic strategy for ACS (72,82-84).

 

There is robust evidence for aspirin therapy in ACS. For example, ISIS-2 demonstrated that aspirin led to an odds reduction in 30-day vascular mortality of 23% in those with acute MI (85). Current recommendations advise a loading dose of around 300 mg followed by maintenance therapy with 75 mg once daily, including in those with DM. However, because of higher platelet turnover in people with DM, 24-hour platelet inhibition is greater with twice-daily compared with once-daily aspirin administration (86-88). Any effects of clinical outcomes are yet to be determined, but are being studied in the ANDAMAN trial that aims to recruit 2573 participants (NCT02520921) and is estimated to finish in December 2023.

 

In ACS, the newer P2Y₁₂ inhibitors prasugrel and ticagrelor are recommended in preference to clopidogrel due to their greater pharmacodynamic and clinical efficacy (83,84). Post-hoc analysis of the TRITON-TIMI trial suggested an impressive benefit of prasugrel over clopidogrel in people with DM (89). Similar findings were noted with regards to ticagrelor over clopidogrel in the PLATO trial, for which post-hoc analysis showing that the absolute benefit of was greatest in individuals with both DM and chronic kidney disease (90).

 

Table 3. Key Double-Blinded Randomized Controlled Trials of Dual Antiplatelet Therapy in Acute Coronary Syndrome, Including in People with Diabetes.
Trial	n	ACS group included	Group 1	Group 2	Primary efficacy endpoint – whole trial population	Number with DM	Primary efficacy endpoint – DM subgroup
CURE (91)	12,562	NSTE-ACUTE CORONARY SYNDROME	Aspirin + Clopidogrel	Aspirin + Placebo	CV death/MI/stroke:11.4% vs. 9.3%, HR 0.80 [95% CI 0.72-0.90], p<0.001), ARR 2.1%.	2840 (23%)	CV death/MI/stroke:14.2% vs. 16.7%. RR 0.85. ARR 2.5%.
CLARITY (92)	3491	STEMI	Aspirin + Clopidogrel	Aspirin + Placebo	Occluded infarct-related artery/death/recurrent MI: 15.0% vs. 21.7%, odds reduction 36% [95% CI 24-47], p<0.001, ARR 6.7%.	575 (16%)	NR
COMMIT (93)	45,852	STEMI	Aspirin + Clopidogrel	Aspirin + Placebo	Death/reinfarction/stroke: 9.2% vs. 10.1%, OR 0.91 [95% CI 0.86-0.97], p=0.002, ARR 0.9%.	NR	NR
TRITON-THROMBOLYSIS IN MYOCARDIAL INFARCTION 38 (94)	13,608	ACUTE CORONARY SYNDROME with scheduled PCI	Aspirin + Prasugrel	Aspirin + Clopidogrel	CV death/MI/stroke: 9.9% vs. 12.1%, HR 0.81 [95% CI 0.73-0.90], p<0.001, ARR 2.2%.	3146 (23%)	CV death/MI/stroke: 12.2% vs. 17.0%, HR 0.70, ARR 4.8%.
TRILOGY ACUTE CORONARY SYNDROME (95)	7243	NSTE-ACUTE CORONARY SYNDROME with medical management	Aspirin + Prasugrel	Aspirin + Clopidogrel	CV death/MI/stroke: 13.9% vs. 16.0%, HR 0.91 [95% CI 0.79-1.05], p=0.21, ARR 2.1%.	2811 (39%)	CV death/MI/stroke: 17.8% vs. 20.4%, HR 0.90 [95% CI 0.73 to 1.09]), ARR=2.6%, interaction-p for DM status 0.71, ARR 2.6%.
PLATO (96)	18,624	All ACUTE CORONARY SYNDROME (STEMI patients included only if for PPCI)	Aspirin + Ticagrelor	Aspirin + Clopidogrel	CV death/MI/stroke: 9.8% vs. 11.7%, HR 0.84 [95% CI 0.77-0.92], p<0.001, ARR 1.9%.	4662 (25%)	CV death/MI/stroke: 14.1% vs. 16.2, HR 0.88 [95% CI 0.76-1.03], interaction-p for DM status 0.49, ARR 2.1%.

ACS, acute coronary syndrome; ARR, absolute risk reduction; CV, cardiovascular; DM, diabetes mellitus; HR, hazard ratio; MI, myocardial infarction; NR, not reported; NSTE-ACS, non-ST elevation ACS; OR, odds ratio; PCI, percutaneous coronary intervention; PPCI, primary PCI; PPM, permanent pacemaker; RR, relative risk; STEMI, ST elevation MI; NR, not recorded

 

The recent ISAR-REACT-5 study demonstrated superiority of a prasugrel-based strategy over a ticagrelor-based strategy in reducing cardiovascular events in ACS patients but was an open-label trial with limited power (97,98). Furthermore, data from the pre-specified subgroup with DM suggested there was no difference between the drugs (99).

 

Early de-escalation from dual antiplatelet therapy (DAPT) to ticagrelor monotherapy after PCI, including for ACS, has recently been trialed as an alternative strategy. In the TWILIGHT study, de-escalation from aspirin and ticagrelor to ticagrelor monotherapy at 3 months after PCI for ACS or stable coronary artery disease (CAD) was compared with continued DAPT in 7,119 participants (100). De-escalating to ticagrelor monotherapy led to a lower incidence at 12 months of the primary end point of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding compared with DAPT (4.0% vs 7.1%, HR 0.56 [95% 0.45-0.68], p<0.001). This finding appeared similar regardless of DM status. There was no evidence of an increase in the secondary combined endpoint of death, MI or stroke. Conversely, 1 month of DAPT followed by ticagrelor alone for 23 months was not superior to 12 months of standard DAPT followed by 12 months of aspirin alone in reducing the primary endpoint of all-cause mortality or new Q-wave MI following PCI in the GLOBAL LEADERS trial, in which 47% of participants had ACS (101). Antiplatelet strategy had no significant effect on BARC type 3 or 5 bleeding in those with and without DM (102). Currently, de-escalation of DAPT may be an option for individuals with high bleeding risk and relatively low risk of vascular re-occlusion but guidelines are yet to recommend more widespread adoption.

 

In summary, following ACS in individuals with diabetes, DAPT for 12 months with aspirin and prasugrel or aspirin and ticagrelor is recommended by the majority of guidelines/experts and early de-escalation should be reserved to those at high bleeding risk. Longer term DAPT should be considered in those at high thrombosis/low bleeding risk, which is further detailed below. 

 

ACUTE ISCHEMIC STROKE

 

If no contraindications exist, the first-line treatment for significant acute ischemic stroke is thrombolysis with an intravenous tissue plasminogen activator, or percutaneous mechanical thrombectomy (103). Antiplatelet therapy (APT), typically aspirin monotherapy, is then administered from 24 hours later (104,105).

 

In those with minor stroke (National Institutes of Health Stroke Score <3), high-risk transient ischemic attack (TIA) (Age, blood pressure, clinical feature, duration and presence of diabetes score>4) or TIA not requiring thrombolysis or thrombectomy, APT can be initiated as soon as hemorrhagic stroke is excluded. The current regimen of choice may be dual antiplatelet therapy (DAPT) with aspirin 75-100 mg once daily and clopidogrel 75 mg once daily, based on findings from the CHANCE and POINT trials (106,107). After 21 days, DAPT should be de-escalated to clopidogrel monotherapy (105).

 

Both ticagrelor monotherapy and aspirin plus ticagrelor have also been compared to aspirin alone after acute non-severe ischemic stroke or high-risk TIA. The SOCRATES trial narrowly failed to demonstrate statistically-significant difference in the primary endpoint of stroke, MI or death (6.7% vs. 7.5%, HR 0.89 [95% CI 0.78-1.01], p=0.07) between participants receiving ticagrelor vs. aspirin (108). However, exploratory analysis suggested those who received both aspirin and ticagrelor in the peri-event period appeared to gain more benefit compared to individuals not having aspirin pre-randomization (HR 0.76 [95% CI 0.61-0.95], p=0.02; vs. 0.96 [0.82-1.12]). This was explored further in the THALES trial, which demonstrated a significant reduction in the primary composite endpoint of stroke or death at 30 days (5.5% vs. 6.6%, HR 0.83 [95% CI 0.71-0.96, p=0.02) when receiving aspirin plus ticagrelor compared to aspirin alone, but at the expense of more frequent severe bleeding (0.5% vs. 0.1%, HR 3.99 [95% CI 1.74-9.14], p=0.001), defined using the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial criteria (109). Findings from SOCRATES appeared similar in the subgroups with and without DM, whereas in THALES there was less signal of benefit of DAPT in those with DM vs. those without (HR 0.93 [95% CI 0.72-1.20] vs. 0.78 [0.64-0.94]).

 

In summary, following major stroke requiring thrombolysis or thrombectomy, aspirin monotherapy should be administered 24 hours later. In minor stroke or high-risk TIA, DAPT should be initiated as soon as intracerebral bleeding is ruled out and continued for 21 days with aspirin then withdrawn and individuals treated with long-term clopidogrel monotherapy.

 

Preventing Atherothrombotic Events in Individuals with Diabetes and Established Cardiovascular Disease

 

CORONARY ARTERY DISEASE

 

In those with established CAD, even without an ACS event in the last 12 months, the benefits of antiplatelet therapy (APT) are well-established. Robust evidence for vs. against use of APT in patients with ASCVD, including CAD comes, for example, from the Antithrombotic Trialists Collaboration, who performed a meta-analysis including 135,000 individuals (110). This demonstrated clear benefit, mainly with aspirin as single-antiplatelet therapy (SAPT), in reducing MACE by around a quarter (110).  The incidence of diabetes in these studies, many of which are now several decades old, was relatively low, however.

 

There is evidence from trials with both pharmacodynamic and clinical outcomes that increasing daily aspirin dose beyond 75-100 mg in patients with DM leads to neither greater platelet inhibition nor improved outcomes (111,112).

