The US population is aging. In the last 100 years the life expectancy has increased by 30 years. In 2004, 12.4% of US population was in the Medicare age group and this percent is expected to increase progressively in the future . In this segment of the population, cardiovascular disease is by far the main cause of mortality in both men and women. This justifies cardiovascular prevention as a subject of academic research and policy debate. Lipid pharmacological intervention is one of the most successful cardiovascular preventative interventions. Concerns about its safety and efficacy in this age group have led different countries to adopt different strategies concerning the use of lipid lowering drugs in the elderly. This is based on physiologic, socio-economic and ethical considerations.

Lipoproteins are large particles with a hydrophilic surface and a hydrophobic core. The structure of the surface consists of protein referred to as apolipoproteins and phospholipids. The core contains free and esterified cholesterol and triglycerides. The apolipoproteins are responsible for the binding of the lipoproteins to receptors and enzymes and therefore direct lipoprotein metabolism. Table 1 shows the lipoprotein classes:

The most recent average levels for lipoproteins in the US are reported in the NHANES 1999-2002 . Table 3 shows these levels for the older age groups.

There were ethnic differences in the distribution of these concentrations: Hispanic subjects of both gender had higher total cholesterol and triglycerides and lower HDL cholesterol while Nonhispanic black women had higher HDL cholesterol and lower triglyceride level. There was a progressive decrease in the level of total cholesterol, and a trend towards increase in the triglyceride level from 1960 to 2002. The trends are particularly striking in older subjects and are probably accounted for by the increased prevalence of treatment with lipid lowering drugs and of obesity. Across all age groups, triglycerides increased with aging and reached a peak in men aged 50-59 and women aged 60-69. Apo B increased progressively with age from the younger group to the elderly groups, and this was associated with an increased prevalence of small dense LDL. HDL cholesterol did not seem to vary with age.

The data show an increase in the number in atherogenic particles with age and a decrease in their number in the oldest population group. As a result, studies show changes occurring with age depending on the population studied. This variable trend with age can be explained by three factors: increased prevalence of metabolic syndrome, attrition (survival bias) and frailty.

Most studies have shown that the prevalence of metabolic syndrome increases with aging . Aging parallels the changes occurring with metabolic syndrome in both carbohydrate and lipid metabolism. The total cholesterol, Apo B, the prevalence of small dense LDL and triglyceride concentration are increased while HDL cholesterol decreases. Lipoprotein kinetics studies have shown a decrease in fractional clearance rate of VLDL, IDL and LDL Apo B as well as an increase in VLDL Apo B production . The Apo A1 kinetics shows an increase in both production and removal, and the changes are more pronounced in men . On the other hand, metabolic syndrome is a strong risk factor for increased mortality through cardiovascular disease and cancer , and a large number of patients are lost in the transition from younger to an older cohort (survivor bias). Longitudinal studies show the trend for decrease in VLDL and LDL concentration with age to be less striking when compared with cross sectional studies.

The increase in the prevalence of metabolic syndrome with age is shown in national data. In the age group 60-69 it approaches 50% of the population, with the highest prevalence in Hispanic and Nonhispanic black women. In postmenopausal women, the lipids correlate well with BMI, insulin levels and the amount of intra-abdominal fat showing again the strong impact of metabolic syndrome on lipoproteins in older subjects . The increased prevalence of metabolic syndrome in the old is not associated with changes in energy intake but rather with decreases in energy expenditure and this in turn is associated with decreased functioning . In addition the trends towards reduction of body weight seen in longitudinal studies of elderly subjects are associated with a disproportionate reduction in lean body mass, further decreasing the ability to function .

As related to the increased prevalence of metabolic syndrome, there is an increased prevalence of diabetes in the elderly . Disorders of carbohydrate metabolism do not increase with age after adjustment for visceral obesity . The presence of diabetes in suboptimal glycemic control results in abnormalities of lipoproteins of the same type as those of metabolic syndrome but much more severe, in proportion to the degree of hyperglycemia. Other causes of secondary hyperlipidemia which are more prevalent in the elderly age group are those of untreated or sub-optimally treated hypothyroidism, chronic kidney disease and liver disease. These have to be ruled out at the time of the assessment of lipoproteins.

