Ezetimibe: Rationale and role in the management of hypercholesterolemia

Elevated low-density lipoprotein (LDL) cholesterol plays an important role in the development of atherosclerosis. In part, plasma LDL levels are dependent on cholesterol absorption in the intestine and the rate of intrinsic cholesterol synthesis. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors has often proven to be successful in reducing plasma LDL levels. However, a significant number of patients do not reach their target LDL levels despite statin therapy. As is reviewed, drugs that inhibit cholesterol absorption are a useful adjunct to lipid-lowering therapy by statins. This review discusses the mechanisms involved in intestinal absorption of cholesterol and its transport as potential targets of newer agents that affect cholesterol absorption. The use of bile acid sequestrants and esters of plant stanols, as well as other intestinally active agents for reducing plasma LDL levels, has been limited by side effects and difficulties in patient compliance. In contrast, the new selective cholesterol transporter inhibitor ezetimibe has been demonstrated to reduce plasma LDL alone or in combination with statins without significant adverse effects. In spite of the robust lipid-lowering data with ezetimibe, questions about clinical outcomes, safety, and efficacy in various combinations remain.