 

Daily doses of aspirin in the range 75-100 mg and no higher are recommended for use as APT. Recent data on clinical outcomes relating to aspirin dosing comes from the ADAPTABLE trial, in which the regimens 81 mg OD and 325 mg OD were compared in 15,076 patients with ASCVD (113). After a median of 26 months, there was no significant difference in the rates of a composite primary endpoint of all-cause death, hospitalization for myocardial infarction or hospitalization for stroke (7.28% [81 mg] vs. 7.51% [325 mg], HR 1.02, 95% CI 0.91-1.14; p=0.75). Furthermore, this finding appeared replicated in the subgroup (n=5676) with diabetes (HR 0.99 [0.84-1.17]). This is supported by pharmacodynamic data showing that, whilst individuals with DM have reduced response to aspirin 75 mg once daily compared with healthy controls, increasing the dose to 300 mg does not alter the response (111).

 

In the CAPRIE study, clopidogrel 75 mg once daily was compared with aspirin 325 mg once daily (114). There was a slightly lower rate of MI, ischemic stroke or CV death with clopidogrel (5.32% vs. 5.83%, RRR 8.7% [95% CI 0.3-16.5], p=0.043) as well as less gastrointestinal bleeding. A fifth of participants in CAPRIE had diabetes and a retrospective subgroup analysis suggested an amplified benefit of clopidogrel over aspirin compared to those without diabetes. Clopidogrel monotherapy is currently recommended in those people with chronic coronary syndromes (CCS) who are unable to take aspirin, or, based on pre-specified subgroup analyses of CAPRIE suggesting particular benefit, as a first-line agent in those with either concurrent CAD and cerebrovascular disease or PAD.

 

Beyond single antiplatelet therapy (SAPT), there is good evidence for intensification of antithrombotic therapy in select people with CAD who are at high risk of ischemic events but without high risk of bleeding. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study randomized 19,185 stable aspirin-treated individuals with established atherothrombotic disease or multiple risk factors to receive clopidogrel 75 mg once daily or placebo (115). Though the point estimate of the hazard ratio was below 1, there was no significant reduction in the primary efficacy endpoint of MACE when receiving dual antithrombotic therapy (DAPT) vs. aspirin alone (HR 0.93, [95% CI 0.83-1.05], p=0.22). However, in the subgroup with prior MI, prior stroke or PAD, there was some evidence of benefit (0.77 [0.61-0.98], p=0.031) (116). Around 30% of the participants in CHARISMA had DM and there was in fact a trend towards less benefit of DAPT over SAPT in this group compared to those without DM.

 

The DAPT study similarly showed that 30 vs. 12 months of clopidogrel (65%) or prasugrel (35%) given to aspirin-treated individuals undergoing PCI significantly reduced death, MI or stroke in those with prior MI (HR 0.56 [95% CI 0.42-0.76], p<0.001), but not those without (0.83 [0.68-1.02], p=0.08) (117). Like CAPRIE, there was some evidence that those in the trial with DM gained less benefit in reduction of MACE from continued thienopyridine vs. placebo, when compared to those without DM (6.6% vs. 7.0% in those with DM, p=0.55; 3.3% vs. 5.2% in those without, p<0.001; interaction-p=0.03). Conversely, DM did not appear to be an interacting factor with regards to stent thrombosis or bleeding.

 

There is perhaps more convincing evidence, particularly in those with DM, for use of long-term ticagrelor-based DAPT. In the PEGASUS-TIMI 54 study, DAPT with aspirin plus ticagrelor, either 60 mg or 90 mg twice-daily, reduced MACE vs. aspirin alone (e.g. 60 mg twice-daily vs. placebo: HR 0.84 [95% CI 0.74-0.95], p=0.008) in participants with prior MI (>1 year ago) and an additional risk factor (age ≥65 years, DM, recurrent MI, multivessel CAD or non-end stage CKD) (118). Thrombolysis In Myocardial Infarction (TIMI)-major bleeding was significantly more frequent in ticagrelor-treated individuals, but serious events such as intracranial hemorrhage, hemorrhagic stroke or fatal bleeding showed no increase. In contrast to the thienopyridine trials, the 6806 participants with diabetes demonstrated a significant benefit of DAPT over SAPT in reducing MACE (HR 0.84 [95% CI 0.72-0.99], p=0.035) with a greater absolute risk reduction than in the cohort without diabetes (1.5% vs. 1.1%) (119). Patients without a history of anemia or hospitalization for bleeding, important risk factors for bleeding, appeared to derive greater benefit from long-term DAPT (120).

 

As well as in those with prior MI, ticagrelor-based DAPT has also been tested against aspirin alone in people with type 2 DM and chronic coronary syndromes (CCS) but without prior MI. THEMIS included 19,220 participants randomized to receive ticagrelor (90 mg twice daily, reduced to 60 mg during the trial) or placebo, on a background of aspirin treatment (121). After an average follow-up of 40 months, there was a lower incidence of MACE in those receiving ticagrelor when compared to placebo (HR 0.90 [95% CI 0.81-0.99], p=0.04).  Notably, however, there was a relatively greater increase in TIMI-major bleeding (2.32 [1.82-2.94], p<0.001). Whilst meeting its primary endpoint, the net clinical benefit has not supported adoption in European practice, although subgroup analysis has suggested this may have been more favorable in those patients with prior PCI (122). Furthermore, based on the THEMIS data, the US Food and Drug Administration has recently extended the licensed indication for ticagrelor to include the prevention of a first MI or stroke in people with CCS at high risk of MI or stroke, including in those with DM (123).

 

An alternative to long-term DAPT is low-dose dual antithrombotic therapy (DATT) with aspirin 75-100 mg once daily and rivaroxaban 2.5 mg twice daily.  The COMPASS trial included randomization of 27,395 participants with prior MI or multivessel CAD (38% with DM) or PAD to receive either low-dose DATT, rivaroxaban 5 mg twice daily alone or aspirin alone (124). Compared to aspirin alone, low-dose DATT led to a significantly reduced incidence of MACE [4.1% vs 5.4%, HR 0.76 [95% CI 0.66-0.86], p<0.001], people with DM gaining an even greater absolute net benefit.

 

Current guidelines recommend long-term DAPT or low-dose dual antithrombotic therapy (DATT) in those individuals with CCS without an indication for therapeutic oral anticoagulant (OAC) who are at high ischemic risk but not high bleeding risk (22).

 

In those undergoing PCI for stable CAD, including in those individuals with DM, the standard DATT regimen is DAPT with aspirin and clopidogrel for 6 months (125).

 

In summary, individuals with DM who have CCS should be treated with at least one antiplatelet agent, usually aspirin, although clopidogrel can be used if aspirin is contraindicated. However, more recent evidence indicates that those with a previous MI benefit from long-term DAPT (aspirin and ticagrelor) or a combination of antiplatelet and anticoagulant (DATT with aspirin and rivaroxaban) provided they have a low bleeding risk. Individuals with significant CAD but without a previous MI may also benefit from DAPT or DATT, which is best reserved for people with high vascular risk but low bleeding risk. 

 

CEREBROVASCULAR DISEASE  

 

There is good evidence for use of APT with aspirin, clopidogrel, ticlopidine or aspirin and dipyridamole in combination for secondary prevention in people with cerebrovascular disease, including those who also have DM (126). Aspirin plus dipyridamole offers better long-term protection than aspirin alone, but has a frequent adverse effect of headache that can limit its use (127). Clopidogrel monotherapy, without this side effect, offers similar levels of secondary prevention to aspirin plus dipyridamole and is the current preferred agent. In the first 3 months after an ischemic stroke, if reperfusion therapy has been given, aspirin alone is typically prescribed. In cases where reperfusion therapy has not been given, there is good evidence for using either aspirin and clopidogrel or aspirin and ticagrelor over aspirin alone (128,129).  After 3 months, typically clopidogrel monotherapy is then given long-term, though aspirin and dipyridamole or aspirin alone are used instead at some centers (127,130,131).

 

PERIPHERAL ARTERY DISEASE

 

The effectiveness of APT for secondary prevention of ASCVD, including in those with symptomatic PAD, was established by the Antithrombotic Trialists’ Collaboration as discussed above. Similarly, in the CAPRIE trial, P2Y₁₂inhibitor monotherapy with clopidogrel was compared with aspirin, including in people with PAD (114). Whilst in the overall trial population there was only a modest reduction in MACE, there was evidence of greater efficacy in the subgroup with PAD, meaning clopidogrel may be preferred to aspirin. Current ESC guidelines recommend either aspirin or clopidogrel for patients with symptomatic PAD and/or those who have required revascularization, including in individuals with DM (132).

 

In those with symptomatic PAD, ticagrelor monotherapy has also been compared with clopidogrel in the EUCLID trial (133). There was no significant difference in the primary composite endpoint of MACE during a median follow-up period of 30 months and therefore ticagrelor monotherapy is not licensed for use in PAD. Prasugrel monotherapy has not been well tested in clinical-outcome studies but may offer pharmacodynamic advantages over clopidogrel, including in individuals with DM (134).

 

Comparison of DAPT (aspirin plus clopidogrel) with aspirin alone in people with PAD was included in CHARISMA (n=3,096 with PAD, 36.2% with DM). There was no significant difference in MACE (7.6% vs 8.9%, HR 0.85 [0.66–1.08], p=0.18) (135).

 

Conversely, there is good evidence for intensification of aspirin monotherapy to low-dose DATT with aspirin 75-100 mg once daily and rivaroxaban 2.5 mg twice daily in people with PAD, supported by the analysis of 7,470 participants with PAD in the COMPASS trial (136). The combination of rivaroxaban and aspirin reduced incidence of MACE over a median follow up of 21 months versus aspirin alone [5.1% vs 6.9%, HR 0.72 (0.57-0.90); p=0.0047]. Particularly important benefits observed included a lower incidence of major adverse limb events [1% vs 2%, HR 0·63 [95% CI 0.41–0.96], p=0·032], and lower incidence of major amputation [0.30 [0.11–0.80], p=0.011].

 

Subsequently, the evidence base for low-dose DATT in people PAD has been enhanced by the results of the VOYAGER-PAD trial, which randomized 6564 individuals with PAD treated by revascularization to receive either low-dose DATT or aspirin alone (137). After a median follow-up of 28 months (interquartile range 22-34), the primary composite endpoint of acute limb ischemia, amputation, MI, ischemic stroke or CV death occurred in 17.3% vs. 19.9% (HR 0.85 [0.76-0.96], p=0.009) without a significant increase in the incidence of TIMI major bleeding (2.65% vs. 1.87%, HR 1.43 [0.97-2.10, p=0.07). Forty percent of the trial population had DM with a similar response observed in this group.

