Management Strategies of Dyslipidemia in the Elderly: 2005

Tarek Helmy, MD; Amar D. Patel, MD; Fadi Alameddine, MD; Nanette K. Wenger, MD, FACC, FAHA

Disclosures
In This Article

Treatment

Dyslipidemia can be significantly improved by therapeutic lifestyle changes, such as dietary modification, physical activity, and weight reduction. The potential for diet to prevent cardiovascular disease is often underappreciated by patients. Furthermore, changing ingrained dietary habits is not usually an easy task for most patients. Diet favorably alters the lipid/lipoprotein profile and may allow the use of lower doses of lipid-lowering agents, thus reducing the potential for adverse effects. ATP III recommends reduced intake of saturated fatty acids (< 7% of total calories) with the remainder of total fats from polyunsaturated and monounsaturated fatty acids (25% to 35% of total calories), and intake of less than 200 mg cholesterol/day. The addition of plant stanols/sterols (2 g/day) and soluble fiber (10-15 g/day) can further reduce LDL-C by approximately 10%. Carbohydrates should be limited to 60% of the total daily caloric intake. The Lyon Diet Heart Study is a secondary prevention trial that randomized 605 patients to a Mediterranean-type or a Western-type diet.[16] Despite a similar coronary risk profile between the groups, there was an approximate 50% to 70% relative risk reduction of cardiovascular events (death, MI, stroke, angina, congestive heart failure, and hospitalization) in favor of the Mediterranean-type diet group over a mean follow-up duration of 46 months.

The benefits of the Mediterranean diet were also shown in a prospective study of 22,043 subjects with an age range of 20-86 years. An extensive, validated, food frequency questionnaire was completed at baseline, and subjects were followed for a median of 44 months. Calculation of dietary intake included 14 food groups: potatoes, vegetables, legumes, fruits and nuts, dairy products, cereals, meat, fish, eggs, monounsaturated lipids (mainly olive oil), polyunsaturated lipids (vegetable seed oil), saturated lipids and margarines, sugar and sweets, and nonalcoholic beverages. Evaluation of occupational and leisure-time physical activity was also included. Adherence to the Mediterranean diet was associated with reduced mortality, with a strong association with cardiovascular mortality.[17]

The HALE project was another study evaluating the effects of a Mediterranean diet in the elderly. This included 1507 healthy men and 832 women aged 70-90 years in 11 European countries who were followed for 10 years. A Mediterranean diet, moderate alcohol consumption, moderate-to-high physical activity levels, and nonsmoking were associated with lower mortality rates, including CHD, cardiovascular disease, cancer, and other causes of mortality.[18]

A study by Lemaitre and colleagues[19] investigated the effects of plasma phospholipid concentrations of n-3 polyunsaturated fatty acids (docosahexanenoic acid [DHA]), eicosapentaenoic acid (EPA), and alpha-linolenic acid on ischemic heart disease in elderly patients (age > 65). DHA and EPA are commonly found in fatty fish, whereas alpha-linolenic acid is found in vegetable oils. This was a case-control study nested in the prospective trial of cardiovascular risk factors and outcomes (the Cardiovascular Health Study). Subjects were included if they were free of ischemic heart disease and stroke at baseline, and experienced an MI (fatal or nonfatal) during follow-up. Cases were matched to subjects with the same age, sex, clinical site, and follow-up period in a random fashion. Higher dietary intake of DHA, EPA, and possibly alpha-linolenic acid was associated with a decrease in the incidence of nonfatal ischemic events, when the analysis was adjusted for other coronary risk factors.[19]

Physical inactivity is a major risk factor for CAD.[20] Physical exercise and weight reduction are important elements of therapeutic lifestyle changes, and have a favorable impact on the lipid profile, blood pressure levels, and improve insulin sensitivity. Physical exercise has been reported to reduce the risk of developing CAD by as much as 40%, independent of standard risk-factor modifications.[20] Most patients underestimate their dietary intake and overestimate their level of physical activity and exercise. Scheduled, regular exercise promotes the energy expenditure that is necessary to maintain a desirable body weight. This is especially important because the lifestyles of an increasing percentage of the US population are becoming more sedentary.