Attrition contributes by selecting in the older population groups survivors with lower levels of major risk factors. Consequently the prevalence of severe familial dyslipidemias diminishes in the older age groups.

Frailty is a syndrome associated with aging and increasing in frequency with age. There is no consensus definition of frailty. The syndrome encompasses weakness, fatigue, weight loss, decreased balance, low level of physical activity, slowed motor processing and performance, social withdrawal, mild cognitive changes and increased vulnerability to stressors . It is associated with weight loss, increased inflammatory markers , decreased level of IGF-1 , 25-hydroxy vitamin D , DHEAS and hypercoagulable state . It is usually associated with a lowering of total, LDL and non-HDL cholesterol . The average Lp (a) level seems to be unchanged with age . It is conceivable that the stable levels of Lp (a) with aging represent the effect of two opposite effects: attrition tending to diminish the levels and frailty increasing the levels and paralleling the rise of inflammatory markers.

Socioeconomic factors, comorbidity and treatment with lipid lowering drugs also contribute to changes in lipoproteins in the elderly. By 2003, 10.2% of the population over age 65 years was living under the nation’s poverty level . Of these 41.6% reported not having natural teeth. As measured by Healthy Eating Index, only 8.8% of the people over age 65 below the poverty level have a “good” rating . Socioeconomic factors are most of the time associated with comorbidity. Neurological or psychiatric disorders may result in decreases in socioeconomic status and ultimately result in malnutrition. Cancer and frequent hospitalizations contribute to the deterioration of the nutritional status. In some studies, a paradoxical association of high non-HDL cholesterol with survival or recovery from disability in basic activity of daily living was documented . An analysis of the data shows a trend towards increased risk of myocardial infarction and stroke and a decreased likelihood of disability and cognitive impairment to be associated with higher non-HDL cholesterol.

The current NCEP guidelines for treatment of adults with hyperlipidemia do not have age limits but specify that “clinical judgment” is necessary for management of patients older than 65 years. The AHA Evidence-based Guidelines for Cardiovascular Disease Prevention in Women: 2007 update specifies that “many studies used to formulate recommendations did not include older women, especially those >80 years of age”. Because of this gap in knowledge the need for clinical trials in the very old is being raised frequently.

The fact that the number of atherogenic particles, expressed as total cholesterol or LDL cholesterol or Non-HDL cholesterol or Apo B concentration, is a risk factor for coronary artery disease was known since the 1950’s. Numerous cohorts, including elderly enrollees reported a high risk of coronary artery disease for subjects with high but also with low cholesterol concentrations . This phenomenon was interpreted as a loss of ability of total cholesterol to predict coronary events, increasing with age . This lack of association of coronary disease with total cholesterol levels seems to be more striking in elderly women . A recent meta-analysis of the relationship between total cholesterol and coronary events shows a significant association for men aged 65 to 80 years but none for women over 65 years or for men over 80 years . Non-HDL cholesterol does not appear to be a better predictor of cardiovascular risk in older subjects. The loss of power of total cholesterol concentration to predict events is shared by other risk factors such as systolic blood pressure, BMI, cigarette smoking and alcohol. This difficulty in identifying subjects at higher cardiovascular risk in older populations was attributed to multiple confounders.

The most important confounder is frailty. With aging the prevalence of frailty increases, and since frailty results in lower cholesterol level and higher risk of death, high total cholesterol in the very old is shown in many studies to be a marker of longevity . Low cholesterol is associated with a poor prognosis in the very old and predicts an increased risk of death from infection and cancer . Although frailty is associated with weight loss, obesity is not a negative risk factor for frailty, and some authors believe that it might predispose to frailty later in life . Since frailty may occur in patients with advanced atherosclerosis, low cholesterol may predict cardiovascular events. This results in a “J” curve of relationship between cholesterol and coronary risk . The highest risk of death, including death from cardiovascular disease, is present in subjects with low cholesterol and low BMI or low serum albumin . The association between low cholesterol and frailty is also accountable for data showing low cholesterol as a predictor of dementia . Because of the fact that there is no consensus of an easy definition of frailty, there are no data showing the relationship between total cholesterol and coronary disease corrected for frailty. For other forms of atherosclerosis the predictive effect of cholesterol is variable.