 

It should be noted that DM individuals with symptomatic PAD are likely to have extensive vascular pathology and therefore DATT is likely to offer benefit in more than one vascular bed. Discussion of antithrombotic therapy for those people with DM and asymptomatic PAD is included in the next section.

 

Preventing First Atherothrombotic Event in Patients with Diabetes and No Symptomatic Atherosclerotic Cardiovascular Disease

 

It is rational to hypothesize that antithrombotic therapy (ATT) therapy may reduce the chance of a first atherothrombotic event or limit its severity by preventing thrombosis or reducing its impact.  ATT in several distinct groups with DM but without symptomatic ASCVD have been investigated in a number of trials. The largest individual-level meta-analysis was performed in 2009 and included 95,000 participants from 6 trials (138). In individuals with DM, though aspirin led to a 12% proportional reduction in the rate of serious vascular events, this did not reach statistical significance. However, the point estimate was consistent with the statistically significant benefit of aspirin in the non-DM population and the DM population showed an identical trend. Three further trials have been added to the literature since this meta-analysis was performed. Two, JPAD (n=2539) and POPADAD (n=1276) were not adequately powered to draw firm conclusions (139,140). However, most recently ASCEND provided data from 15,480 individuals with DM but without symptomatic ASCVD who were randomized to receive aspirin 100 mg once daily or placebo (141). After a mean follow up of 7.4 years, those randomized to aspirin had a significantly reduced rate of serious vascular events (MI, stroke or TIA, or vascular death excluding intracranial hemorrhage) (RR 0.88 [95 % CI 0.79-0.97], p=0.01). However, major bleeding was significantly more frequent when receiving aspirin (1.24 [1.09-1.52], p=0.003), the majority being gastrointestinal. The investigators concluded that the absolute benefits were largely counterbalanced by the risks, despite a favorable, albeit modest, risk-benefit ratio.

 

Antiplatelet drugs other than aspirin have not been widely studied for primary prevention in individuals with DM and this remains an area for future research.

 

CONCLUSIONS

 

DM leads to a prothrombotic milieu that increases the risk of atherothrombotic and thromboembolic events compared to the non-DM population. Changes in platelets, coagulation, and inflammation appear central to this increased risk. Antithrombotic therapy (ATT) can help treat or prevent thrombotic events but increases bleeding risk. In those with a history of symptomatic ASCVD, long-term antiplatelet therapy (APT) with aspirin or clopidogrel is indicated. Intensification to long-term dual antiplatelet therapy (DAPT) or low-dose dual antithrombotic therapy (DATT) should be considered in those with chronic coronary syndromes (CCS) who have high ischemic risk but not high bleeding risk. Low-dose DATT can also be beneficial to people with symptomatic PAD. Therapeutic levels of oral anticoagulant (OAC) should be considered in all individuals with DM who develop AF. Accurately assessing and balancing a patient’s risk of ischemic and bleeding events is key to making rational treatment recommendations for ATT in DM (Figure 3).

 

Looking to the future, further work to determine more precisely an individual’s thrombotic and bleeding risk would greatly enhance our ability to make the best treatment recommendations for patients with DM. Whether this is achieved by more complex statistical modelling, novel imaging techniques, and/or better appreciation of circulating biomarkers remains to be determined. This would allow a greater move towards personalized strategies in order to more appropriately balance the benefits and risks of ATT. People with DM often have complex co-morbidities meaning choosing the best regimen is difficult, but is at the same time crucial to ensure an optimal outcome.

 

Emerging strategies such as early de-escalation of DAPT are encouraging new tools giving more options for subtle adjustment of ATT intensity, but require definitive proof they lead to no significant ischemic penalty and ratification by guideline committees before wider adoption can be recommended. No doubt further clarity will follow in the coming years.

 

The lack of an ability of ATT to meaningfully improve net clinical outcomes in those with DM without established ASCVD is a source of disappointment and demands future attention. Trials have focused on aspirin but it is clear that people with DM may have a poor response (111). As well as trials exploring novel regimens of aspirin, trials testing P2Y₁₂ inhibitor monotherapy, which may offer pharmacodynamic advantages over aspirin in this group, are warranted (134).

 

Finally, targeting the pathological abnormalities that cause hypofibrinolysis in diabetes, such as inhibition of PAI-1 activity, may offer an alternative management strategy to further reduce vascular occlusive disease in diabetes, while keeping the risk of bleeding to a minimum.

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ABSTRACT  

 

Depression is characterized by a disturbance of mood, affecting between 3–5% of the general population at any one time. The prevalence of depression is approximately doubled in people with diabetes compared to the general population, with similar rates between type 1 diabetes and type 2 diabetes. Although many cases of depression are coincidental to the presence of diabetes, certain diabetes factors including diabetes-related complications, diabetes treatments and obesity are associated with an increased risk of depression. There is a bi-directional relationship between diabetes and depression with specific disease and treatment factors explaining why diabetes pre-disposes to depression and vice versa. Genetics, early intra-uterine development, and social determinants of health may create a “common soil” for both conditions. The presence of depression in people with diabetes worsens both diabetes and depression outcomes. Mortality is increased, quality of life diminished, and healthcare costs are increased. Diabetes self-management is also impaired. It may be possible to reduce the incidence of depression in people with diabetes by considering the way in which the diagnosis of diabetes is conveyed and the psychosocial support that is given through an individual’s journey with diabetes. Several short screening questionnaires have been validated in people with diabetes. A diagnosis should be confirmed by a diagnostic interview. The main aims of treatment are to improve both diabetes and mental health outcomes with complete remission of depressive symptoms.  Various psychological treatments, including cognitive behavioral therapy, problem-solving, and psychodynamic techniques have been used to treat depression in people with diabetes. Antidepressants reduce depressive symptoms in people with diabetes as well as the general population. All antidepressants appear to have similar effects on depressive symptoms as long as adequate doses are used. Treatment should be maintained for at least 4–6 months after remission of symptoms to reduce the risk of relapse and recurrence. The choice of antidepressant depends largely on the side-effect profile, individual preference, and response. Selective serotonin reuptake inhibitors are widely used as first-choice agents. A common model of care for depression is the Stepped Care Model which is designed to provide a rational approach to the treatment of depression, while reducing costs and side effects of antidepressants through more appropriate prescribing. A case management model known as collaborative care is a clinical- and cost-effective treatment of depression that also improves diabetes outcomes by involving a multidisciplinary team that works together to identify and treat depression within primary care settings. Although diabetes and depression remain a considerable clinical challenge, there are grounds for considerable optimism as the scientific knowledge that underpins clinical practices has expanded markedly in the last two decades. However, further research is needed to understand what can be done to prevent depression in people with diabetes and to identify the optimal treatment for an individual that improves both depressive symptoms and diabetes outcomes.

 

INTRODUCTION

 

The importance of considering the interaction between mind and body in the management and outcome of chronic diseases has been recognized for over 2,500 years but is particularly poignant for people with diabetes. Diabetes places high behavioral demands on those living with the condition whilst mental disorders, such as depression, may compromise an individual’s ability to perform the self-care needed to optimize health and prevent the long-term consequences of diabetes. Much of diabetes care is focused around the identification and treatment of long-term diabetes-related complications and diabetes healthcare professionals are adept in managing microvascular and macrovascular conditions. An appreciation, however, of the psychological consequences of diabetes has lagged behind, despite these being common and the morbidity, mortality, and health costs associated with the co-morbidity being disproportionately increased compared with the effects of either condition alone (1, 2).

 

Several factors contribute to the poorer health outcomes seen in people with diabetes and mental disorders. Despite the increased burden of disease, people with co-morbid mental disorders have often been disadvantaged by health services and have received sub-optimal medical care (3). They have been less likely to receive the necessary diabetes processes of care, self-management education, and cardiovascular preventative medication despite increased visits to their primary healthcare teams and despite similar interest in caring for their physical illness as the general population (4). Clinicians may fail to recognize that those with mental illness are more likely to develop physical illnesses and so physical complaints are either ignored or not taken seriously. Mental health symptoms often “over-shadow” other complaints leading healthcare professionals to focus on the mental illness to the detriment of any physical illness (5). Health services are often poorly configured with clinics focusing on either the treatment of physical illnesses or mental disorders rather than treating both conditions at the same time (3). The stigma associated with mental illness may prevent people and their families from seeking help for mental illness, thereby depriving them of effective treatments, which not only harms mental well-being but is detrimental to diabetes management (6).

 

Diabetes and mental disorders are both common, and so a degree of co-occurrence would be expected purely by chance. The evidence suggests, however, that diabetes is more frequently associated with a range of mental and psychosocial disorders than expected (7, 8). Furthermore, several mental disorders, including depression, are associated with an increased risk of developing diabetes. An understanding of this complex interaction is crucial to the management and outcome of people with diabetes.

 

This chapter focuses on the co-morbidity of diabetes and depression; both are common, are relatively easy to diagnose, and have established effective treatments (8). They may also serve as an exemplar for other mental disorders and provide a model for the successful management of other co-morbid mental and physical health conditions. The chapter will describe the epidemiology of diabetes and depression and will discuss the mechanisms underlying the association between diabetes and depression. It will also highlight the clinical implications and consequences of co-occurring diabetes and depression. Diabetes healthcare professionals need to be aware of how to screen for depression and to provide “first response” management, while recognizing when to refer for specialist psychiatric care (9).

 

DEPRESSION

 

Depression belongs to a group of mental disorders where the primary abnormality is a disturbance of mood. The cardinal features of depression are low mood, and loss of interest or pleasure, lasting longer than two weeks. During a depressive episode, other symptoms may include poor concentration, feelings of excessive guilt or low self-worth, hopelessness about the future, thoughts about dying or suicide, disrupted sleep, changes in appetite or weight, and feeling especially tired or low in energy. People with depression are at an increased risk of suicide. Depressive symptoms exist on a continuum of severity, and it is important to recognize that depression is different from usual fluctuations in mood that occur with everyday life. 

 

Major depressive disorder (also known as clinical depression, unipolar depression, or major depression) is defined by the diagnostic criteria of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders(DSM-5), based on the number and duration of symptoms (Table 1) (10). The DSM-5 definition approximates a level of severity of symptoms that is associated with both disability and dysfunction. DSM-5 also recognizes several sub-types of depressive disorder where the symptoms are less severe but nevertheless may still compromise diabetes self-care and outcomes.

