Case Vignette

An 87-year-old man with well-controlled hypertension and no known cardiovascular disease had his cholesterol checked at a local health fair. He comes to the physician’s office with the following results: total cholesterol 245 mg/dL, triglycerides 141 mg/dL, high-density lipoprotein cholesterol (HDL-C) 57 mg/dL, and low-density lipoprotein cholesterol (LDL-C) 160 mg/dL. He is very functional and active, with no symptoms of angina or heart failure. How should this patient be managed?

Introduction

The National Cholesterol Education Program (NCEP) guidelines for the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults recommend management based on the patient’s individual risk of coronary events without providing age-specific treatment guidelines (Table I).1 However, estimating the risk of developing coronary artery disease (CAD) is particularly challenging in older persons, as projections based on population studies such as Framingham have not been validated in patients over 75 years of age. In addition to uncertainty regarding the risk of CAD in this age group, there is also debate as to the degree to which hyperlipidemia contributes to this risk, and whether or not the risk is materially modified by cholesterol-lowering therapy. In this review, we discuss the relationship between age and lipid levels, the role of hyperlipidemia as a risk factor for CAD in older patients, the data supporting lipid-lowering therapy for primary and secondary prevention, and special treatment considerations when treating older patients.

Normal Lipid Levels in Older Adults

Several cross-sectional population studies have demonstrated that total cholesterol and LDL-C levels increase after the onset of puberty until 50 years of age, and then plateau until 70 years of age. After 70 years of age, cholesterol and LDL-C levels decline somewhat, with the effect being stronger in men than in women.2,3 In addition, although women have lower cholesterol levels than men prior to menopause,3 older women have higher total cholesterol, LDL-C, and HDL-C levels than men of similar age.2 Some of the differences observed across age groups in cross-sectional analyses can be explained by the earlier death of people with an atherogenic lipid profile; however, longitudinal analyses indicate that these changes are unlikely to be due to survival bias alone.4 While many factors may contribute to alterations in the lipid profile, the most important appears to be a gradual decrease in weight after the age of 50 years.4 Declines in sex hormones in both women and men, cessation of smoking, and reduction in alcohol intake and exercise contribute to lower HDL-C levels in older adults. Thus, although screening older persons who have never been tested may be appropriate, repeated screening is probably not necessary because lipid levels are unlikely to increase after 60 years of age.

Despite the fact that lipid levels decrease modestly with age, there are still large numbers of older persons with elevated cholesterol. In the Cardiovascular Health Study,5 among 4810 men and women age 65 years and older not taking lipid-lowering therapy, 24% had total cholesterol levels higher than 240 mg/dL and 46% had LDL-C levels higher than 160 mg/dL. However, as a result of improved nutritional habits and other health behaviors, in addition to increased pharmaceutical treatment of hyperlipidemia, population-based studies have encouragingly shown that lipid levels have been decreasing over time.3,6

Role of Cholesterol in Coronary Artery Disease in the Elderly

While high total cholesterol and LDL-C levels are well-established risk factors for cardiovascular events and mortality in middle-aged patients,7,8 the relationship between lipid levels and mortality among older individuals is less certain. Although some studies showed a positive association between cholesterol level and cardiovascular risk,9,10 others found no association between cholesterol levels and the risk of myocardial infarction (MI) or cardiac death in older adults.11,12 Since cholesterol is a major component in the causal pathway of atherosclerosis, a pathological process that typically progresses with age, it would logically follow that higher serum cholesterol levels would result in an increased risk for the development of CAD and its consequences. However, due to the increasing absolute risk of CAD with advancing age, as well as the increased risk of death from other causes, the relative risk (RR) associated with hyperlipidemia decreases with age. However, this does not necessarily imply that hyperlipidemia is not an important risk factor for cardiovascular disease in older patients. For example, in a meta-analysis of 25 populations in 22 U.S. and international cohort studies, total cholesterol and LDL-C levels predicted fatal cardiac events in older men and women (≥ 65 yr). Although RR estimates were generally lower for older than for middle-aged subjects, absolute excess risk was greater.13

Confounding the relationship between cholesterol levels and mortality in older persons is the association of low LDL-C levels with cancer, diabetes, and lower levels of serum albumin and factor VII14 (ie, lower LDL-C levels may be a marker of comorbid illness or poor overall health). Likely for this reason, several studies have found an inverse relation between total cholesterol and LDL-C levels and mortality.15,16 Corti et al17 illustrated this complex interaction in a study of over 4000 older men and women, in which LDL-C levels were inversely related to death from CAD in unadjusted analyses. However, after adjustment for coronary risk factors and markers of frailty (serum albumin and iron levels), LDL-C demonstrated a positive association with cardiac mortality. Thus, while hyperlipidemia in older patients does carry an increased risk for mortality from CAD, the relationship is more complex than in middle-aged patients. Consequently, the interpretation of lipid levels and the decision to treat older patients require increased clinical judgment.

