US Pharm. 2006;2:20-27.

Coronary heart disease (CHD) is the leading cause of death in the United States, accounting for about one third of deaths per year, regardless of gender.1 Due to increased incidence and prevalence of the disease secondary to aging, 80% of the deaths from CHD occur in people o lder than 65 years.2 Based on the projected rapid growth of the population older than 85 by 2030, a huge increase in the overall burden of CHD is predicted.2

While care strategies for CHD in elderly individuals are similar to those in younger patients, health care providers should consider age-related differences, such as variation in disease presentation, alterations in drug pharmacokinetics, more complex disease management secondary to comorbid illness, and differences in patients' preferences for care and health expectations, compared to those of younger adults.3 Major complications of CHD include angina pectoris, unstable angina, myocardial infarction (MI), and sudden cardiac death due to arrhythmias.1 The plan of care for elderly patients with CHD must be formulated with a patient-centered approach.3 This philosophy should be balanced with a growing emphasis on maintaining or increasing functional independence and quality of life for older individuals.2

Pathophysiology
While patient-to-patient variability does not render CHD inevitable with advancing age, certain cardiovascular changes are more commonly seen in older individuals. Accumulated damage to the endothelium results in an increasing number and severity of atherosclerotic plaques.3 These plaques, or sub­ intimal deposits of lipids and connective tissue, reduce or obstruct blood flow, causing CHD, cerebrovascular disease (e.g., stroke), and peripheral vascular disease.4 The association between high cholesterol levels and CHD is well established.4 This article will focus on the special considerations for cholesterol management in older persons.

Although cholesterol levels increase with age, diet and genetic factors can also contribute to cholesterol and triglyceride (TG) levels (table 1). A diet high in saturated fats, trans fatty acids (i.e., artificially processed hydrogenated fats), and refined or simple carbohydrates increases the total cholesterol level in most people. 5 Ingesting large quantities of alcohol and excess calories can also raise TG levels. An individual's genetic factors influence the rate that fats are manufactured, utilized, and eliminated in the body.


Dyslipidemia
The processing of exogenous dietary fat in the gastrointestinal (GI) tract and the endogenous synthesis and secretion of lipoproteins rich in TGs by the liver is known as lipoprotein metabolism.2 The physiologic regulation of this process provides an understanding of the pathogenesis of atherosclerosis and the metabolic mechanisms by which therapies can reduce CHD risk.2

Disorders of lipoprotein metabolism arise either from accelerated synthesis, decreased degradation of the lipoproteins, or both.2 Dyslipoproteinemia may be primary (e.g., single-gene mutation, polygenetic, multifactorial) or secondary to other systemic disorders (e.g., diabetes mellitus, thyroid, renal, or liver disease). It is unknown to what extent inactivity, secondary factors (e.g., abnormal body composition), and drugs (e.g., thiazide diuretics, beta-adrenergic blockers, cyclosporine, glucocorticoids) may be related to dyslipidemia.6,7

Lipoprotein particles contain TG, cholesterol, cholesterol esters, phospholipids, and apolipoproteins. Five classes of lipoprotein particles in the plasma are classified by their density and include: chylomicrons (very-low-density lipoproteins, VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Particles of LDL complexed to glycoprotein apo(a), known as Lp(a), are also present in the plasma. In general, total cholesterol, low-density lipo­ protein cholesterol (LDL-C), and TG concentrations increase during the third to seventh or eighth decades of life in both men and women, with a more pronounced increase in LDL-C
levels in women.2 

According to the American Heart Association (AHA), total cholesterol levels of 240 mg/dL or above in adults are considered high, and levels from 200 to 239 mg/dL are considered borderline-high.8 According to the National Health and Nutrition Examination Survey III 1988–
1994, LDL-C levels of 130 mg/dL or above are associated with a higher risk of CHD; HDL-C levels lower than 40 mg/dL are also associated with a higher risk of CHD.8 TGs are considered elevated if they exceed 150 mg/dL after an eight-hour fast.5 Secondary causes of hyperlipidemia, especially diabetes mellitus (DM) and thyroid and renal disease, should be considered when levels in multiple lipoprotein classes are abnormal in the older patient. 2 

