"The lower the better" in hypercholesterolemia therapy: a reliable clinical guideline?

Since the publication of the second set of guidelines by the National Cholesterol Education Program, a solid body of data from landmark clinical studies has demonstrated that reduction in low-density lipoprotein (LDL) cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ("statin") therapy sharply diminishes the risk for coronary artery disease. These trials include the Scandinavian Simvastatin Survival Study, the West of Scotland Coronary Prevention Study, the Air Force/Texas Coronary Atherosclerosis Prevention Study, the Cholesterol and Recurrent Events investigation, and the Long-Term Intervention with Pravastatin in Ischaemic Disease trial. Coronary event rates and, in some cases, all-cause mortality decreased significantly after about 5 years of statin therapy in patients at risk for and those who had coronary artery disease at baseline. In contrast, recent subgroup analyses of these pivotal studies have in the aggregate challenged the premise that lower LDL cholesterol levels necessarily lead to further declines in risk for coronary artery disease, particularly among the patients most likely to be seen by the clinician: those with moderately elevated or normal cholesterol profiles. Indeed, when LDL cholesterol levels are in this range, further lowering with statin therapy elicits diminishing returns in terms of coronary event rates. These findings are readily accommodated by the curvilinear, or log-linear, model between serum cholesterol level and risk for coronary artery disease, which is predicated on data from large epidemiologic studies. In light of the current climate involving competing health care costs, the pursuit of progressively diminishing returns in terms of reductions in coronary artery disease risk through more aggressive lowering of LDL cholesterol levels appears to be unwarranted. Until data are published from ongoing randomized, clinical trials that can more effectively resolve the clinical utility of aggressive lipid-lowering strategies to improve coronary event rates, a prudent, evidence-based strategy seems warranted.