Combination therapy: Its rationale and the role of ezetimibe

Despite the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of statins, many patients, especially those at the highest risk for coronary heart disease (CHD), do not reach LDL-C goals. Although there are many reasons for this observation, one possible solution is to treat hyperlipidemic patients with a combination of two lipid-altering agents that have different mechanisms of action. Several trials have illustrated the potential utility of combining resins with statins or niacin, and niacin or fibrates with statins. However, many patients poorly tolerate resins and niacin, and fibrates combined with statins may increase the risk of myopathy. An 'ideal' second drug to add to statins or niacin would: (a) lower LDL-C by 15-18%; (b) not potentiate the liver or muscle toxicities associated with high dose statins; and (c) cause few side effects or drug-drug interactions that would compromise compliance. Ezetimibe is a new cholesterol absorption inhibitor that exhibits all of these characteristics. Ezetimibe inhibits the intestinal absorption of dietary and biliary cholesterol without interfering with the absorption of fat-soluble vitamins. When added to statins, ezetimibe produces significant reductions in LDL-C and triglycerides beyond reductions seen with a statin alone. Moreover, ezetimibe has a favorable safety and tolerability profile without any clinically important drug interactions. Thus, the combination of statins with ezetimibe offers a promising new approach to lowering LDL-C.