 

Table 1. DSM-5 “Major” Depressive Episode
A.        Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood, or (2) loss of interest or pleasure. •           Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g. feels sad or empty) or observation made by others (e.g. appears tearful). •           Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others). •           Significant weight loss when not dieting or weight gain (e.g. a change of >5% of body weight in a month) or decrease or increase in appetite nearly every day. •           Insomnia or hypersomnia nearly every day. •           Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). •           Fatigue or loss of energy nearly every day. •           Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). •           Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). •           Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.
B.    B.        The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
C.    C.        The symptoms are not due to the direct physiological effects of a substance (e.g. a drug of abuse, a medication) or a general medical condition (e.g. hypothyroidism).

 

Epidemiology of Depression

 

Depression is one of the commonest mental disorders, affecting between 3–5% of the general population at any one time; the lifetime prevalence is 8-12% but there is considerable geographical variation ranging from 3% in Japan to 17% in India. The highest rates of depression are found in the United States of America (USA), the Middle East and South Asia (11). In 2019, 280 million people were living with depression, including 23 million children and adolescents (12). The incidence of depression worldwide increased by 50% between 1990 and 2017 to an age standardized rate of 3.25 per 1000 (13). Depressive disorders are now ranked as the single largest contributor to non-fatal health loss (7.5% of all years lost to disability) (14).

 

Depression can affect any age group, with depression being seen in infants as young as 6 months old after separation from their mothers (15). The commonest age of onset is between the ages of 30 and 40 years, but there is a second, smaller peak in incidence between ages 50 and 60 years (16). The risk of depression is doubled in women compared with men (17). Although the cause of depression remains uncertain, other risk factors for a depressive episode are recognized and include a family history of depression, certain personality types, childhood adversity, the postpartum period, social isolation, and a lack of close interpersonal relationships (18). An episode of depression is often triggered by a stressful life event, particularly for the first few depressive episodes (Table 2). Depression may accompany other mental illnesses and long-term physical conditions (19). All these risk factors apply to people living with diabetes and so consequently much of the depression seen in people living with diabetes is coincidental to the diabetes.

 

Table 2. Risk Factors for Depression

·       Female gender ·       Age ·       Family History o   Genetics o   Shared Environment ·       Personality type o   Introversion o   Neuroticism §  Insecure, worried §  Obsessive o   Unassertive, dependent o   Low conscientiousness o   Disorganization o   Stress-sensitive ·       Childhood adversity o   Separation o   Neglect o   Abuse §  Mental §  Physical §  Sexual o   Early bereavement o   Unequal parental treatment of siblings ·       Life Events o   Childbirth o   Menopause o   Rape or assault o   Natural disasters o   Job loss or unemployment o   Stress o   Financial difficulties o   Bullying o   Relationship or marriage breakdown o   Bereavement o   Catastrophic injury

·       Mental illness o   Schizophrenia o   Drug or alcohol misuse ·       Physical illness o   Infection §  HIV o   Nutritional deficiencies o   Cardiovascular disease §  Myocardial infarction §  Stroke o   Pernicious anemia o   Neurological §  Parkinsonism §  Multiple sclerosis o   Endocrine §  Diabetes §  Obesity §  Hypoandrogenism §  Cushing syndrome §  Hypothyroidism §  Hyperparathyroidism o   Cancer o   Arthritis o   Chronic pain o   Inflammation ·       Side effects of medication o   β-blockers o   α-interferon o   Finasteride o   Isotretinoin o   Dopamine receptor agonists o   Some anticonvulsants o   Some antimigraine agents o   Some antipsychotics

 

DIABETES AND DEPRESSION

 

The association between diabetes and depression has been recognized for many years. In the 17^th century, Thomas Willis, an English physician, described how “diabetes is a consequence of prolonged sorrow” (20). Until the last two decades, the focus of any discussion of mood and diabetes was on the increased likelihood of depression in people with diabetes, where the comorbidity was viewed as an understandable reaction to the difficulties and challenges of living with a demanding and life-limiting long-term physical illness. In this regard, it was treated no differently from other long-term physical conditions that are also associated with increased rates of depression. We now understand that the relationship between the two conditions is more complex and, at least for type 2 diabetes, is bidirectional (8).

 

Understanding the scale of the co-morbidity is challenging because the epidemiological studies examining the relationship have been hampered by considerable variation in measurement, study design, and use of terminology that have contributed to significant heterogeneity and inconsistency between studies (8). An example of this variability is illustrated by one meta-analysis that reported a range of prevalence rates of depression in people with diabetes from 1.8% to 88% (21).

 

The gold standard for the diagnosis of depression is a diagnostic interview, but many studies have relied on self-rating scales (22). These scales identify depressive symptoms rather than depression and do not differentiate between symptoms that could be caused by either diabetes or depression, for example, fatigue or weight change. This can lead to significant overestimates of the prevalence of depression in those with diabetes, as shown in an early meta-analysis where the prevalence of depression in people with diabetes identified by diagnostic interview was 11.4% compared to 31.0% in studies using self-rating questionnaire (23). However, a more recent meta-analysis argued that the symptom overlap does not affect prevalence (21). Nevertheless, the authors argue that depression measures that focus on the cardinal symptoms of depression rather than overlapping symptoms may most accurately diagnose depression.

 

Studies have often used mixed populations of people with type 1 diabetes and type 2 diabetes. This distinction is important because people with type 2 diabetes are generally older, and depression prevalence varies with age (16).There are differences in the prevalence of diabetes-related complications and other comorbid conditions such as obesity and heart disease, which independently affect the likelihood of developing depression (24). The pathogenesis and etiology of the two main types of diabetes differ, which may affect the risk of depression in different ways (25). Finally, the burden of management differs between type 1 diabetes and type 2 diabetes.

 

Many studies have not taken broad population approaches but have concentrated on convenience samples, usually drawn from specialist diabetes clinics, where the participants may not reflect the wider population of people living with diabetes. This bias is illustrated in the meta-analysis by Farooqi et al which reported that the prevalence of depression in people with diabetes was 36% in studies carried out in specialist care compared to 12% in community or primary care settings (26). Biases may also occur where there are low or unknown response rates, because the presence of depressive symptoms may affect the willingness of an individual to participate.

 

A further confounding factor is the concept of diabetes distress which describes the emotional response to living with diabetes, including the demands of self-management, the threat of complications, the social impact of stigma and discrimination, and the financial costs of treatment (27). Diabetes distress can fluctuate over time and may peak during challenging periods such as soon after diagnosis, during major treatment changes, or during the development or worsening of long-term complications (Table 3). Diabetes distress is distinct from depression in its association with self-management and glycemic levels, but the two conditions may co-exist in about 5-15% of people with diabetes. By contrast depression occurs without distress in 5-10% of people while distress alone affects 20-30% (28). The importance of diabetes distress was first proposed in 1995, and it is likely that early studies of diabetes and depression were capturing distress as well as depression, thereby contributing to an overestimate of the prevalence of depression.

 

Table 3. Common Features of Diabetes Distress

•           Feeling overwhelmed by the demands of living with diabetes •           Feeling concerned about “failures” with diabetes management •           Feeling powerless or hopeless •           Worrying over the risk of low blood glucose or long-term complications •           Feeling frustrated that diabetes cannot be predicted or controlled from one day to the next •           Feeling frustrated with care givers •           Feeling guilty when the diabetes management go ‘off track’.

 

Despite these caveats, several meta-analyses have indicated that the prevalence of depression is approximately doubled in people with diabetes compared to the background population (23, 26), with the prevalence of depression similar between type 1 diabetes (22%) and type 2 diabetes (19%) (26). Although most studies come from Western Europe or North America, the increased rates of depression or depressive symptoms have been found across the world (29, 30), with the prevalence being higher in low- and middle-income countries (26). A meta-analysis of 248 observational studies including over 8 million people with type 2 diabetes found a global prevalence of depression of 28%, with the highest rates observed in Asia and Australia whilst the lowest rates were found in studies from Europe (31). Cohort studies have shown an increase in incident depression in people with diabetes; one meta-analysis of 11 studies involving approximately 50,000 people with type 2 diabetes but without depression at baseline reported that the incidence of depression was 24% higher in people with diabetes (32), while another meta-analysis of 13 studies found incident depression was increased by 15% in people with diabetes (33).

 

An increased prevalence of depression has also been found in children with diabetes. A meta-analysis of 109 studies involving over 50,000 children with diabetes estimated that the prevalence of depression was 22.2% among children with type 1 diabetes and 22.7% in children with type 2 diabetes (34). Consistent with studies in adults, the prevalence of depression was higher among girls than boys (29.7% vs. 19.7%) and in low- to- middle-income countries.

 

Type 2 diabetes is a common comorbidity in people with mental disorders, with a reported prevalence ranging from 5% to 22% depending on the specific psychiatric disorder. Overall, the prevalence of diabetes in people with depression is 9% but there is considerable heterogeneity between studies (35). Consistent with this finding, the incidence of diabetes in people with depression is increased by 18-60% (33, 36, 37). People with depression, however, may receive more screening for diabetes than those without because of their increased contact with healthcare professionals and an awareness of the risk of diabetes by mental health practitioners, which may lead to an overestimate of the difference in diabetes risk between those with and without depression, particularly in studies that rely on routinely collected healthcare data.

 

Diabetes Factors That Increase the Risk of Depression

 

Although many cases of depression are coincidental to the presence of diabetes, certain diabetes factors including diabetes-related complications and obesity are associated with an increased risk of depression (38).

 

DIABETES COMPLICATIONS

 

The development of macrovascular and microvascular complications increases the risk of depression in people with type 1 diabetes and type 2 diabetes  (24, 39). Overall, the presence of diabetes complications increases the risk of incident depressive disorder by 14% but the increased risk of developing depression is 24% higher for microvascular complications compared with 9% higher for those with macrovascular complications (39). The risk of depression increases as more complications develop such that the presence of two or more complications more than doubled the risk of depression in people with type 2 diabetes in one specialized outpatient clinic, with neuropathy and nephropathy showing the strongest association (40).