Treatment with Statins

Primary Prevention

Lipid-lowering medications, in particular 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins), have demonstrated efficacy in reducing cardiovascular events and deaths in middle-aged patients with risk factors for CAD, with a recent meta-analysis of over 65,000 patients showing a RR of 0.77 (95% confidence interval [CI], 0.63-0.95) for MI and 0.89 (95% CI, 0.81-0.98) for cardiovascular death.18 Unfortunately, there are little data regarding the benefit of statins for primary prevention of cardiovascular disease in older adults, as few primary prevention trials enrolled patients over age 75 years. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)19 included patients up to age 79 years with at least three other cardiovascular risk factors. Among patients older than age 60 years, atorvastatin significantly reduced the risk of nonfatal MI and cardiovascular death with a hazard ratio of 0.64 (95% CI, 0.47-0.86), which was identical to the overall population.19 The Collaborative AtoRvastatin Diabetes Study (CARDS)20 enrolled patients up to age 75 years with type 2 diabetes and one additional cardiac risk factor. In a post-hoc analysis comparing patients age 65-75 years to younger patients, atorvastatin resulted in a 38% relative risk reduction (RRR; 95% CI, 8% to 58%) of first major cardiovascular events in older patients as compared to a 37% reduction (95% CI, 7% to 57%) in younger patients; however, there was no significant reduction in all-cause mortality over the 4-year follow-up in either age group.20

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study,21 which included both primary and secondary prevention patients, evaluated the effects of a statin in older individuals. In the 3239 men and women age 70-82 years with cardiovascular risk factors but without overt vascular disease (ie, primary prevention), there was no overall benefit with pravastatin for reducing coronary death, nonfatal MI, or stroke, with a RR of 0.94 (95% CI, 0.77-1.15).21 However, although there is uncertainty regarding the benefit of lipid-lowering therapy for primary prevention of cardiac events and death in older patients, for selected high-risk patients age 65-75 years, statins likely confer the same cardiovascular protection as they do for younger patients (Table II). Patients older than age 75 years with multiple risk factors may also benefit from statin therapy, but an individualized approach is needed in this group due to the lack of established evidence to guide decision making.

With the recent publication of the Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, some experts have advocated measuring high-sensitivity C-reactive protein (hs-CRP) in older patients to help guide treatment decisions. In this study, patients without known CAD or diabetes, LDL-C lower than 130 mg/dL, and hs-CRP of 2 mg/L or higher were randomized to rosuvastatin or placebo and followed for a median of 1.9 years.22 Patients treated with rosuvastatin experienced a 44% reduction in the primary endpoint (MI, stroke, revascularization, hospitalization for unstable angina, cardiovascular death) and a 20% reduction in all-cause mortality, with similar effects in patients older or younger than age 65. However, the implications of this trial for patients older than age 75 years is unclear, particularly given the myriad of noncardiovascular disease conditions that can increase hs-CRP in this age group (eg, depression, periodontal disease, pulmonary disease, osteoporosis, arthritis, cognitive impairment).23 In addition, although the RRRs with rosuvastatin were striking, the absolute RRs were small, with the number needed to treat for 2 years to prevent one primary endpoint event being 169 and to prevent one death being 400. Thus, in selected patients age 65-75 years with borderline LDL-C levels (ie, 100-130 mg/dL), it may be reasonable to measure hs-CRP as an aid to decision making; however, the net benefit of statin therapy is likely to be very small. In addition, there is insufficient evidence to recommend this approach in older patients due to the marked lack of specificity of inflammatory markers in this population.

