Relation of clinical benefit to metabolic effects in lipid-lowering therapy.

Studies of lipid-modifying therapy show that inhibition of cholesterol synthesis is required in at least 2 sites-in hepatic cells and in cells located in the walls of coronary arteries-if the progression of coronary atherosclerosis is to be decreased in patients with relatively normal levels of low-density lipoprotein (LDL) cholesterol. This is clinically important, because the majority of patients with coronary artery disease do not have severely elevated LDL cholesterol levels. Of the 2 angiographic trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ("statins") in patients with coronary artery disease and average cholesterol levels, only the Lipoprotein and Atherosclerosis Study (LCAS) of fluvastatin reported slowed angiographic progression of coronary artery disease in these patients. The change in LDL cholesterol levels during treatment with fluvastatin did not predict the extent of change in coronary atherosclerosis or incidence of clinical cardiac events. Apparently, the metabolic effects of treatment with fluvastatin were more important than the extent to which blood cholesterol levels were lowered. The clinical benefits of treatment with statins should be directly compared in randomized controlled clinical trials among patients with average cholesterol levels.