Alternative approaches to cholesterol-lowering therapy

Abstract

duced a new era into cholesterol-lowering therapy. 1 Although clinical trials in the pre-statin era provided strong evidence that lowering of serum cholesterol, particularly low-density lipoprotein (LDL) cholesterol, will reduce risk for coronary heart disease (CHD), subsequent clinical trials using statins revealed the full potential for lowering of serum cholesterol for reducing major coronary events, coronary procedures, stroke, and total mortality rates. 2 The results of these statin trials have changed the practice of preventive cardiology. High-risk patients of many types, that is, those with established CHD, other forms of atherosclerotic disease, diabetes, and those with multiple risk factors, have become candidates for statin therapy. At the present time, millions of people in the United States and worldwide are being treated with statins. The action of statins to lower serum LDL cholesterol was anticipated by the discovery of the LDL receptor by Brown and Goldstein. 3 These investigators demonstrated that reduction of hepatic cholesterol content upregulates synthesis of LDL receptors and thereby lowers serum LDL cholesterol concentrations. Statins competitively inhibit hydroxymethylglutaryl coenzyme A reductase, a rate-limiting enzyme in cholesterol synthesis. 4 In this way, statins lower hepatic concentrations of cholesterol, which increases LDL receptor activity. Some workers propose that the inhibition of cholesterol synthesis will reduce lipoprotein formation, 5 but the major effect of statins on serum LDL levels appears to be mediated through a higher LDL receptor activity. 6