Secondary Prevention

Clinical trials of statins for secondary prevention have consistently demonstrated a benefit in reducing recurrent cardiovascular events and mortality, and treatment with a statin now has a Class I recommendation (Level of Evidence: A) following an acute coronary event, regardless of the baseline LDL-C level.24 While more inclusive than the primary prevention studies, most secondary prevention trials excluded patients older than age 80 years. Among trials that enrolled older patients, there has been no evidence of a differential treatment effect in older as compared to younger patients (Table II). Among 5806 patients age 70-80 years in the Heart Protection Study (HPS),25 treatment with simvastatin resulted in a RRR for major vascular events of 19%, as compared to 24% in patients younger than age 65; however, absolute RRs were nearly identical (5.1% vs 5.2%, respectively). In a pooled analysis of three large randomized trials with pravastatin (the West of Scotland Coronary Prevention Study, the Cholesterol And Recurrent Events [CARE] trial, and the Long-term Intervention with Pravastatin in Ischemic Disease [LIPID] study), lipid-lowering therapy was associated with a 26% RRR (95% CI, 14% to 35%) in coronary death or nonfatal MI in patients age 65-75 years as compared to a 32% RRR (95% CI, 19% to 43%) in patients younger than age 55 years with no evidence for heterogeneity in treatment effect.26

In the secondary prevention arm of the PROSPER trial, which included 2565 patients age 70-82 years, treatment with pravastatin resulted in a 22% RRR (95% CI, 7% to 34%) in coronary death, nonfatal MI, and stroke.21 A meta-analysis of nine clinical trials, which also included unpublished subgroup data on older patients, evaluated the effect of statins in secondary prevention of cardiovascular events in nearly 20,000 patients age 65-82 years. Pooled estimates demonstrated a RR of 0.78 over 5 years for all-cause mortality (95% CI, 0.65-0.89) and similar risk reductions for cardiovascular mortality (RR, 0.70; 95% CI, 0.53-0.83) and nonfatal MI (RR, 0.74; 95% CI, 0.60-0.89).27

Evaluation of the benefits of statins in patients over age 80 years is restricted to analyses of observational data.28,29 Although limited by issues of confounding (ie, patients treated with statins are fundamentally different from patients not taking statins), these studies suggest that statin therapy is beneficial in reducing recurrent cardiovascular events and mortality in very old patients. Since the available evidence points to a significant benefit in secondary prevention in older patients, statin therapy should be offered to those patients with established cardiovascular disease in the absence of contraindications. However, additional observational studies and clinical trials that include patients over age 80 years are needed to define the true impact of statins in reducing cardiovascular events in very elderly patients. In the meantime, while the decision to treat older patients with lipid-lowering therapy must take into account the patient’s overall health and prognosis for reasonable survival (eg, it may not be appropriate to treat patients with class 4 heart failure with statins), it seems inappropriate to withhold treatment based on age alone.

Non-Statin Lipid-Lowering Therapies

While statins are the most effective medications for reducing total cholesterol and LDL-C, as well as for decreasing cardiovascular events and mortality, other therapies may be necessary in statin-intolerant patients or to augment the effect of statins. Lifestyle modification can be markedly effective in older patients and the importance of these interventions should not be underestimated, as older patients may be more motivated to reduce their cardiovascular risk through nonpharmacologic means than their younger counterparts. Diet and weight loss are particularly important in patients with mixed dyslipidemia, as a 10% decrease in weight alone has been shown to result in a 22% reduction in triglyceride levels and a 9% increase in HDL-C.30 However, although simple dietary changes can be beneficial, overly-restrictive diets should generally be avoided because they can negatively impact quality of life and may also adversely affect overall nutritional status and energy balance. In addition, weight loss regimens must aim to minimize muscle and bone losses (ie, by focusing on low-fat meals, supplementation with vitamin D and calcium, and advocating physical exercise), and should generally be reserved for patients with at least class II obesity (body mass index ≥ 35 kg/m2) to prevent unfavorable changes in body composition. Moderate aerobic exercise, in addition to its benefits on cardiovascular health, muscle strength, and balance, is also modestly effective at improving the lipid profile—most consistently causing an increase in HDL-C.31

Fibrates, niacin, omega-3 fatty acids, and ezetimibe exert favorable effects on the lipid profile, particularly in patients with dyslipidemia associated with metabolic syndrome and diabetes. However, data supporting improved cardiovascular outcomes for each of these medications are scarce, especially in older patients.