Several agents are available for lipid lowering, such as hydroxyl-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ("statins"), nicotinic acid, fibrates, bile acid sequestrants, and intestinal absorption inhibitors, such as ezetimibe. These agents have specific and different effects on the lipid profile. Fibrates lower TG by 20% to 50%, lower LDL-C by 5% to 20%, and raise HDL-C by 10% to 20%. Nicotinic acid lowers LDL-C by 5% to 25%, lowers TG by 20% to 50%, and raises HDL-C by 15% to 35%. Bile acid sequestrants lower LDL-C by 15% to 30%, raise HDL-C by 3% to 5%, and have no consistent predictable effect on TG levels, thus warranting caution in patients with mixed lipid abnormalities with hypertriglyceridemia. Statins lower LDL-C by as much as 50% with some agents, raise HDL-C by 5% to 15%, and lower TG by approximately 30%. Statins also may have "pleiotropic effects" that are independent of lipid lowering. They include vasodilator (through nitric oxide release) and anti-inflammatory effects on vascular endothelial cells, as well as antiproliferative and antimigratory effects on vascular smooth muscle cells. Statins also reduce tissue factor release, inhibit thromboxane activity (leading to inhibition of platelet activation), modulate the recruitment of inflammatory cells, and reduce expression of adhesion molecules in the vascular wall.[21]

Statins are the drug of choice for patients with elevated LDL-C levels. Clinical trials have unequivocally demonstrated that treatment of dyslipidemia with statins reduces cardiovascular events both in patients at high risk for CAD (primary prevention)[10,11,22,23] and in patients with documented CAD (secondary prevention)[10,12,14,15,24,25,26] (Table 2). Unfortunately, large multicenter, clinical trials, such as West of Scotland Coronary Prevention Study (WOSCOPS),[22] excluded patients over age 65; the Scandinavian Simvastatin Survival Study (4S)[26] excluded patients older than 70; and the Cholesterol and Recurrent Events (CARE)[24] and Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID)[25] trials excluded patients over the age of 75. Although outcomes data are relatively limited in the elderly, some studies included a sizable elderly cohort. In the 4S trial,[26,27] patients 65 years and older derived more benefit from simvastatin than patients ≤ 65 years (Table 3). A significant reduction in all-cause mortality was evident at 18 months, whereas coronary event rates (coronary death, nonfatal MI, resuscitated cardiac arrest, and silent MI) decreased significantly after 6 months of statin therapy. The CARE trial enrolled 4159 patients (1283 patients aged 65-75) with a history of MI and a serum LDL-C ≥ 115 mg/dL.[24] After a 5-year mean follow-up, the incidence of major coronary events (fatal MI, ischemic cardiomyopathy, and sudden death) was reduced by 27% in patients aged 60-75 compared with a 20% reduction in patients younger than age 60. The LIPID trial had similar findings showing that for every 1000 patients treated with pravastatin for 6 years, 133 coronary events were prevented in the 65-75 age group.[25]

The HPS, the largest statin therapy trial conducted to date, randomized 20,563 patients aged 40-80 years (10,697 patients ≥ 65 years) with coronary disease, other occlusive arterial disease, or diabetes to either 40 mg of simvastatin or placebo during a scheduled 5-year treatment period.[10] All-cause mortality was significantly reduced in the simvastatin group, mainly driven by an 18% relative risk reduction in the coronary death rate (MI, ischemic cardiomyopathy, and sudden death) (5.7% vs 6.9%; P = .0005). There was a trend toward a reduction in other vascular deaths (.9% vs 2.2%; P = .07) and an insignificant reduction in nonvascular deaths (5.3% vs 5.6%; P = .4). Furthermore, there was a 25% reduction in the incidence of nonfatal MI or coronary death (8.7% vs 1.8%; P < .0001), stroke (44.3% vs 5.7%; P < .0001), and coronary or noncoronary revascularization (9.1% vs 1.7%; P < .0001). The reduction in major vascular events was not significant during the first year, but was highly significant during each subsequent year. The proportional reduction in the event rate was similar and statistically significant when predesigned subgroup analysis was performed by age (under or over 70 years at study entry). There was also a 27% decrease in stroke incidence. The annual excess risk of myopathy with this regimen was about .01%. There were no significant adverse effects on cancer incidence or on hospitalizations for any nonvascular cause. Statin therapy conferred a decrease in total and cardiovascular mortality without an increase in noncardiovascular mortality. This was true even in patients with baseline LDL-C ≤ 100 mg/dL in a post hoc analysis. The safety profile was identical in both groups and no deterioration in cognitive function was noted.