 

DIABETES TREATMENTS

 

The use of insulin in type 2 diabetes is associated with higher rates of depression compared to non-insulin medications or dietary and lifestyle interventions alone. One meta-analysis of 28 studies reported an overall 59% higher risk of developing depression in people taking insulin and 42% higher risk when compared with oral anti-diabetes agents (41). It seems unlikely that insulin per se increases depressive symptoms, but insulin is associated with higher treatment demands that not only include self-injection but more intensive self-monitoring, which may adversely affect depressive symptoms (42). Insulin is also used in those with longer duration of type 2 diabetes, which may be associated with a higher prevalence of diabetes-related complications and elevated HbA_1c, a further risk factor of depression (43). Insulin has been used erroneously as a threat by healthcare professionals to encourage people to follow certain health behaviors or take medications. As type 2 diabetes is associated with progressive β-cell decline, many people ultimately need insulin. Where insulin has been used as a threat, commencing insulin can evoke feelings of guilt, blame or failure, which may increase the likelihood of depression. Furthermore, people may have strongly held beliefs about insulin usage, seeing it as an “end of the road” treatment. They may also associate insulin with the development of diabetes complications or death if they have seen a family member with diabetes developing complications while using insulin. Insulin therapy is associated with significant weight gain, again a risk factor for depression, and an increased risk of hypoglycemia. In a 10-year study of 3,742 people with type 1 diabetes requiring emergency room visit or hospitalization, those admitted with a hypoglycemic event were 74% more likely to develop depression (43).

 

Other anti-diabetes treatments, by contrast, may be associated with a reduced risk of depression and there has been discussion about whether these could be re-purposed as treatments for depression (44). A meta-analysis of current therapies indicated that pioglitazone was associated with improved depressive symptoms, more so in women, but metformin had no consistent benefit (44). A more recent systematic review, however, suggested that metformin might help treat comorbid depression, although the evidence was too weak to recommend its use for this indication (45). A review of observational studies also indicated that metformin was associated with reduced depressive symptoms (46). GLP-1 receptors are widely expressed in the brain and have putative neuroprotective properties. A meta-analysis of six studies including 2,071 participants showed a small but significant reduction in depressive symptoms in those treated with GLP-1 receptor agonists (47). Whether the improvement is a direct effect or mediated through weight loss is unknown. This observation was also seen in a large population-based cohort and nested case-control study that found that low doses of metformin, dipeptidyl peptidase-4 (DPP4) inhibitors, GLP-1 receptor agonists, and sodium-glucose transporter 2 (SGLT2) inhibitors were associated with lower risk of depression in people with diabetes compared to those using other treatments, with the lowest risk seen with SGLT2 inhibitors (48). Further studies of the impact of SGLT2 inhibitors are warranted as abnormal brain bioenergetic metabolism occurs in depression and endogenous ketones may exert a neuroprotective effect that might improve mood. As SGLT2 inhibitors induce ketogenesis, there is a rationale to test whether SGLT2 inhibitors improve depressive symptoms (49).

 

MECHANISMS TO EXPLAIN THE LINK BETWEEN DIABETES AND DEPRESSION

 

No one mechanism explains the association between diabetes and depression, but specific disease and treatment factors may account for why diabetes pre-disposes to depression and vice versa (Figure 1). These are, however, superimposed on other factors, such as genetics, early intra-uterine development, and social determinants of health, that create a “common soil” for both conditions.

 

 

Underlying Factors That Predispose to Both Diabetes and Depression

 

GENETICS

 

Modern genetic technologies, such as genome-wide association (GWAS) studies and Mendelian randomization analyses have revolutionized our understanding of how genetics may underlie many polygenic mental and physical disorders and their association as well as health behavior traits, such as smoking and alcohol consumption that influence health. These studies have shown overlap of genetic polymorphisms that increase the risk of several mental disorders, including depression, and physical disorders, including diabetes, metabolic syndrome, and obesity (50). There are nearly 500 single nuclear polymorphisms that are associated with an increased risk of both diabetes and depression across a broad range of pathways that include immune function, lipid metabolism, cancer-related pathways, and cell signaling (51).

 

FETAL DEVELOPMENT

 

The ‘developmental origins of health and disease’ hypothesis emerged from epidemiological studies that found that infants with low birth weight had an increased risk of cardiovascular disease, diabetes, and other chronic conditions in adulthood (52, 53). Although the early studies focused on physical illness, the fetal environment is linked to psychiatric conditions, including depression, although the effect size is weak and inconsistent across studies (54).

 

SOCIAL DETERMINANTS OF HEALTH

 

The broad conditions in which people are born, live, learn, work, play, worship, and age affect a wide range of health, functioning, and quality-of-life outcomes and risks throughout the life course, which together are known as the ‘social determinants of health’ (55). These can be divided into macro-level factors, such as government policy, meso-level factors, such as neighborhood and workplace, and individual factors, such as health behaviors and are broadly grouped into five domains: economic stability, educational access and quality, health care access and quality, neighborhood and built environment, and social and community context, which include gender and race. These social factors are more robust predictors of population health than either the provision of healthcare services or individual health behaviors and explain up to 80% of a person’s health (56).

 

Many of the risk factors for depression described earlier in the chapter include or are affected by social factors, such as childhood adversity, low socio-economic status, or lived environment. Many of these same factors also affect the risk of diabetes. For example, access to recreational spaces, safe housing and surroundings, clean air, and shops that sell nutritious and wholesome foods provide an environment where an individual can more easily choose behaviors that would reduce the risk of diabetes.

 

Diabetes-Specific Factors

 

Both psychological and biological mechanisms contribute to the increased risk of depression in people with diabetes.

 

PSYCHOLOGIOCAL FACTORS

 

The psychological model proposes that depression is an understandable response to the difficulties of living with a demanding and life-shortening long-term physical illness that is associated with potentially debilitating complications. This model is supported by a systematic review of 11 studies that found no difference in the prevalence of depression between those with undiagnosed diabetes, those with impaired glucose metabolism, and people with normal glucose metabolism (57). By contrast, an increased prevalence of depression was only found in those with diagnosed diabetes suggesting that the knowledge of the diagnosis and the burden of managing the condition and its complications are associated with the development of depression. A more recent meta-analysis showed an 11% and 27% increased risk of depression in those with pre-diabetes and undiagnosed diabetes, respectively, compared with people with normal glucose metabolism but this was lower than the 80% increase in those with known diabetes (58). The increase was only seen in people aged less than 60 years old and was partially explained by the presence of comorbid cardiovascular disease. Since this publication, studies from Mexico (59), Germany (60) and rural China (61) did not find increased rates of depression in people with undiagnosed diabetes. However, a large study from the Netherlands found a similarly increased rate of depression in those with diagnosed and undiagnosed diabetes (62).

 

Although these findings generally support the psychological model, it is important to recognize that the people with undiagnosed diabetes differ from those with diagnosed diabetes by more than just the knowledge of their condition. For example, those with diagnosed diabetes are likely to have had diabetes for longer and have developed complications and other co-morbidities that may affect their risk of depression.

 

EFFECT OF DIABETES ON BRAIN STRUCTURE AND FUNCTION

 

It is well recognized that acute hyperglycemia and hypoglycemia can affect mood (63, 64). This is unsurprising because the brain is dependent on a continuous supply of glucose as its principal source of energy, and changes in blood glucose levels rapidly affect cerebral function. However, longer term effects of diabetes on brain structure and function have also been seen in animal models of diabetes and in humans. In animals, diabetes negatively affects hippocampal integrity and neurogenesis, both of which are areas that are important in cognition and mood (65). In adults with type 1 diabetes, magnetic resonance imaging (MRI) studies have shown hippocampal atrophy together with increased prefrontal glutamate-glutamine-gamma-aminobutyric acid (GABA) levels in a way that correlates with mild depressive symptoms (65, 66). In the brain, insulin stimulates glucose uptake, in part by increasing the synthesis of the glucose transporters in neurons and neuroglia (67). Consequently, abnormal insulin signaling in the brain could affect glucose transport across the blood-brain barrier leading to reduced neuronal glucose uptake and neuronal loss. As the amygdala and hippocampus are the regions that contain a high density of insulin receptors, they may be disproportionately affected by insulin resistance, which is independently associated with depression (68).

 

At a cellular level within the hippocampus, diabetes is associated with an increase in astrocytes and microglia reactivity and apoptosis of pyramidal neurons, and reduced neurogenesis and synaptic plasticity with dendritic retraction (69). In addition to the changes in GABA, there are other molecular changes, including increased glucocorticoid signaling, reduced brain-derived neurotrophic factor (BDNF) production, increased mGluR2/3 activity and caspase 3 activation, and an increase in the TLR4/NFκB signaling pathway, together with increased production of reactive oxygen species and pro-inflammatory cytokines, such as TNF-β. These changes lead to increased apoptosis and decreased progenitor proliferation, which in turn lead to a decrease in the hippocampal size.

 

Depression-Specific Factors

 

Depression may increase the risk of diabetes through health behaviors as well as the biological effects of depression and its treatment with antidepressants.

 

ADULT HEALTH BEHAVIORS

 

Health behaviors play an important role in determining an individual’s risk of developing diabetes.

 

Diet

 

A healthy diet protects against many long-term conditions including diabetes, obesity, and depression. Both epidemiological studies and intervention studies have shown how maintaining normal weight, reducing fat, particularly saturated fat, and increasing the fiber content of the diet reduces the risk of type 2 diabetes (70, 71). Certain dietary patterns, such as the Mediterranean diet, are associated with a lower risk of diabetes (72).

 

High levels of refined sugars and saturated fats may also increase the risk of depression, while a Mediterranean diet and diets that include more vegetables, fruits, fish, and whole grains seem to be protective (73). Once present, depression may entrench less prudent eating habits, creating a vicious cycle where poor diet and depression reinforce each other while simultaneously increasing the risk of diabetes. Depression increases the risk of obesity, with those with depression being 58% more likely to develop obesity than those without (74).

 

Excessive alcohol intake is associated with an increased risk of diabetes (75). Alcohol misuse is one of the most prevalent mental disorders, especially in more affluent countries (76). About a quarter of those with alcohol dependency have co-morbid mental disorders including depression, where alcohol is often used as a coping mechanism to manage stress, anxiety, or depressive symptoms.

 

Physical Activity

 

The health benefits of physical activity are overwhelming and include a lowered risk of type 2 diabetes and depression. There is a graded response with some physical activity being better than none, but further benefits accrue with more physical activity. Avoidance of sedentary behavior is also important for health. People with depression are less physically active than the general population; a meta-analysis of 24 studies including 2901 people with major depression disorder found that compared to the general population, those with depression spent less time engaged in overall and moderate to vigorous physical activity and were more likely to be sedentary. People with depression were 50% less likely to meet the recommended physical activity guidelines of taking at least 150 minutes of moderate-to-high intensity physical activity in a week through a variety of activities (77). Over two-thirds of people with depression do not reach this target (78).

