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Ezetimibe, a New Cholesterol Absorption Inhibitor

Am Fam Physician. 2003 Mar 1;67(5):1058-1059.

Reduction of low-density lipoprotein (LDL) cholesterol levels reduces coronary heart disease risk. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have been widely prescribed as inhibitors of cholesterol synthesis, resulting in lower serum cholesterol levels. Another potential cholesterol-lowering mechanism is to inhibit its absorption in the small intestine. Ezetimibe is a selective cholesterol inhibitor that has recently been approved by the U.S. Food and Drug Administration for this purpose. Dujovne and colleagues used a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of ezetimibe in reducing serum cholesterol levels.

Patients older than 18 years with a diagnosis of primary hypercholesterolemia (LDL cholesterol level of 130 to 250 mg per dL [3.36 to 6.47 mmol per L] and triglyceride level of 350 mg per dL [3.96 mmol per L] or less after washout) participated in this three-phase study. The first phase was a drug washout period during which all lipid-lowering medications were removed. The second phase involved a placebo run-in, and the third stage, lasting 12 weeks, was the double-blind treatment phase. Exclusion criteria included moderate or severe congestive heart failure, unstable cardiac disease, newly diagnosed diabetes mellitus, known renal or hepatic impairment, and coagulopathy. Participants were randomly assigned in a 3:1 ratio to receive 10 mg of ezetimibe or placebo daily for the 12-week treatment phase, without regard to meals. Lipid and apolipoprotein levels were quantitated initially and during the trial. All patients received diet information, and diet diaries were monitored throughout the study.

The treatment and control groups were similar in demographics and other pertinent characteristics. Treatment discontinuation rates and dietary saturated fat and cholesterol intake did not differ between groups. At the end of 12 weeks, the ezetimibe group had a mean reduction in LDL cholesterol levels of 16.9 percent compared with an increase of 0.4 percent in the placebo group. The reduction in LDL cholesterol levels in the treatment group began in the second week and persisted throughout the 12-week treatment period. Compared with placebo, total cholesterol, triglyceride, and apolipoprotein B levels also were significantly decreased, while high-density lipoprotein (HDL) cholesterol levels were significantly increased. Adverse events were generally mild to moderate and did not differ between groups. There was an increased frequency of allergic reaction or aggravated allergy in the treated group, but the researchers considered this happening unlikely to be related to treatment.

The authors conclude that ezetimibe, which is absorbed in the intestine and excreted primarily in the stool, potently inhibits dietary and biliary cholesterol absorption in the intestine. There is no evidence that triglyceride or fat-soluble vitamin absorption is affected. The 24-hour half-life allows once-daily dosing. LDL cholesterol reduction with treatment is about 17 percent, while HDL cholesterol increases about 1.3 percent.

In a related study in the same journal, Gagné and associates studied the use of statins with ezetimibe and noted that the combination was significantly better in lowering LDL cholesterol levels than statin therapy alone.

In an editorial in the same journal, Grundy provides alternative protocols for treatment of various dyslipidemias using single- or multiple-drug regimens, including ezetimibe and other lipid-lowering agents.

Dujovne CA, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol November 15, 2002;90:1092–7; Gagné C, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol November 15, 2002;90:1084–91; and Grundy SM. Alternative approaches to cholesterol-lowering therapy [Editorial]. Am J Cardiol. November 15, 2002;90:1135–8.


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