Ezetimibe: A Selective Cholesterol Absorption Inhibitor

Edith A. Nutescu, Pharm.D.; Nancy L. Shapiro, Pharm.D.


Pharmacotherapy. 2003;23(11) 

In This Article

Abstract and Introduction

Ezetimibe is the first agent of a novel class of selective cholesterol absorption inhibitors recently approved by the Food and Drug Administration for treatment in the United States. Ezetimibe inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides, or bile acids. Ezetimibe localizes at the brush border of the small intestine and decreases cholesterol uptake into the enterocytes. Preclinical studies demonstrated lipid-lowering properties of ezetimibe as monotherapy and showed a synergistic effect in combination with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). The efficacy and safety of ezetimibe 10 mg/day have been established in phase III clinical trials. In these trials, ezetimibe was investigated as monotherapy, as an add-on to ongoing statin therapy, and as combination therapy with statins in patients with primary hypercholesterolemia. In addition, ezetimibe has been evaluated in patients with homozygous and heterozygous familial hypercholesterolemia and in those with sitosterolemia. When given as monotherapy or in combination with statins or fenofibrate, ezetimibe reduces low-density lipoprotein cholesterol (LDL) by 15-20% while increasing high-density lipoprotein cholesterol by 2.5-5%. Unlike other intestinally acting lipid-lowering agents, ezetimibe does not adversely affect triglyceride levels and, due to its minimal systemic absorption, drug interactions are few. Ezetimibe's side-effect profile resembles that of placebo when given as monotherapy or in combination with statins. In clinical practice, ezetimibe has a role as monotherapy for patients who require modest LDL reductions or cannot tolerate other lipid-lowering agents. In combination therapy with a statin, ezetimibe is used in patients who cannot tolerate high statin doses or in those who need additional LDL reductions despite maximum statin doses.

Elevated cholesterol represents one of the major risk factors leading to cardiovascular disease, which in turn is the most frequent cause of death in the United States.[1] Primary and secondary prevention trials involving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy consistently have demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL) leads to reduction in cardiovascular morbidity and mortality.[2] Because of these beneficial effects, statins have become the preferred agents for treatment of hypercholesterolemia.[3] However, despite the effective-ness of statins in lowering LDL, morbidity, and mortality, less than 40% of patients achieve their target LDL goals. This percentage is even lower (18%) in the highest-risk patients -- those with established coronary heart disease (CHD).[4]

Inappropriate starting dosage and inadequate dosage titration of statins, and poor patient tolerance of higher doses or of various combination regimens all contribute to this gap in LDL goal attainment.[5] In addition, the dose-response relationship of various lipid-lowering agents is considered a potential barrier in clinical practice. The largest degree of LDL reduction is attained with the starting dosage of a statin, and every subsequent doubling of the dose leads to only an additional 6% decrease in LDL from the original baseline level.[6] A similar dose-response relationship has been reported with other available lipid-lowering agents.[7] Furthermore, side effects of many lipid-lowering agents increase with higher doses or with various combination regimens.[5]

Due to these limitations of the available lipid-lowering therapies, new agents with mechanisms complementary to statins and good side-effect profiles would help more patients to reach their LDL goal. The selective cholesterol absorption inhibitors are a novel class of agents that possess these characteristics. Ezetimibe, the first agent of the class to be approved by the Food and Drug Administration for treatment in the United States, has demonstrated a favorable adverse-event profile while reducing LDL when given as monotherapy or in combination therapy.


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