 

Smoking

 

Tobacco use is the single most preventable cause of death and disease throughout the life-course and increases the risk of diabetes by 30-40% (79, 80). Smoking is one of the most important modifiable risk factors of physical morbidity and mortality in people with mental illness (81). Adults with depression are twice as likely to smoke as adults without depression. There also appears to be a bi-directional relationship where smoking increases the risk of depression while people with depression are more likely to start smoking (82).

 

Sleep

 

The health benefits of sleep include a lower risk of diabetes and maintenance of a healthy weight (83). Sleep problems are a cardinal feature of depression with difficulty falling asleep and waking during the night, being common symptoms of depression (10).

 

BIOLOGICAL EFFECTS OF DEPRESSION

 

Several biological changes occur during an episode of depression that might increase the risk of diabetes. First, acute episodes of depression are associated with hyperinsulinemia and insulin resistance and are unaffected by antidepressant treatment (68). Depression is also associated with a state of chronic inflammation that is characterized by increased C-reactive protein, TNF-α, and proinflammatory cytokines that might partially explain the change in insulin sensitivity. These proteins are linked to sickness behavior in animal models of depression and in humans are associated with an increase in type 2 diabetes and the metabolic syndrome (84, 85). Depression is further associated with abnormalities of hypothalamic-pituitary adrenal (HPA) axis function, which manifests as subclinical hypercortisolism, blunted diurnal cortisol rhythm, or hypocortisolism with impaired glucocorticoid sensitivity (86). Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor expressed in several tissues, including the brain, gut, and pancreas. As described earlier, BDNF plays an important role in maintaining neuronal plasticity, including neurogenesis, synaptogenesis, and neuronal maturation. Depression decreases BDNF expression in the hippocampus and prefrontal cortex (87). Outside the brain, BDNF activation leads to reduced hepatic gluconeogenesis, increased hepatic insulin signal transduction, and protects against pancreatic β-cell loss. Serum BDNF concentrations are lower in people with diabetes (88).

 

ANTIDEPRESSANTS

 

Although essential components of the management of depression, it is possible that the use of antidepressants contribute to the risk of diabetes. Case reports, and observational studies have generally shown that people receiving antidepressant medications have a higher risk of diabetes but whether this relationship is causative remains unproven (89, 90). Randomized controlled trials have emphasized that antidepressants vary considerably in their association with weight gain and both hyperglycemia and hypoglycemic effects have been observed (89). Some antidepressants, including paroxetine, mirtazapine, and various tricyclic antidepressants are associated with significant weight gain which could increase the risk of diabetes in the long term. By contrast, buproprion is associated with weight loss (91).

 

CONSEQUENCES OF DIABETES AND DEPRESSION CO-MORBIDITY

 

The presence of depression in people with diabetes worsens both diabetes and depression outcomes (Figure 2).

 

Mortality

 

Mortality rates from physical illnesses, including cardiovascular disease, cancer, and diabetes, are higher in people with depression. Among people with diabetes, depression increases the risk of mortality by approximately 50% (92, 93). Where depression co-exists with anxiety, which is also more common in people with diabetes, mortality rates are further increased (94).

 

Depression Outcomes

 

Once depressive symptoms occur or a diagnosis of depression is made, the symptoms appear to be persistent and likely to recur in people with diabetes. A longitudinal study of 2,460 people with type 2 diabetes in a primary care setting found that 26% met the criterion for depression on at least one occasion, with incident depression occurring in 14% over a 3-year period (95). Recurrent or persistent depression occurred in two-thirds of those with baseline depression. In two other studies from the USA, self-reported depressive symptoms persisted in 73% of people 12 months after a diabetes education program (96) while major depressive disorder relapsed in 79% of people with diabetes over a 5-year period (97).

 

Depression is a major cause of excess hospitalization in people with diabetes and is the leading cause of psychiatric admissions in people with diabetes accounting for 6.1 admissions per 1,000 person years in people with type 1 diabetes and 7.05 admissions in people with type 2 diabetes in Australia, with higher admission rates for women (98). These rates are 2-3-fold higher than the general Australian population (99).

 

People with diabetes have an increased risk of completed suicide compared with the general population and are more likely to report suicidal ideation, one of the strongest predictors of completed suicide, and intentional self-harm (100). The risk of suicidal behavior is highest in young people with type 1 diabetes, in whom suicide may account for up to 7% of deaths. Suicidal ideation is also increased among adolescents and young adults with type 1 diabetes compared with the general population (15.0% vs. 9.4%) and is seen in all ethnic groups (101). It is likely, however, that the true incidence of suicidal attempts and completed suicides is considerably higher amongst people with diabetes because of ineffective identification and coding (100). Many hospital admissions for diabetes ketoacidosis or hypoglycemia of ‘unknown’ etiology result from insulin omission or overdose, but whether these are deliberate acts is frequently unrecognized or unrecorded. There is also anecdotal evidence that healthcare professionals are unwilling to record suicide as a cause of death because of the associated stigma. Suicide rates are higher in people with long-term health conditions than in people in the general population, but what makes diabetes stand out is access to insulin, providing a means for suicide either by omission or overdose, the latter of which is the commonest method of suicide in people with insulin-treated diabetes. 

 

Diabetes Outcomes

 

ACUTE METABOLIC COMPLICATIONS

 

People with type 1 diabetes and depression have an increased risk of admission to hospital with diabetic ketoacidosis and severe hypoglycemia. In one study involving 3,742 people with type 1 diabetes who attended the emergency room or who were admitted to hospital between 1996 and 2015, those with depression had a 2.5-fold increased risk of severe hyperglycemia events and an 89% increased risk of severe hypoglycemia (43). The risk was greatest within the first 6 months following a diagnosis of depression, when the risk was 7.14-fold higher for hyperglycemia events and 5.58-fold higher for hypoglycemia.

 

MICROVASCULAR COMPLICATIONS

 

An early meta-analysis showed that the risk of microvascular complications was increased with small to moderate weighted effect sizes of 0.17 to 0.32 (24). The increased risk was similar in people with type 1 diabetes and people with type 2 diabetes while sexual dysfunction and painful peripheral neuropathy seemed to be associated with the highest risk. Most of these studies were cross-sectional but a more recent meta-analysis of 16 studies that examined the relationship between baseline depression and incident diabetes complications found that depression was associated with a 33% increased risk of incident microvascular disease (39). Most studies reported a composite of neuropathy, retinopathy, and nephropathy but one study reported nephropathy alone and found a 18% increase in incident chronic kidney disease (102). Depression is associated with a 68% increased risk of a first diabetes-related foot ulcer but not ulcer recurrence (103). This contrasted an earlier study that found a third of all individuals with diabetes-related foot ulcer had depression and that depression was associated with a threefold increased risk of dying (104).

 

MACROVASCULAR COMPLICATIONS

 

A recent meta-analysis has reported that incident macrovascular complications were increased by 38% in people with baseline depression (39). Most studies used a composite macrovascular outcome which included atherosclerotic vascular disease, myocardial infarction, and stroke as well as congestive heart failure and stroke. Some studies also included cardiovascular procedures, such as coronary artery bypass grafting or other revascularization techniques. Only one study reported separate outcomes for stroke (HR 1.22) and coronary heart disease (HR 1.32) (102).

 

QUALITY OF LIFE

 

Quality of life has been assessed by several different measures in people with diabetes and depression, including the Diabetes Specific Quality of Life scale and SF-36. These studies consistently show that quality of life is impaired in people with the co-morbidity (105). The effect of diabetes and depression appears to be additive across several domains with the exception of mental health where most of the effect stems from depression (106).

 

COST OF TREATMENT

 

The presence of depression among people with diabetes can substantially increase health care costs. An analysis of 147,095 adults living in the US found that depression and diabetes alone increased healthcare expenditure by $2,654 and $2,692, respectively, compared with neither condition but when both conditions occurred together, the cost was increased by $6,037 (107). Based on these figures, the estimated total cost of treating co-morbid diabetes and depression in the US was $77.6 billion per year. A more recent study found that total health costs increased from $11,550 for people with diabetes alone to $16,511 for people with diabetes and depression (108). This was in part driven by higher rates of hospitalization (26.1% vs 17.4%) and emergency room visits (55.3% vs 43.0%). Ironically, the increased cost occurred despite decreased healthcare utilization. In a US study of 22,642 people with diabetes enrolled in the 2019 Behavioral Risk Factor Surveillance System, those with a diagnosis of a depressive disorder were 82% more likely to report not seeing a doctor because of healthcare costs in the previous year (109).

 

DIABETES MANAGEMENT

 

Glycemic Levels

 

It has been hypothesized that changes in glycemic levels may mediate the association between depression and diabetes micro- and macrovascular complications and mortality. However, studies that have investigated this have produced inconsistent findings. An early meta-analysis reported a small to moderate association between depression and elevated HbA_1c for type 1 diabetes and type 2 diabetes, but included mainly cross-sectional studies that precluded an inference on temporality (110). A recent meta-analysis investigated the longitudinal association between self-reported depressive symptoms and HbA_1c. The six longitudinal studies had a combined sample size of 3,683 participants who were followed for a mean period of 37 months (range six months to five years). There was a small significant association between baseline depressive symptoms and subsequent HbA_1c levels (111). A further meta-analysis of 14 studies in children and adolescents with type 1 diabetes reported a correlation between depressive symptoms and HbA_1c (112). The timing of the diagnosis of diabetes and depression may also be important. In a study of 11,837 people with type 2 diabetes registered with the UK Biobank followed for a median of 6.9 years, those diagnosed with major depression decades prior to type 2 diabetes had lower HbA_1c over time compared to individuals without depression and those diagnosed closer to their diabetes diagnosis date (113). For individuals whose depression was diagnosed after diabetes, the time since the onset of depression also shaped the trajectory of HbA_1c, with the adverse effect of a diagnosis of depression on HbA_1cbeing greatest in those whose diagnosis occurred shortly after the onset of diabetes. Furthermore, the variability of HbA_1c within any individual was 16% higher in those with post-diabetes depression (113).