Other confounders are “survivor bias” and the “regression dilution” of cholesterol levels when multiple measurements are available. If the mean of multiple readings is used as a predictor, the data tend to regress towards the mean of the population reducing the variability. Corrections for this error or use of cholesterol values 5 years prior to death predict more accurately the risk of coronary death . Another correction was presented from the Framingham Study introducing the concept of “life-time risk of a coronary event” which is higher for subjects with high cholesterol at all ages .

Cholesterol is not included in engines for stroke prediction and a large meta-analysis including 450,000 patients failed to show a relationship between total cholesterol and stroke . More recent studies have documented a relationship between total and LDL cholesterol and thromboembolic, but not hemorrhagic, stroke . The relationship between hemorrhagic stroke and low cholesterol has been questioned since this association was noted in the MRFIT cohort in subjects with uncontrolled hypertension . This relationship was also observed in more recent studies and attributed to excess alcohol intake . Although the average age for stroke is higher than the average age for myocardial infarction, there is no recent analysis of cholesterol and stroke taking into account both type of stroke and age.

Peripheral arterial disease is a form of atherosclerosis in which the average age of the subject is 10-15 years older than that of cohorts of patients with coronary artery disease. As opposed to coronary artery disease, in most recent cohorts, the diagnosis is made by noninvasive tests in asymptomatic individuals. Consequently its prevalence does not reflect the risk factors for events but reflects the risk factors for progression of atherosclerosis. In most large cohorts with populations screened for peripheral arterial disease, subjects with low ankle-brachial index have a significantly higher LDL and total cholesterol, after adjustment for age . High total cholesterol is a risk factor for progression of arterial occlusion and for occurrence of peripheral arterial disease in patients with diabetes .

In statin-treated patients aged 65-70 years, LDL cholesterol remains a powerful predictor of coronary heart disease . This supports the concept of more aggressive cholesterol lowering therapy in this group. The limitation of these data is the fact that the population was restricted to subjects selected by their physicians to receive statins.

Triglycerides are associated with cardiovascular risk in middle age cohorts. A recent meta-analysis including 29 Western countries cohorts and 262,525 participants showed the top quintile of serum triglycerides having 72% higher risk than the lowest quintile, with a very robust level of statistical significance . A similar study including 96,224 participants from Asia-Pacific Region reported for the highest triglyceride quintile a 80% increase in the risk of coronary events, a 70% increased risk of coronary death and a 50% increased risk of stroke . The investigators reported that the data were similar in all age groups, in both genders. A study including only participants over age 65 years showed triglycerides to be a powerful independent predictor of cardiovascular disease in women but not in men .

HDL cholesterol is the most powerful lipid predictor of cardiovascular risk in middle-aged men and women. Subjects with high HDL cholesterol are more likely to achieve high longevity . Conversely, healthy subjects over age 80 have high HDL cholesterol levels compared with middle-aged subjects, and their offspring has higher HDL cholesterol compared to the age-matched population . These subjects seem to have also larger HDL particles, suggesting an enhanced reverse cholesterol transport . Cohort studies have documented the fact that HDL cholesterol loses much less of its predictive power with advancing age than LDL cholesterol. In the Cardiovascular Health Study low HDL cholesterol was the only lipoprotein associated with the risk of myocardial infarction . In the Honolulu Heart Study low HDL cholesterol was a powerful predictor of non-hemorrhagic stroke . In the Leiden 85-Plus Study subjects in the lower tertile of low HDL cholesterol had 2 times the risk of coronary death and 2.6 times the risk of fatal stroke when compared with those in the upper tertile . In this age group HDL cholesterol is also a predictor of total mortality. In nursing home residents low HDL and low albumin were proposed as a mean to diagnose frailty and predicted a 2.5 to 4 fold increase in short term mortality . Since frailty is associated with both low HDL and low total cholesterol, the ratio of these parameters was proposed to predict cardiovascular events in old subjects. In an analysis of the data of the PROSPER Study, the investigators reported that low HDL cholesterol in elderly patients predicts the risk of fatal and nonfatal coronary events and stroke as well as the benefit of statin therapy .