Fibrates decrease triglycerides by about 36%, decrease LDL-C by about 8%, and increase HDL-C by approximately 10%.32 A meta-analysis of eight clinical trials showed that treatment with fibrates reduced major coronary events but not all-cause mortality.32 In addition, there are no outcomes data on the use of fibrates in combination with statins. The ongoing Action to Control Cardiovascular Risk in Diabetes study is comparing simvastatin plus fenofibrate with simvastatin alone for reducing cardiovascular events and mortality; results are expected in 2010. Since the combination of a fibrate and a statin is associated with increased risk of myotoxicity,33 use of the combination in older patients should be reserved for those with very high triglyceride levels (> 1000 mg/dL) in order to decrease the risk of pancreatitis.

Niacin is the most potent agent currently available for raising HDL-C, increasing levels by 15-20%. Niacin also reduces LDL-C by 10-15% and triglycerides by about 20%.32 In the Coronary Drug Project, the only study that has investigated niacin monotherapy for reducing cardiovascular risk, men with prior MIs treated with niacin had a 14% RRR for nonfatal MI at 5 years and an 11% RRR in all-cause mortality during extended follow-up at 15 years.34 In another trial, niacin prevented the progression of carotid artery disease in patients with known CAD who were already receiving statin therapy; however, the effect was only significant in the subgroup of patients without diabetes or metabolic syndrome.35 Although niacin has no major toxicity, it often induces flushing, which causes many patients to discontinue therapy.32 Flushing can be minimized by administering aspirin prior to dosing, using extended-release niacin formulations, combination therapy with laropiprant (not currently FDA-approved for use in the United States), and the avoidance of alcohol, hot beverages, spicy foods, and hot showers close to dosing time. While niacin is generally safe and produces favorable changes in the lipid profile, no long-term outcomes data are available evaluating the combination of niacin with statins. However, two trials comparing the combination of niacin with simvastatin versus simvastatin alone are ongoing, with results expected in 2012-2013.36,37

Supplementation with omega-3 fatty acids can lower triglyceride levels and may reduce cardiovascular events, although the data are somewhat conflicting. A meta-analysis of 48 randomized trials and 41 cohort studies showed no effect on cardiovascular events or mortality, but there was significant heterogeneity across studies.38 A more recent meta-analysis limited to eight randomized trials demonstrated that in patients with prior MIs, omega-3 fatty acids significantly reduced all-cause mortality, primarily through a 57% reduction in sudden cardiac death (RR, 0.43; 95% CI, 0.20-0.91). Conversely, in patients with angina but no prior MI, omega-3 fatty acids had no effect on all-cause mortality but there was an increase in the incidence of sudden cardiac death (RR, 1.39; 95% CI, 1.01-1.92).39 Additional study is clearly needed before routine supplementation can be recommended for primary or secondary prevention of cardiac events, particularly for older patients, who were generally not included in these trials.

Ezetimibe is effective in lowering total cholesterol and LDL-C with minimal side effects, producing reductions in LDL-C of about 20% as monotherapy or about 15% in combination with statins.40 Safety and efficacy data for LDL-C reduction are available for patients up to age 84 years,40 but outcomes data are lacking for any age group. Until results are available from the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (expected in 2012), a large secondary prevention trial comparing simvastatin plus ezetimibe to simvastatin alone, treatment with ezetimibe should be reserved for patients who are intolerant to statins or cannot achieve goal LDL-C levels with high-potency statins alone.

Special Treatment Considerations

Treatment of older patients with lipid-lowering therapies requires a partnership between the practitioner and patient such that side effects are recognized early. Approximately 9% of patients report myalgias (proximal or diffuse muscle pain or weakness) after statin initiation.41 Myopathy—muscle pain or weakness accompanied by elevations of creatine kinase more than 10 times the upper limit of normal—is much rarer, affecting only 0.04-0.08% of patients.41 Although most trials of statins do not present safety data in detail, older patients are probably at increased risk for myotoxicity with statin therapy, as patient-related factors known to be associated with increased risk of myalgias include low body mass index, polypharmacy, and other changes related to increasing age (eg, declining hepatic and renal function, changes in albumin and alpha-1 acid glycoprotein levels, alterations in lean body mass and body fat content).33 Further complicating treatment of older patients is the fact that myalgias often occur independent of statin use; as a result, the decision to discontinue statin therapy may be challenging. Nonetheless, recognition of statin-associated myalgias and myopathies is paramount, as any muscle-related side effect can be debilitating in ambulatory elderly persons, especially in those with limited functional capacity.