 

Diabetes Self-Management

 

Optimizing glucose levels is highly dependent on self-care activities that include regular glucose monitoring, taking medication as prescribed, and engaging in health behavior change to improve diet and physical activity. Depression compromises an individual’s ability to self-manage their diabetes. A meta-analysis of 47 studies reported that depression significantly reduced the likelihood of engaging in self-management behaviors, including missed medical appointments, less medication taking and glucose monitoring, and less foot care (114, 115). Similar to anti-diabetes medications, people with co-morbid depression are also less likely to take anti-hypertensive medications and lipid-lowering therapy (115). Depression is associated with a less nutritious diet that is characterized by lower consumption of fruit and vegetables and increased refined carbohydrates (116). Physical activity is reduced while smoking and alcohol consumption is increased (115). The effect of depression appears to be mediated through its adverse effects on self-efficacy and illness perception (115).

 

MANAGEMENT OF DIABETES AND DEPRESSION

 

Preventing Depression in People with Diabetes

 

The implication of the psychological model of depression in diabetes is that healthcare professionals could play an important role in moderating the psychological burden associated with diabetes by considering the way in which the diagnosis of diabetes is conveyed and the psychosocial support that is given through an individual’s journey with diabetes. Many people with diabetes experience stigma, some of which stem from their healthcare team. They report feelings of shame and blame because they are held responsible for developing overweight, obesity, or diabetes (117). However well-intentioned the healthcare professional is, it is clear that evoking these feelings is associated with worse clinical outcomes. By contrast, the use of person-centered, non-stigmatizing language can create a trusted and safe space for meaningful clinical discussion (118).

 

Several individual and group-based interventions with the aim of preventing the development of depressive symptoms have been trialed in people with diabetes. Of the twelve studies reported in a recent narrative review, half had a positive effect (119). Features associated with a reduction in the likelihood of developing depressive symptoms included diabetes self-management education and support, problem-solving and resilience-focused approaches, and emotion-targeted techniques.

 

Screening and Diagnosis of Depression

 

Given the importance of depression in people with diabetes and the availability of effective treatment, there is a strong rationale to screen for depression in people with diabetes (120), not least because depression is under-recognized in clinical practice. Primary care doctors do not diagnose and treat depression in 50–77% of cases (121, 122), while diabetologists only initiate antidepressant treatment in approximately one-third of their patients with clinical depression (123). Similarly diabetes nurses do not recognize depression and anxiety, missing 75-80% of those with the conditions (124).

 

A formal diagnosis of depression requires a validated interview method, such as the Mini International Neuropsychiatric Interview (MINI) or Composite International Diagnostic Interview (CIDI). No laboratory investigations are needed to diagnose depression, but it is prudent to rule out general medical conditions that may mimic the symptoms of a depressive episode. The diagnostic interviews are too labor-intensive to make them suitable for population screening or for screening in primary care or other clinical settings. However, numerous brief screening instruments or questionnaires that are simple to administer and have reasonable clinical specificity and sensitivity have been developed (Table 4). Not all screening questionnaires are appropriate because of the overlap of symptoms of depression and diabetes, including tiredness, lethargy, lack of energy, appetite changes, and sleeping difficulties. However, the Beck Depression Inventory (BDI), the Centre for Epidemiologic Studies Depression Scale (CED), the Patient Health Questionnaire (PHQ-9), and the Hospital Anxiety and Depression Scale (HADS) are all suitable for use in people with diabetes (22). Of these, the PHQ-9 is the best validated and most widely used in people with diabetes (125). It is also short, containing nine questions making it easy to administer in primary and secondary care settings. It has been suggested that the cut-off for major depression, which is ≥10 in primary care populations, should be increased by two points to ≥12 points in people with diabetes to help differentiate between diabetes-related symptoms and depressive symptoms (126).

 

Table 4. Reported sensitivity, specificity, positive and negative predictive value and reliability and validity in tools screening for depression in people with diabetes. Adapted from (22).
Tool	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Reliability/ Validity (α)
CES.	60.0 – 100	86.7	28.6	97.0	0.80
PHQ-9	66.0 - 100	52.0 - 80.0	43.8 - 64.4	93.4 - 100	0.80 - 0.84
BDI	82.0 - 90.0	84.0 - 89.0	59.0 - 89.0	82.0 - 97.0
HADS	74.0 - 85.0	37.5 – 86.0	28.0 – 49.0	95.0 - 96.0	0.55 – 0.78

Sensitivity= Number of true positives (cases of depression)/Number of true positives + number of false negatives; Specificity = Number of true negatives/ Number of true negatives + false positives; Positive Predictive Value (PPV) = the proportion of cases with positive test results who are correctly diagnosed. Negative Predictive Value (NPV) = the proportion of cases with negative test results who are correctly diagnosed.

 

Another simple approach with good sensitivity and reasonable specificity is to ask two questions (127):

• During the past month, have you been bothered by having little interest or pleasure in doing things?
• During the past month, have you been bothered by feeling down, depressed, or hopeless?

 

If the answer to either is yes, and the person with diabetes wants helps with this problem, the healthcare professional should undertake a diagnostic interview and offer appropriate referral and treatment.

 

Although screening for depression is acceptable to people living with diabetes (128), its value has not been proven and remains controversial despite being recommended by several professional bodies, including the International Diabetes Federation (129), American Diabetes Association (130), and the UK National Institute for Health and Clinical Excellence (131). A 2008 Cochrane review reported that depression screening alone in the general population had little or no impact on the detection and management of depression (132). However, a more recent meta-analysis of depression screening interventions, many of which included additional components beyond screening, showed these were associated with less depression or depressive symptoms in the general population 6-12 months after screening (133). This issue is important because of the potential harms of screening, which include the stigma associated with depression, the risk of transient distress being labelled as having depression, and discrimination from insurance companies, and so studies demonstrating the effectiveness of screening in people with diabetes are needed.

 

Primary care depression screening in people with diabetes was introduced in the UK in 2006 as part of the Quality and Outcomes Framework (a performance management and payment scheme for NHS general practitioners) with mixed results. In one semi-rural general practice, 365 of 435 eligible people with diabetes or ischemia heart disease were screened, but only three people without a current diagnosis of depression screened positive and none were subsequently diagnosed with depression (134). By contrast, in a study of 112 general practices in Leeds, UK, the rates of diagnosis of depression increased from 21 to 94 per 100,000 population per month after introduction of the screening compared with 27 to 77 per 100,000 population per month in people without screening (135). Despite the increased diagnosis, after an initial increase in antidepressant treatment, screening had little impact on prescribing habits.

 

Two clinical trials of depression screening in people with diabetes have not demonstrated a benefit. In the first study from the Netherlands, written feedback was provided to both the person with diabetes and the doctor following depression screening, but this did not change use of mental health services or improve depression scores compared with routine care (136). The second study from the USA examined the benefits of training healthcare technicians about the importance of discussing mental health with their patients (137). Although there was an improvement in depressive symptoms, this was no different from the control group and all the participants continued to have moderate to severe depressive symptoms.

 

Several reasons may explain the lack of effectiveness of depression screening in people with diabetes including a low acceptance of screening and subsequent referral to further care by people with diabetes, failure to screen those at highest risk of depression, reluctance by healthcare professionals, and generally poor quality of depression care in primary care systems (138). While identification of those with depression is an essential first step in treatment, screening alone will not improve clinical outcomes unless linked to appropriate care pathways and treatment (120, 139).  By contrast, studies of care pathways that have clearly linked screening to diagnosis and treatment improved depression outcomes (140, 141).

 

Treatment of Depression

 

The main aims of treatment are to improve both mental health and diabetes outcomes (Table 5). Ideally, any depression treatment for people with diabetes would simultaneously improve both sets of outcomes, but from a clinical perspective, the rapid improvement or remission of depression should be the first priority (138). This recommendation partly reflects the time course of treatment responses, which can be seen within 2–4 weeks for depression but also because treating the depression may aid optimal diabetes self-management.

 

Table 5. Aims of Depression Treatment in People with Diabetes
Mental health outcomes	Diabetes outcomes
Decreased depressive symptoms	Optimal diabetes self-management
Remission of depression	Decreased HbA1c
Suicide prevention	Increased time in glucose range
Improved health-related quality of life	Less hypoglycemia
Restoration of psychosocial functioning	Reduced long-term complications
	Reduced mortality

 

Until relatively recently, people with diabetes have been under-represented in trials of depression treatment and so, there were few studies examining antidepressant and psychological treatment of depression. However, over the last two decades, the evidence base for treatment has grown substantially and has clearly indicated that treatment with either psychological therapies or antidepressant medication is effective (142) .

 

PSYCHOLOGICAL TREATMENT

 

Various psychological treatments, including cognitive behavioral therapy, problem-solving, and psychodynamic techniques have been used to treat depression in people with diabetes. Different members of the healthcare team have been utilized to deliver these interventions in primary and secondary care either in person or virtually through the internet or telephone (142, 143). The majority of trials have included people with type 2 diabetes with no trials conducted solely in people with type 1 diabetes.

 

A meta-analysis of psychological treatments, including group-based and online therapies, reported they were effective for the treatment of depression with large effect sizes (142). The follow-up ranged between 4 weeks and 1 year and thus, the longer term effects are unknown. Cognitive behavioral therapy is the most studied intervention, with its core components being cognitive restructuring, behavioral activation, and problem solving. This intervention was judged to be moderately effective in two recent meta-analyses (144, 145). Mindfulness also has an moderate benefit in treating depression (146), but there is mixed evidence on the benefit of motivational interviewing in reducing depressive symptoms (147, 148). Although psychological treatments are better than no treatment, the rates of recovery are low post-psychological intervention (17% vs 9% in controls) (149), indicating that many people will need additional support if they are to recover fully from their depression.

 

There is more debate about the effect of psychological interventions on diabetes outcomes (138) with one systematic review reporting a reduction in HbA_1c of ~0.6 % (6 mmol/mol) (150) while another only reporting a non-significant improvement in glycemic levels (151). A meta-analysis of cognitive behavioral therapy showed a statistically significant but clinically insignificant reduction in HbA_1c of 0.14% (1 mmol/mol). There was a greater effect on HbA_1c if the intervention was delivered in a group-based and face-to-face fashion and included psycho-education, behavioral, cognitive, goal-setting, and homework assignment strategies as central components (145).