Apo B and Apo A1 are important predictors of cardiovascular risk and some studies have reported that they might be superior to the measurement of standard lipid parameters . In 77-years old men, in the Uppsala Longitudinal Study, Apo A1 was the best predictor of coronary death . In the Leiden 85-Plus Study, Apo E was documented to be a powerful predictor of cardiovascular death, independent of Apo E genotype and lipid levels . In the Cardiovascular Health Study , the risk of stroke was increased 3 times, the risk of coronary death was increased 2.5 times and that of death from all causes twice if the participant was in the higher quintile of Lp (a). The Health, Aging and Body Composition Study has documented the increased risk for coronary heart disease in the upper quintile of oxidized LDL, after adjustment for LDL concentration . Serum antioxidants have been associated with a reduced cardiovascular mortality in the elderly , but, unfortunately, studies of antioxidant supplementation have failed to show benefit in all age groups.

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The advent of inflammatory markers as predictors of atherosclerosis related disorders and events have changed the thinking in cardiovascular prevention. Multiple meta-analyses have documented the powerful ability of high sensitivity C Reactive Protein (CRP) in predicting risk, and recent studies have documented the benefit of targeting CRP when titrating statin therapy in high risk patients. A recent engine for predicting cardiovascular risk in women included this measurement . The engine was recommended for use up to 79 years. The Cardiovascular Health Study has documented that high sensitivity CRP remains a powerful predictor of 10-year coronary disease risk in participants over age 65 years, independently of any other known risk factor . The risk of total mortality is even stronger when participants have other elevated inflammatory markers . The risk appears to be higher for the immediate rather than for the remote future. Other inflammatory markers have been also associated with mortality but they are either not standardized or not available commercially . In addition, inflammatory markers are associated with procoagulants, and an increased risk of death was shown for high levels of factors such as Factor VIII and D-dimer . CRP has been associated with the burden of atherosclerosis documented as decreased ankle brachial index, increased carotid intima-media thickness or vascular calcifications . This has been shown to be true in elderly patients.

The reason why inflammation is such a powerful predictor of total and cardiovascular mortality in the elderly is that it is associated with both atherosclerosis and frailty. In younger cohorts, CRP is positively associated with total and LDL cholesterol. In the elderly this relationship is negative. This is attributed to nutritional factors accompanying the frailty syndrome. In the Duke Established Populations for Epidemiologic Studies of the Elderly, participants with the highest levels of Interleukin-6 had the highest mortality and also the highest decline of functional status . Inflammatory cytokines have been associated in cross-sectional studies of older patients with dementia, weight loss, functional decline and incidence of osteoporosis, chronic obstructive pulmonary disorders and rheumatoid arthritis. A recent publication entitled “Risk factor paradox in wasting diseases” reviews the relationship between cholesterol and mortality in chronic diseases . The authors showed that in subjects older than 80 years as well as in subjects with dialysis and predialysis, chronic heart failure, chronic obstructive pulmonary disease, cancer and AIDS, low total cholesterol parallels weight loss and predicts total and, in some studies, cardiovascular mortality. In dialysis patients where this phenomenon is best studied, frailty syndrome is described as “malnutrition-inflammation-atherosclerosis syndrome”. It describes a group of patients characterized by high levels of CRP, advanced atherosclerosis with vascular calcifications and high risk of death. Prevention of mortality in this patient group is still being debated. This group is probably analogous with that of elderly frail subjects in whom cardiovascular prevention is not evidence based.