Several strategies can be employed to reduce the likelihood of statin-associated myotoxicity. Avoiding coadministration of drugs metabolized by the cytochrome P-450 3A4 isoenzyme can reduce the incidence of myalgias, which have been reported when statins (particularly atorvastatin, lovastatin, or simvastatin) are combined with fibrates, cyclosporine, macrolide antibiotics, digoxin, azole antifungals, protease inhibitors, and warfarin. This interaction is less likely with rosuvastatin, fluvastatin, and pravastatin because these agents do not use this common metabolic pathway.33 Other dietary and herbal supplements that may also interact with statins are shown in Table III.42

Use of the lowest dose necessary to achieve goal LDL-C levels will also decrease the likelihood of muscle-related side effects, as the risk of myotoxicity is directly related to dose, whereas the magnitude of LDL-C reduction is not.33 Other pharmacologic factors of particular statins associated with a lower risk of myalgias include low bioavailability and systemic exposure, high protein binding, and hydrophilia—for these reasons, fluvastatin may be useful in patients who require lipid-lowering therapy but who have been intolerant to other statins. Alternatively, low-dose rosuvastatin, which is hydrophilic and has a long systemic half-life, can be used with an every-other-day or weekly dosing strategy.33

Supplementation with coenzyme Q-10 (CoQ10) has been recommended by some to mitigate symptoms of statin-associated myalgia. Although statins decrease circulating levels of CoQ10 by 16-54%,43 data on intramuscular CoQ10 levels in myopathic patients and the effect of CoQ10 supplementation in these patients are inconclusive.43 Since CoQ10 appears to be safe, it is reasonable to consider CoQ10 supplementation in patients with statin-associated myalgias. Finally, emerging evidence suggests that treatment of vitamin D deficiency, which is highly prevalent among older patients, may be able to prevent or reverse statin-induced myalgias without necessitating statin discontinuation.44,45

Outcome of the Case Patient

No primary prevention trials are directly relevant to the case patient, who has moderately high total cholesterol and LDL-C levels. The patient is active and otherwise healthy with only well-controlled hypertension as an additional cardiac risk factor, and at age 87 his projected life expectancy is 3-5 years. In this case, we would recommend implementation of lifestyle modifications, with dietary changes, modest weight loss if indicated, and moderate aerobic exercise. If lifestyle modification alone does not reduce his LDL-C level below 130 mg/dL within 6-12 months, and if the patient is committed to reducing his risk of cardiovascular events, it would be reasonable to initiate a low-dose statin and monitor him closely for myotoxicity. Clearly, treatment of elderly patients with hyperlipidemia requires an individualized approach, taking into account the patients’ overall cardiovascular risk as well as their likelihood of reasonable survival to derive the benefits of lipid-lowering therapy. More research is needed to guide these decisions in the older adult population, particularly in patients older than age 80 years. In addition to evaluating the effects of treatment on cardiovascular morbidity and mortality, such studies should also examine the impact of therapy on quality of life and healthcare costs.

Conclusion

Older patients carry the highest risk for coronary heart disease morbidity and mortality, yet they have been excluded from the majority of primary and secondary prevention trials of lipid-lowering therapies. Nonetheless, the available evidence supports the use of statins in patients up to age 80 years with established atherosclerotic disease, and the routine use of these agents for secondary prevention in patients over age 80 years also seems justifiable. In select high-risk patients without clinically evident atherosclerotic disease and a good expectation for reasonable survival, use of lipid-lowering therapy for primary prevention may be considered, with the understanding that there is no clear evidence for benefit in this population. Lifestyle modification should be the first line of primary prevention, with drug therapy considered for patients at highest risk. Lipid management should be undertaken in the context of a global risk assessment, such that an increasing number of risk factors should lower the threshold for starting a statin. While statins and other lipid-lowering agents are generally well tolerated by older patients, early recognition of myopathic side effects of statins must be a priority in order to minimize the risk of potentially disabling side effects.

The authors report no relevant financial relationships.

From the Cardiovascular Division, Washington University School of Medicine, St. Louis, MO.