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Does Ezetimibe ENHANCE the Benefits of Statins?

Perhaps not, suggest these findings from a study of combination therapy’s effect on carotid-artery intima–media thickness

Ezetimibe, a novel cholesterol-absorption inhibitor marketed in the U.S. since October 2002, lowers LDL cholesterol levels. However, little is known about its effect on atherosclerosis progression. In the ENHANCE trial, 720 patients with familial hypercholesterolemia were randomized to a daily regimen of simvastatin (80 mg) plus either ezetimibe (10 mg) or placebo. The primary endpoint was the mean change in carotid-artery intima–media thickness. The study was sponsored and administered by the manufacturers and completed in April 2006. On January 14, 2008, the sponsor released some information about the trial; the present analysis is of the complete data set.

The mean age of the patients was 46; 80% had previously taken statins. At 24 months, as expected, the addition of ezetimibe to simvastatin was associated with significantly reduced mean LDL and median C-reactive protein levels but with no significant change in mean HDL level. Despite the improvements in LDL and CRP levels, the change in mean carotid-artery intima–media thickness in the combination group was nonsignificantly greater than that in the simvastatin-only group (0.0111 mm vs. 0.0058 mm; P=0.29). The change in mean femoral-artery intima–media thickness, a secondary endpoint, was also nonsignificantly greater with combination treatment (0.0182 mm vs. –0.0067 mm; P=0.16).

Cardiovascular events occurred in 7 patients in the simvastatin group and 10 patients in the combination group. Adverse events that were considered to be treatment-related occurred in 29.5% of patients in the simvastatin group and 34.2% of patients in the combination group (P=0.18).

Comment: The ENHANCE trial failed to support the efficacy of ezetimibe added to simvastatin for reducing the progression of atherosclerosis in patients with familial hypercholesterolemia — even though the drug achieved its expected effects on LDL cholesterol and CRP levels. Many explanations for these findings will surely be discussed, but one distinct possibility is that this drug somehow improves a patient’s lipid and inflammatory marker profile without conferring clinical benefit. Given the absence of an outcomes study of ezetimibe’s safety and efficacy, its clinical value is currently uncertain. As emphasized in two accompanying editorials, until more information is available, clinicians treating patients who require medication for hypercholesterolemia should maximize statin dosages first and then turn to niacin, fibrates, and resins before considering ezetimibe. At that point, the decision to use ezetimibe would be based on the as-yet unproven presumption that it will reduce risk for cardiovascular events.

— Harlan M. Krumholz, MD, SM

Published in Journal Watch Cardiology March 30, 2008

Citation(s):

Kastelein JJP et al. for the ENHANCE investigators. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008 Apr 3; 358:1431. (http://dx.doi.org/10.1056/NEJMoa0800742)

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Brown BG and Taylor AJ. Does ENHANCE diminish confidence in lowering LDL or in ezetimibe? N Engl J Med 2008 Apr 3; 358:1504. (http://dx.doi.org/10.1056/NEJMe0801608)

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Drazen JM et al. Cholesterol lowering and ezetimibe. N Engl J Med 2008 Apr 3; 358:1507. (http://dx.doi.org/10.1056/NEJMe0801842)

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• Medline abstract (Free)