Most guidelines for cardiovascular prevention recommend lifestyle changes as an important measure for therapeutic intervention. There are very few randomized clinical trials with clinical endpoints addressing the benefit of different recommendations and none addressing directly the older age group. Most studies of dietary intervention in postmenopausal women and older men have addressed weight reduction as a method of correction of lipoprotein changes associated with the increased prevalence of metabolic syndrome in these groups. Reduction of intra-abdominal fat, irrespective of age, results in a decrease in LDL and Non-HDL cholesterol, triglycerides, hepatic lipase, Apo E and Apo C3 and an increase in HDL cholesterol and in the more buoyant fractions of LDL and HDL. The changes are usually proportional to the percent decrease of body weight and abdominal fat. Other interventions have been tried and are derived from epidemiological studies. Large cohorts followed into the age groups of old and very old have identified use of grains, nuts (particularly walnuts) as predictors of decreased risk of diabetes and coronary artery disease . Foods with high glycemic index or containing trans fatty acids have been associated with the risk of coronary artery disease events . Mediterranean diet has been recommended for cardiovascular intervention, and some authors have attributed its benefit to monounsaturated fat (olive oil). The rationale is that substitution of carbohydrates with monounsaturated fat increases the HDL cholesterol. Unfortunately HDL cholesterol is not a trans-cultural indicator of coronary artery disease. Vegetarians have lower HDL cholesterol, lower risk of coronary artery disease and higher longevity. More studies are necessary in order to refine our current recommendations for dietary changes. Until then it is reasonable to reduce body weight in subjects with metabolic syndrome and to attempt to reproduce the diet of populations characterized by a lower cardiovascular risk.

The effect of dietary changes on lipoproteins is limited when compared with the effect of lipid lowering drugs. In addition most studies addressing lifestyle changes in order to reduce coronary endpoints have used complex interventions including smoking cessation and exercise. The subjects enrolled have usually been younger survivors of myocardial infarction. Exercise is a powerful predictor of cardiovascular risk two ways: as leisure time exercise and as “time spent in watching television” as an indication of sedentarism . Exercise decreases insulin resistance and induces changes in risk factors associated with metabolic syndrome.

Of particular interest has been the use of diet enriched in 3 fatty acids. Vegetables which are sources of 3 fatty acids contain alpha-linolenic acid. Fish containing diets or fish oil supplements are another source of 3 fatty acids. The active ingredients of fish oil are two 3 polyunsaturated fatty acids: docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. If the diet is low in fish, alpha-linolenic acid is used as a source for the synthesis of DHA and EPA. The risk of coronary events is lower in some studies in subjects using a diet high in fish content. Unfortunately the use of fish seems to be less beneficial if the products contain mercury . This led to the marketing in the US of a prescription product of fish oil supplement (see below). The use of fish oil is poorly understood. The cardiovascular benefit of supplements of these components has been documented in clinical trials but is not dependent on their effect on lipoprotein levels. On the other hand, the administration of fish oil will result in a decrease of triglycerides in hypertriglyceridemic subjects. The dosage of over the counter products is expressed in grams of fish oil, but the content of DHA and EPA is variable. In order to achieve cardiovascular prevention the dose is 1 gram per day. The dose for triglyceride reduction is much higher: 2-4 grams per day. If the capsules used have 120 mg DHA and 180 mg EPA this will mean a dose of 7-13 grams of fish oil per day.

Smoking cessation is strongly advised in patients at increased cardiovascular risk from dyslipidemia. Unfortunately it usually results in weight gain and worsening of the features of metabolic syndrome other than low HDL cholesterol. Weight gain is associated with decreases in HDL cholesterol, but smoking is also associated with low HDL cholesterol. Consequently, the effect of smoking cessation on HDL cholesterol is unpredictable.

Table 4 shows the prescription drugs available in the US for lipid intervention. Different classes of drugs have a different mode of action, and within the class there are differences between the drugs in activation of different metabolic pathways.

Much of the evidence regarding cholesterol-lowering and its role in reducing CHD risk has been derived from trials using statins. The statin trials addressing cardiovascular risk reduction in high risk patients with no limitation to the type of disease resulting in atherosclerosis other than diabetes or hypertension is shown in Table 5. In a recent meta-analysis including most of these trials, total mortality was reduced by 12%, cardiovascular death was reduced by 18%, main coronary events were reduced by 23%, stroke by 17% and coronary revascularizations by 24% . Higher differences in LDL cholesterol between the arms have resulted in higher benefit. In another meta-analysis the authors included only trials enrolling subjects with no documented atherosclerosis . Statins reduced the risk of main coronary events by 29%, of stroke by 17% and of revascularizations by 34%. Coronary death was reduced by 23%, but the results did not reach statistical significance.