Benefits of Reducing Low Density Lipoprotein Cholesterol Concentrations to <100 mg/dL

An elevated low density lipoprotein cholesterol (LDL-C) level is an independent risk factor for premature coronary heart disease (CHD),1–3 with a value of ≥160 mg/dL designated as high risk by the National Cholesterol Education Program Adult Treatment Panels I and II.4,5 Goals of therapy for all patients with elevated LDL-C include reducing levels to: <160 mg/dL in those with fewer than two CHD risk factors; <130 mg/dL in those with two or more CHD risk factors; and <100 mg/dL in patients with established CHD. However, debate remains as to how aggressively patients should be treated, especially those with CHD. This report reviews recent primary and secondary intervention trials in which 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, or statins, have been used to reduce LDL-C concentrations, with particular emphasis on trial subjects having CHD and average baseline LDL-C concentrations. For each trial, the percent change from baseline in LDL-C, triglyceride (TG), and high density lipoprotein cholesterol (HDL-C) concentrations are provided for the statin group. The results of two primary prevention trials are summarized in Table I. In the West of Scotland Coronary Prevention Study (WOSCOPS), 6595 men with hypercholesterolemia, having baseline LDL-C levels of at least 155 mg/dL, were randomized to receive pravastatin at a dose of 40 mg/day or placebo.6 Pravastatin reduced LDL-C by 26% (192?140 mg/dL) and TG by 12%, while increasing HDL-C by 5%. These changes resulted in significant risk reduction (−31%, p<0.001) for the primary end points of nonfatal or fatal myocardial infarction (MI) in the pravastatin group, despite the fact that the mean LDL-C level was 140 mg/dL post-treatment. In contrast, the goal of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) was to reduce LDL-C levels to <130 mg/dL. Over 5600 men and 997 women with LDL-C values between 130–190 mg/dL and HDL-C levels <50 mg/dL, received 20–40 mg/day of lovastatin or placebo.7,8 Lovastatin reduced LDL-C levels by 25% (150?115 mg/dL), TG by 15%, and increased HDL-C levels 6%. Subjects treated with lovastatin experienced a 37% decrease (p<0.001) in the primary end points of nonfatal and fatal MI, unstable angina, or sudden cardiac death, demonstrating the benefits of reducing LDL-C to <130 mg/dL. A number of secondary prevention trials have also been conducted to evaluate the effect of cholesterol lowering with statins on morbidity and mortality in patients with CHD (Table II). In the Scandinavian Simvastatin Survival Study (4S), 4444 men and women with CHD were randomized to receive simvastatin (20–4 mg/day) or placebo.9,10 Over the 5-year follow up period, simvastatin decreased LDL-C by 35% (185?120 mg/dL) and TG by 10%, with an 8% increase in HDL-C levels. These changes were associated with a 34% reduction in CHD risk (p<0.00001), as well as with a 30% reduction in total mortality (p<0.0003), relative to placebo. Recently, it was reported that the reduction in CHD events in the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total cholesterol (TC), LDL-C, and apolipoprotein B,11 with no clear relationship observed with triglyceride levels. In the Cholesterol and Recurrent Events (CARE) trial, 4159 men and women were enrolled to investigate the effectiveness of lowering LDL-C levels with 40 mg/day of pravastatin in post-MI patients having average baseline LDL-C values.12,13 Entry criteria included a TC level of <240 mg/dL and a LDL-C level of between 115–174 mg/dL. Pravastatin reduced LDL-C levels by 28% (139?98 mg/dL) and TG by 14%, while increasing HDL-C levels by 5% (p<0.001). Patients treated with pravastatin had a 24% lower incidence of the primary end points, fatal CHD or confirmed MI, than patients in the placebo group (p<0.003). Further analysis revealed that the LDL-C levels achieved during treatment with pravastatin were associated with reduction in coronary events down to a LDL-C of approximately 125 mg/dL, with LDL-C levels <125 mg/dL not associated with added benefit.14 In the Post Coronary Artery Bypass Graft (Post CABG) trial, aggressive lowering of LDL-C levels to <100 mg/dL significantly reduced the progression of atherosclerosis in grafts of patients who had undergone bypass surgery.15 The primary angiographic outcome was defined as the mean percentage per patient of grafts with a decrease of 0.6 mm or more in lumen diameter. Patients assigned to the aggressive treatment group took a mean of 76±13 mg of lovastatin per day relative to a mean of 4±1 mg/day for the moderate treatment group. The mean LDL-C level of patients who received aggressive treatment ranged from 93–97 mg/dL (−37%), whereas that of the moderate treatment group ranged from 132–136 mg/dL (−14%) (p<0.001). After 4 years, the mean percentage of grafts with progression of atherosclerosis was 27% for the aggressive treatment group vs. 39% for the moderate treatment group (p<0.001), with a 29% decrease in the need for another revascularization procedure also noted in the former group (p<0.01). A broad range of TC levels (155–271 mg/dL) and TG levels of <443 mg/dL were used as entry criteria for the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, a study initiated in 1989 to investigate the effects of pravastatin at 40 mg/day in 9014 CHD patients.16,17 In the pravastatin group, LDL-C was reduced by 25% (150?112 mg/dL) and TG by 11%, with a 5% increase in HDL-C (p<0.001). Pravastatin reduced CHD mortality by 24% and overall mortality by 22% relative to placebo, providing further evidence of the benefits of LDL-C lowering in CHD patients. The most recent study to address the issue of LDL-C lowering in CHD patients was the Atorvastatin Versus Revascularization Treatment (AVERT) study.18,19 In this trial, patients with stable CHD, asymptomatic or mild-to-moderate angina, and a LDL-C level of at least 115 mg/dL were randomly assigned to receive medical treatment with atorvastatin, at 80 mg/day (n=164), or to undergo angioplasty followed by usual care (n=177). Atorvastatin therapy reduced LDL-C levels by 46% (142?77 mg/dL), TG levels by 11%, and increased HDL-C levels 8% (p<0.05), whereas the changes from baseline for the angioplasty group were −18% (144?118 mg/dL), +10%, and +11% respectively. Although carried out in a small number of patients, this study did document a 36% reduction in the incidence of ischemic events, as well as a prolonged time to the first ischemic event, in the atorvastatin group (p<0.03). Overall, the preceding studies demonstrate that lowering LDL-C to <130 mg/dL is of significant benefit to CHD risk reduction in patients with or without CHD having elevated to average concentrations of LDL-C. A few studies suggest that it may be even more beneficial to reduce LDL-C to <100 mg/dL in those with CHD. It is important to note that other lipid abnormalities, such as low HDL-C, elevated lipoprotein(a), and high TG, also predispose patients to premature CHD, and therefore, these values should be considered when designing an optimal treatment strategy. In this regard, a recent American Heart Association panel has recommended lowering triglycerides to <200 mg/dL and raising HDL-C to >35 mg/dL in the primary prevention of CHD.