 

One of the challenges in delivering psychological interventions is the lack of trained personnel, a situation which appears to be worsening, at least in the United Kingdom (152). To address this deficiency, interventions have been designed to be delivered online or using mobile technologies, a trend which has increased dramatically since the Covid-19 pandemic. This has the potential to increase accessibility to treatment while limiting costs (142). One meta-analysis reported large effect sizes on depressive symptoms for online therapy and a moderate effect for telephone interventions, although no change in diabetes outcomes was seen (142). The beneficial effect on depressive symptoms up to 12 months after the interventions was supported by another systematic review, albeit again without improvement in diabetes outcomes (153). However, this finding was contradicted by a recent meta-analysis of 24 randomized controlled trials, 14 non-randomized controlled trials and three observational studies which reported no significant effect on depression outcomes (154). The discrepancy may partly explained by drop-out rates which vary from 13% to 42%; for those who remain in treatment, the interventions appear effective (155) and so the challenge will be to deliver services that engage people with diabetes and depression.

 

In the United Kingdom in 2008, the National Health Service introduced the Improving Access to Psychological Therapies (now NHS Talking Therapies for anxiety and depression) program to improve the delivery of, and access to, psychological therapies for depression. By 2021/22, nearly 1.2 million people had accessed these services. Although the clinical workforce is appropriately trained and supervised, many practitioners do not have experience of the challenges of living with diabetes. To address this issue, the Southampton diabetes team has formed a partnership with the local NHS Talking Therapies service. A practitioner joins the multidisciplinary team in the young adult clinic once a fortnight, helping to engage the person with diabetes and facilitate referral and access to the service. There is also a wider benefit to the city as the NHS Talking Therapies team have become much more aware of the challenges of living with diabetes. Introducing this service led to reductions in depressive symptoms and diabetes distress and was well received by people with diabetes and staff alike (156).

 

ANTIDEPRESSANTS

 

Antidepressants have been used to treat depressive symptoms since the late 1950s. There are many different antidepressants, but these fall into five main categories:

• Selective Serotonin Reuptake Inhibitors (SSRI)
• Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
• Noradrenaline and Specific Serotoninergic Antidepressants (NASSA)
• Tricyclics (TCA)
• Monoamine Oxidase Inhibitors (MAOI)

 

The discovery of the first clinically useful antidepressants paved the way for an understanding of the underlying biological or neuroanatomical basis for depression. The first antidepressant was the tricyclic antidepressant (TCA), imipramine. It was first synthesized in 1951 as a potential antipsychotic and derived from work on chlorpromazine, which had pronounced sedative and antihistamine effects (157). Although imipramine has no antipsychotic effect, it was found to possess antidepressant effects. Other TCAs, such as amitriptyline, were subsequently synthesized by modifying the structure of imipramine. Iproniazid, a monoamine oxidase inhibitor (MAOI), was the next antidepressant to be discovered; again, this drug was initially developed for a different purpose, the treatment of tuberculosis, before its antidepressant effect was recognized. MAOIs prevent the breakdown of monoamine neurotransmitters (e.g. noradrenaline, dopamine and serotonin) while TCAs block the uptake of serotonin and noradrenaline resulting in an elevation of the synaptic concentrations of these transmitters. An understanding of the pharmacology led to the hypothesis that depression was caused by low catecholamine levels in the central nervous system (158). Both TCA and MAOI affect the serotonin system and in 1967, Coppen proposed that this was a more important neurotransmitter in depression than noradrenaline (159). Fluoxetine was the first in the class of selective serotonin re-uptake inhibitors (SSRI) and was developed by design following a search for molecules that could selectively block the re-uptake of serotonin. A major advantage of this approach was that it minimized adverse effects such as cardiovascular toxicity and anticholinergic effects. First synthesized in 1972 and launched in 1987, fluoxetine became the most widely prescribed drug in North America by 1990 (157). Although better tolerated than earlier antidepressants, SSRI still caused side effects, including sexual dysfunction, appetite change, nausea and vomiting, irritability, anxiety, insomnia, and headaches. In an attempt to reduce these adverse effects, other antidepressant classes were developed, including serotonin and noradrenaline reuptake inhibitors (SNRI, e.g. venlafaxine) and noradrenaline and specific serotoninergic antidepressants (NASSA, e.g. mirtazapine).

 

Antidepressants reduce depressive symptoms in people with diabetes as well as the general population; however, there have been relatively few formal efficacy trials in people with diabetes and even these have been are limited to a small group of antidepressants, including fluoxetine, sertraline, paroxetine, citalopram, escitalopram, agomelatine, nortriptyline, and vortioxetine (138, 160). Furthermore, most studies are short-term and so the medium- and long-term sustainability of pharmacological interventions after treatment cessation is uncertain. A systematic review and meta-analysis suggested that all antidepressants have similarly large effect size on depression outcomes as long as adequate doses are used (151). However, a more recent network meta-analysis of 12 randomized controlled trials involving 792 participants reported that there may be a greater reduction in depressive symptoms with escitalopram and agomelatine (160). Vortioxetine was associated with the greatest reduction in HbA_1c with escitalopram, agomelatine, sertraline and fluoxetine also associated with a fall in HbA_1c. No antidepressant was found to disrupt glucose levels (160). These differences should be viewed with caution as the number of trials and participants for each drug is small. Further head-to-head randomized controlled trials would help us understand more about the relative benefits and safety of different antidepressants on depression and glucose metabolism.

 

Given the similar efficacy between antidepressants, the treatment of choice depends largely on the side-effect profile, individual preference, and response. SSRI are widely used as first-choice agents because they are less cardiotoxic than TCA and are safer in overdose. Some antidepressants, notably mirtazapine, paroxetine and some TCA, may cause undesirable weight gain (91) and should be used with caution in people with type 2 diabetes. By contrast, buproprion, which is available in the USA, is associated with weight loss and, unlike SSRIs, does not appear to worsen sexual function (161).

 

The aim of treatment is complete remission of depressive symptoms. Treatment should be maintained at an adequate dose for at least 4–6 months after remission of symptoms to reduce the risk of relapse and recurrence. Recovery from depression may lead to a change in the individual’s behavior and routine which may have an effect on diabetes self-management. For example, if appetite improves, insulin requirements may increase, while on the other hand, if the person becomes more active, they may decrease. An individual approach is therefore needed to support the person’s glycemic management. There are important drug–drug interactions between antidepressants and oral anti-diabetes agents through inhibition of the cytochrome P450 3A4 and 2C9 isoenzyme. For example, the use of fluoxetine may potentiate the effect of sulfonylureas precipitating hypoglycemia (84).

 

EXERCISE

 

Many depression guidelines recommend exercise and other aspects of a healthy lifestyle as an integral component of management. Coupled with the importance of exercise in glycemic management, interventions to increase physical activity have been trialed and shown to be effective in reducing depressive symptoms and improving glycemic measures (162).

 

PREVENTING SUICIDE

 

A detailed description of the many effective interventions to prevent suicide is beyond the scope of this article (163),however, it is important for diabetes healthcare professionals to understand how to identify those at risk, particularly given the high prevalence of suicidal ideation and acts and immediate availability of a means of suicide. It is crucial that suicide can be discussed with people with diabetes in a safe and non-judgmental way. Talking about suicide remains highly stigmatized and choosing to reveal suicidal ideation can be difficult. The isolation that suicidal people feel can be reinforced by a critical response from the healthcare team. A recent survey of diabetes healthcare professionals found that the vast majority of respondents believed it is their professional responsibility to ask about suicide and self-harm, with nearly half reporting that this should be addressed every visit (164). Around three-quarters reported feeling comfortable discussing these issues, but those who were more reluctant to do so were concerned about their lack of training and uncertainty about what to do if someone reported self-harming behavior. Once an individual has discussed suicidal intention, it is important that the person is supported and has access to mental healthcare and suicide prevention interventions.

 

ORGANIZATION OF CARE

 

A common model of care of depression is the Stepped Care Model which provides a framework in which service delivery is organized to help those with depression, their caregivers, and healthcare professionals identify and access the most effective interventions (Figure 3) (131). The model utilizes a sequenced treatment process depending on the severity of depressive symptoms and response to previous treatments. The model allows a rational approach to the treatment of depression, while reducing costs and side effects of antidepressant through more appropriate prescribing.

 

 

The first step involves the recognition of depression through screening and diagnostic interview and is reserved for those with suspected depression. For those with mild depression, step 2 involves the use of guided self-help, computerized CBT, and brief psychological interventions which can be delivered by the primary healthcare team or psychologist. The third step, which is also delivered in primary care settings, is indicated for those who do not respond to step 2 interventions, or for those with moderate and severe depression. Treatments include medication, high-intensity psychological interventions, or combined treatment. Step 4 corresponds to severe or treatment-resistant depression; the interventions are similar to those used in step 3 but now involve the mental health team. The final step is for those with life-threatening depression and/or severe self-neglect. In addition to medication and high-intensity psychological interventions, electroconvulsive therapy may be required under the supervision of a mental health crisis services and involve hospitalization.

 

A meta-analysis of 18 randomized controlled trial of stepped care showed improvements in depressive symptoms and better remission rates (165). A significant benefit on quality of life was also observed. More people in the stepped care model were prescribed antidepressants.

 

The increasing fragmentation of medical services and super-specialization in modern medicine has resulted in clinicians focusing on the conditions with which they are most familiar and being unable or unwilling to recognize and treat comorbid illnesses when they occur (166). The need for integrated holistic healthcare has never been greater but many diabetes healthcare professionals feel ill-equipped to manage depression. To address this, a case management model known as collaborative care was developed in the U.S., that involves a multidisciplinary team working together to identify and treat depression within primary care settings. The prototype intervention led to improvements in depression symptoms but without change in glycemia (167). Subsequently, greater attention was paid to intervention strategies for diabetes, resulting in simultaneous improvements in glycemic and blood pressure management and improved depressive symptoms (140). In a meta-analysis of five studies from the U.S., collaborative care was shown to be a clinical- and cost-effective treatment of depression, with a moderate effect size for depression outcomes and a small effect size for glycemic levels (142, 168).

 

CONCLUSION

 

Diabetes and depression remain a considerable clinical challenge. While an awareness of this co-morbidity has increased in recent years, this has not necessarily translated into better care or outcomes. Effective treatments are available and these need to be made available to those with diabetes and depression in clear treatment pathways. There are grounds for considerable optimism as the scientific knowledge that underpins clinical practices has expanded markedly in the last two decades. However, further research is needed to understand what can be done to prevent depression in people with diabetes and to identify the optimal treatment for an individual that improves both depressive symptoms and diabetes outcomes.

 

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