Another landmark study, PROSPER,[12] randomized an elderly cohort of men and women aged 70-82 years with, or at risk of developing, vascular disease (coronary, cerebral, or peripheral) to pravastatin (40 mg per day; n = 2891) or placebo (n = 2913). Pravastatin lowered LDL-C concentrations by 34% and demonstrated a 15% relative risk reduction in the composite primary end point of coronary death, nonfatal MI, and fatal or nonfatal stroke over a mean follow-up duration of 3.2 years (hazard ratio, .85; 95% confidence interval [CI], .74-.97; P = .014). CHD death and nonfatal MI risk were also reduced (hazard ratio, .81; 95% CI, .69-.94; P = .006). Stroke risk was unaffected (hazard ratio, 1.03; 95% CI, .81-1.31; P = .8), but the hazard ratio for transient ischemic attack was .75 (95% CI, .55-1.00; P = .051). The small number of strokes in this study may explain the lack of statistical significance observed. New cancer diagnoses were more frequent with pravastatin than with placebo (hazard ratio, 1.25; 95% CI, 1.04-1.51; P = .020). However, incorporation of this finding in a meta-analysis of all pravastatin and all statin trials showed no overall increase in cancer risk. Mortality from coronary disease fell by 24% (P = .043) in the pravastatin group. Pravastatin had no significant effect on cognitive function or disability. The study authors of PROSPER concluded that pravastatin similarly reduces the risk of CAD in elderly patients as demonstrated in younger aged populations. In addition, this study supported the well-documented safety profile and tolerability of statin therapy. Statin drugs appear to have similar efficacy and safety in nonelderly and elderly populations and should be strongly considered for use in elderly patients.[28,29,30] A soon to be completed study in elderly patients is the Study Assessing Goals in the Elderly (SAGE), which is designed to compare the effects of atorvastatin 80 mg with pravastatin 40 mg on myocardial ischemia, as assessed by Holter monitoring.

New targets for LDL-C reduction, now an optional recommendation from the NCEP-ATP III guidelines, are strongly supported by 2 recent studies. In PROVE-IT, 4162 patients with an acute coronary syndrome were randomized to an aggressive strategy of LDL-C reduction, with high-dose atorvastatin vs usual therapy, with a moderate dose of pravastatin.[14] At 2-year follow-up, the combined end point (time from randomization to death/MI/stroke/coronary revascularization/unstable angina requiring hospitalization) was significantly better in the aggressive therapy group (LDL-C 62 mg/dL) compared with the usual therapy group (LDL-C 95 mg/dL). The recently published TNT trial was the first randomized clinical trial to prospectively assess the efficacy and safety of treating patients with stable CAD to LDL-C levels significantly below 100 mg/dL.[15] The TNT trial compared the effects of a lower goal of LDL-C reduction with high-dose (80 mg) atorvastatin to current LDL goal, with low-dose (10 mg) atorvastatin, and included patients as old as 75 years. At the end of a 5-year follow-up period, the mean LDL-C level in the high-dose atorvastatin group was 77 mg/dL compared with 102 mg/dL in the lower dose group. There was a significant (> 20%) reduction in the primary combined end point of death, MI, and stroke in the lower LDL-C group.

In addition to trials focusing on the use of statin therapy, several studies have also been conducted regarding the therapeutic efficacy of fibrate therapy on secondary prevention. The Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) study evaluated the use of gemfibrozil in patients with low levels of HDL-C. In this trial, 2531 male patients with documented CAD were randomized to gemfibrozil or placebo.[31] During a follow-up period of 5 years, there was a 24% relative risk reduction in the combined outcomes of CHD death, nonfatal MI, or stroke. At 1 year, HDL levels were 6% higher and TG levels were 31% lower in the gemfibrozil group. Further analysis of the data revealed that gemfibrozil therapy was cost-effective and efficacious across a wide age range (55-75 years). Another study of post-MI patients that included a large elderly cohort described a 28% reduction in total mortality in patients treated with the lipid-lowering agents clofibrate and nicotinic acid.[32]

A new class of lipid-lowering drugs is the cholesterol absorption inhibitors. The first drug of this class, ezetimibe, was approved by the US Food and Drug Administration (FDA) in November 2002. It interferes with the absorption of dietary and biliary cholesterol at the intestinal brush border without interfering with uptake of TGs.[33,34] It should be considered as an adjunct to therapy in patients in whom LDL-C reduction is suboptimal, despite maximal statin monotherapy. Ezetimibe can achieve as much as an additional 10% to 15% reduction in the LDL-C level. To date, clinical outcomes data are lacking for ezetimibe, but these trials are ongoing. Although ezetimibe has been administered in the elderly,[35] its therapeutic efficacy has not been specifically evaluated in this population subset.

Combination therapy is also now evolving in which agents targeting different, but usually coexistent, disease processes are combined in a single pill. Observational data have shown that coexistent risk factors, such as hypertension and dyslipidemia, have multiplicative effects on the risk for development of cardiovascular events.[36] The marked relative risk reduction of adverse cardiovascular events in both the hypertension and lipid-lowering arm of the ASCOT trial prompted a premature termination of both arms of this study. Results from this study as well as the aggressive LDL-C lowering trials have led to the emergence of combination preparations, including combined classes of lipid-lowering agents (simvastatin/ezetimibe), and lipid-lowering and antihypertensive agents (atorvastatin/amlodipine).

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