Relation between lipids and atherosclerosis: epidemiologic evidence and clinical implications. Coronary artery disease (CAD) is the leading cause of death in most developed countries. Therefore, elucidation of risk factors and associated mechanisms for CAD has been a high priority. Data from the Framingham Heart Study and other large-scale epidemiologic studies have identified major risk factors associated with CAD, demonstrating the adverse effects of increased total and low-density lipoprotein cholesterol levels and the protective effect of high-density lipoprotein cholesterol. Other more recent investigations, including the Lipid Research Clinics Trial and the Helsinki Heart Study, have shown that lowering total cholesterol and raising high-density lipoprotein cholesterol significantly reduce the risk for CAD. Because hypertension is also a significant risk factor for CAD, the assumption has been that blood pressure reduction should offer significant benefits in terms of CAD risk. However, despite their antihypertensive efficacy, diuretics and beta blockers have failed to significantly reduce CAD morbidity or mortality. The adverse effects of these antihypertensive agents on lipid profiles, glucose metabolism and other metabolic parameters may account for their disappointing performance in reducing CAD morbidity and mortality. As a result, newer agents such as angiotensin-converting enzyme inhibitors and calcium antagonists that appear to be free of such adverse effects have garnered considerable attention for their potential to reduce CAD risk. 