Therapeutic Interventions
Diet, weight loss, and exercise: Weight loss, aerobic exercise training, and diets reduced in saturated fat and cholesterol (AHA Step 1 diet) are widely advocated for the initial treatment of hyperlipidemia.2 The AHA diet provides the greatest absolute improvements in hyperlipidemia; however, its universality in the primary prevention of CHD in individuals older than 75 years and in some patients with type 2 DM is questioned. While a strict lipid-lowering diet may be effective in elderly patients, it may lead to or exacerbate malnutrition. In addition, unappetizing low-fat diets can precipitate anorexia and lead to nutritional deficiencies.4 Complications of protein energy malnutrition (e.g., pressure sores, anemia, decreased muscle strength, infections) must be weighed against those of moderate hypercholesteremia on a patient-by-patient basis. 4 The positive effects of the AHA diet and aerobic exercise on other CHD risk factors (table 2) and quality of life have been enhanced by weight loss and should be considered, if appropriate, as part of the overall treatment plan.2


Studies have shown fewer atherogenic profiles associated with higher levels of physical activity in young and middle-aged individuals.6 Although physical activity has an apparent lack of effect on total cholesterol and LDL-C levels in many studies, trained subjects consistently show reduced plasma TG and VLDL concentrations, as well as more elevated HDL-C, HDL2-C, and Lp(a-1) levels, as compared to sedentary controls.6 Many studies suggest, although not all agree, that weight loss (or fat loss) in general is necessary to increase HDL-C levels with exercise training.6 Vigorous exercise, with or without hormone replacement therapy (HRT), has been examined in postmenopausal women. Results indicate indepen­ dent effects of exercise and HRT, and exercise alone mitigated the elevation of TG associated with HRT.6

Weight loss and a reduced risk of developing hypertension may be achieved through aerobic exercise at least 30 minutes three times per week.9 Stress management techniques such as yoga may help control high blood pressure (BP), while other relaxation techniques (e.g., music therapy combined with deep breathing) have demonstrated a reduction in BP in hypertensive patients.9 Clinical trials with long-term follow-up are necessary to determine if these lifestyle interventions will decrease the risk of CHD and overall morbidity and mortality in patients older than 65 years.

Pharmacologic treatment: Pharmacologic intervention can be considered for individuals who continue to require treatment for hypercholesteremia despite adequate dietary therapy, regular physical activity, and weight loss. Drug treatment strategies for hyperlipidemia are directed at key regulatory sites of lipoprotein metabolism. 2 Several classes of agents are marketed for lowering serum cholesterol ( table 3). These agents appear to be as efficacious in the elderly as in middle-aged people, and numerous clinical trials of lipid-lowering therapy found substantial reductions in cardiac morbidity and mortality in the "young" elderly (ages 65 to 75 years).2,3 Many researchers believe that in the "older" elderly (persons older than 75 years), pharmacologic treatment should generally be reserved for patients with overt CHD or atherosclerotic vascular disease, or for patients with multiple CHD risk factors in whom the benefits of treatment have been balanced against the potential risks and costs. 2 In a vigorous "older" elderly individual, treatment for primary prevention may be reasonable as well.2 LDL-C levels associated with the goals and considerations of drug therapy are listed in table 4.10


It is important to note that assessments using Framingham risk prediction scores (a method of identifying individuals at risk for CHD) may be less reliable in seniors.10 A partial solution is the measurement of subclinical atherosclerosis by noninvasive techniques.10 If an older person is found to have advanced coronary or systemic atherosclerosis, LDL-lowering therapy can be intensified even in the absence of clinical coronary symptoms. The relative risk of hyperlipidemia for CHD is lower in seniors due to competing causes of mortality and cumulative effects of comorbid illness. However, due to a high absolute risk in the elderly and the high attributable risk for CHD events, older patients with CHD and multiple risk factors are particularly expected to benefit from pharmacologic intervention.2 Treatment such as HMG-CoA reductase inhibitor (statin) therapy will prevent a greater number of events in older patients than in their younger counterparts due to a high absolute risk and a high attributable risk for CHD in seniors.2 A recent literature search found that for women with known CHD, pharmacologic treatment of hyperlipidemia is effective in reducing CHD events, CHD mortality, nonfatal MI, and revascularization but does not affect total mortality.11 



The use of pharmacologic intervention for hyperlipidemia in elderly patients should be carefully balanced with factors against such treatment, including: (1) a potential lag time (two years) between initiation of therapy and reduction of morbidity and mortality from CHD; (2) possible greater drug side effects; (3) cost of treatment for el­ derly persons with limited insurance and a fixed income; (4) the presence of comorbid illnesses limiting life span or quality of life; (5) polypharmacy and the risk of side effects; (6) lack of evidence that primary or secondary prevention decreases CHD morbidity and mortality in individuals older than 75 years.2,4

