Enhanced hypercholesterolemia therapy: The ezetimibe/simvastatin combination

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While therapy with HMG-CoA reductase inhibitors, or statins, has provided the principal pharmacological innovation in the treatment of hypercholesterolemia in recent years, extensive use of these agents has shown that not all patients respond to them and that still greater reductions in low-density lipoprotein (LDL) cholesterol can further protect patients from cardiovascular events. The strategy of increasing the doses of statins is effective but associated with an increase in adverse effects. The combination of statins with other agents has also, in some cases, increased efficacy, but has likewise been limited by toxicity. The administration of a new agent with a novel mechanism of action, ezetimibe, with a well-characterized and effective statin, simvastatin, in a single tablet now appears to provide enhanced treatment without compromising safety. Monotherapy with either ezetimibe or simvastatin has demonstrated the ability to significantly lower LDL cholesterol. Simultaneous administration of the two agents benefits from their two distinct mechanisms of action: inhibition of biliary and dietary cholesterol absorption by ezetimibe and inhibition of hepatic cholesterol synthesis by simvastatin. The two mechanisms have exhibited complementary activity in preclinical evaluation and have demonstrated an absence of pharmacokinetic interaction in humans. Large clinical trials have consistently shown that the addition of ezetimibe to simvastatin produces significantly greater reductions in LDL cholesterol than simvastatin alone, with tolerability similar to statin monotherapy. Ezetimibe/simvastatin has also been associated with other beneficial effects on lipids, and it achieves greater efficacy than monotherapy with the use of lower, safer doses of the statin. These findings indicate that use of the ezetimibe/simvastatin single tablet will allow more patients to meet increasingly stringent LDL cholesterol goals, thereby avoiding negative cardiovascular outcomes.