Reductions in low-density lipoprotein (LDL) cholesterol levels attained by therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have provided primary and secondary prevention of coronary events. The justification for targeting LDL cholesterol to its lowest possible level, however, is less clearly evidence-based. There is significant epidemiologic evidence indicating that the relationship between levels of total or LDL cholesterol and risk for coronary artery disease is curvilinear, or log-linear. Thus, in most persons with normal or mildly elevated serum cholesterol levels, lipid-lowering therapies are likely to produce progressively less benefit in terms of reducing the rate of coronary events.

Jacobson reviewed the argument that “the lower the better” is appropriate in cholesterol treatment in patients with or without baseline coronary artery disease. The three landmark trials that established the secondary preventive value of lipid reduction, the Scandinavian Simvastatin Survival Study, the Cholesterol and Recurrent Events trial and the Long-Term Intervention with Pravastatin in Ischemic Disease study, tested statins in patients with previous myocardial infarction. These trials provide evidence supporting the institution of therapy with these agents even when the cholesterol level is not markedly elevated. Subgroup analysis, however, shows diminishing absolute reductions in the risk for recurrent coronary artery disease in patients with initially lower cholesterol levels.

In primary prevention of coronary vascular disease, two major studies, the West of Scotland Coronary Prevention Study and the Air Force/Texas Coronary Atherosclerosis Prevention study, also demonstrated that lowering the LDL cholesterol level by more than 24 percent or doubling the statin dosage did not further diminish risk. The data in these studies are also compatible with the curvilinear relationship between LDL cholesterol level and coronary artery disease risk. The Second Joint Task Force of European and other Societies on Coronary Prevention established a target LDL cholesterol level of 115 mg per L (3.0 mmol per L). Patients at the absolute highest risk for coronary heart disease with nonlipid risk factors such as hypertension, diabetes and smoking should be targeted for treatment.

The author concludes that evidence seems to contradict the “lower is better” argument for LDL cholesterol management. Special populations such as persons with diabetes may be exceptions and, according to the new American Diabetes Association guidelines, the target LDL cholesterol level for patients with diabetes is 100 mg per L (3.6 mmol per L) or less, regardless of whether the patient has evidence of coronary artery disease. More study is also needed of other cardioprotective effects offered by statin therapy that are not related to lipid levels, including improvements in endothelial function, plaque stabilization, fibrinolysis and C-reactive protein levels. Two trials are in progress evaluating the value of aggressive lipid-lowering strategies, including the Treat to New Targets study of atorvastatin and the Study to Evaluate Additional Reductions of Cholesterol and Homocysteine of simvastatin. Until the results of these trials are released, a cautious proportionate approach to the treatment of hypercholesterolemia is appropriate.