Metabolic Syndrome
While alterations in lipoprotein metabolism are most apparent in patients with diabetes, they are often present to a lesser degree in patients with metabolic syndrome (i.e., visceral [truncal] obesity, hyperinsulinemia, elevated blood glucose levels, low HDL-C, elevated TG, hypertension, and prothrombic state contributing to an increased CHD risk).2,12 These individuals do not yet manifest a degree of hyperglycemia that supports a diagnosis of diabetes. As mentioned above, secondary causes for hyperlipidemia (especially DM, thyroid disease, and renal disease) should be considered when multiple lipoprotein classes are abnormal in an older patient.2 Incidents of atypical antipsychotic (AAP)-induced hypertriglyceridemia have been reported, although the biochemical causes are still unclear.13 One study summarized 14 cases of severe hypertriglyceridemia (TG >600 mg/dL) with a subset of those patients who also developed new-onset DM.13 The identified cases occurred within three to eight months of treatment with an AAP medication, and the documented weight gain (8.5 to 12.3 lb) did not correlate with the severity of hypertriglyceridemia. 

Monitoring and Patient Education
In general, lipid-lowering agents are safe in seniors, but routine monitoring is recommended. With the initiation of statin therapy, testing for liver, renal, and muscle toxicity should be performed monthly for three months (including baseline), then every six months and following
a dose increase. Quarterly monitoring is recommended when combination therapy is used.2,3,7 Assessing the interactions between hypolipidemic agents and other prescribed and over-the-counter medications and vitamins is essential. The potential benefits of statins and niacin may be altered with concomitant supplemental antioxidant vitamin therapy.2 The most common cause of drug-induced rhabdomyolysis is direct myotoxicity from statins. 14 This condition leads to intratubular precipitation of myoglobin and, if severe, results in acute renal failure. The risk of rhabdomyolysis is increased when statins are concomitantly administered with gemfibrozil, niacin, or CYP3A4 inhibitors (e.g., erythromycin, itraconazole, cyclo­ sporine).14 Baseline and follow-up creatine phosphokinase (CPK) measurements every six months have been used to identify patients who develop subclinical rhabdomyolysis while receiving lipid-lowering therapy.7

In general, patients receiving statins should be instructed to report excessive or acute muscle cramping or weakness, unresolved diarrhea, changes in mood or memory, yellowing of skin or eyes, easy bruising or bleeding, and unusual fatigue to their health care pro­ vider.15 Patients should be instructed to take niacin with food to avoid GI upset and should be advised that flushing and sensation of warmth, especially of the face and upper body, may occur; headache and itching or tingling have also been reported.15

Patients treated with AAPs should be considered at high risk of developing DM and should be routinely screened for DM and other metabolic abnormalities, including hyperlipidemia. 16-18 Close monitoring of weight, fasting plasma glucose, and serum lipid levels should be considered during extended treatment with AAPs. 13,18,19 Many clinicians advocate intervention at the first sign of DM onset or im­ paired glucose tolerance.20 Glucose metabolism impairment is a major area of concern requiring attention by the psychiatric team and primary care clinicians.21 Pharmacists are well positioned to take a proactive role in identifying patients at risk and to participate in vigilant monitoring and patient/caregiver education.

Hypocholesteremia
Hypocholesteremia, usually defined as total cholesterol levels less than 160 mg/dL, has been studied in older individuals and associated with increased death from intracranial hemorrhage, lymphatic and hematopoietic cancers, chronic obstructive pulmonary disease (particularly in smokers), and cirrhosis.2 Older adults were also at an increased risk for adverse events. Low cholesterol levels may indicate an acute illness associated with the release of cytokines.4 When total cholesterol levels fall below 160 mg/dL in nursing home patients, mortality is predicted, presumably because such low levels reflect malnutrition.4 Biological mechanisms that may explain low total cholesterol as a cause of death include alterations in cell membrane structure and function, abnormalities in steroid hormone metabolism, and fat and vitamin deficiencies.2

Conclusion
Despite advances in the treatment and prevention of CHD, the disease continues to be a major health problem and the most common causeof death in old age. The prevalence and mortality rates of CHD increase with age, and the association between high cholesterol levels and CHD is well established. There is much interest and need for research to further explore the efficacy and safety of treatment and prevention strategies for CHD in older adults. While substantial evidence supports the use of lifestyle and pharmacologic interventions in treating
hyperlipidemia in the elderly, the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults acknowledges that clinical judgment plays a critical role in developing the appropriate management strategy for these individuals.10

REFERENCES
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