Editorial

Given the ENHANCE trial results, ezetimibe is still unproven

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Ezetimibe (Zetia) was licensed by the US Food and Drug Administration in 2002 on the basis of its ability to reduce low-density lipoprotein cholesterol (LDL-C) levels. The reductions are mild, approximately 15%, 1 which is comparable to the effects of a stringent diet and exercise or of a statin in titrated doses.

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However, there was no evidence that ezetimbe, which has a unique mechanism of action, delivers a benefit in terms of clinical outcomes. Despite this, the use of ezetimibe (alone or in fixed-dose combination with simvastatin, a preparation sold as Vytorin) grew rapidly, generating annual sales of $5.2 billion. Clinicians and the manufacturer (Merck/Schering-Plough) broadly assumed that LDL-C reduction would carry ezetimibe’s day as clinical trials emerged.

The assumption seemed reasonable, since evidence from the past 3 decades has established a clear link between lowering LDL-C levels via diverse mechanisms and positive clinical outcomes, particularly lower rates of cardiovascular disease and death. Indeed, LDL-C measurement is now a focus of cardiovascular risk assessment and management, as reflected in national treatment guidelines.

THE ENHANCE TRIAL: EZETIMIBE FAILS A KEY TEST

Unexpectedly, ezetimibe failed its first step in clinical trial validation, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. 2 Apart from the scientifically irrelevant political regulatory intrigue generated by the sponsor’s conduct in this trial, ENHANCE’s findings challenge us to confront issues of what we assume vs what we really know, and how to interpret the complex results of clinical trials.

To be fair to the trial’s investigators, ENHANCE achieved its objective of enrolling a population with a very high LDL-C level, which is ezetimibe’s target and has been widely used in the study of atherosclerosis progression as a marker of potential drug benefit. Nevertheless, and even though the LDL-C level 2 years later was 52 mg/dL lower in the group receiving ezetimibe/simvastatin than in the group receiving simvastatin alone (Zocor), at LDL-C levels that are typically associated with atherosclerosis progression (140–190 mg/dL), ezetimibe failed to reduce the progression of atherosclerosis.

Supplementary appendix to Kastelein JJ, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358:1431–1443. doi:10.1056/NEJMoa0800742. Copyright 2008, Massachusetts Medical Society.
Figure 1. Differences in the change from baseline at 24 months in carotid intima-media thickness between patients treated with ezetimibe/simvastatin or simvastatin alone in prespecified subgroups in the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. Bars = 95% confidence intervals, CV = cardiovascular, FH = familial hypercholesterolemia, CHD = coronary heart disease, LDL-C = low-density lipoprotein cholesterol, IMT = intima-media thickness.
In fact, after 2 years of therapy, the intima-media thickness had increased more in the ezetimibe/simvastatin group than in the simvastatin-only group, most notably in the most-diseased carotid and femoral segments, although the differences between groups were not statistically significant. A lack of effect or a trend toward a worse effect with ezetimibe was seen in 22 of 25 subgroups, including key subgroups based on prior statin treatment (patients with no prior statin therapy did not benefit), baseline carotid intima-media thickness (patients with thicker arteries did not benefit), and baseline LDL-C levels (those with higher baseline levels did not benefit) ( Figure 1

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