ABSTRACT
The lipid hypothesis of atherosclerosis was proposed more than a century ago and is based on the premise that dyslipidemia is central to the initiation and progression of coronary and peripheral arterial disease. The corollary is that modification of the lipid profile [reduction of total, low-density lipoprotein (LDL), and very low-density lipoprotein] will reduce the risk for vascular morbidity and mortality by altering the inexorable progression of atherosclerosis. The lipid hypothesis has been verified in epidemiologic experimental, pathologic, and genetic studies. However, the statistical association between dyslipidemia and atherosclerosis does not necessarily prove that pharmacologic modification of various lipid subtypes will alter the course of vascular disease. The early clinical trial data investigated lipid lowering with bile acid sequestrants, fibric acid derivatives, or nicotinic acid compared to placebo and demonstrated statistically significant improvement in cardiovascular morbidity and mortality, although reductions in total mortality were not achieved. Despite the positive relative risk reduction, the absolute benefits were minimal and the pharmacologic agents employed were difficult to administer due to lack of patient compliance secondary to the inherent side-effect profile of the agents employed. The advent of 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors revolutionized the ability of the clinician to optimize the lipid profile via a predominant effect on LDL cholesterol levels. Statin therapy was subsequently demonstrated to reduce cardiovascular morbidity and mortality in both primary and secondary prevention trials. Additionally, in adequately powered studies, total mortality has also been decreased by the administration of inhibitors of cholesterol synthesis.
