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Given the ENHANCE trial results, ezetimibe is still unproven

Cleveland Clinic Journal of Medicine. 2008 July;75(7):497-498, 502, 505-506
July 1, 2008|Cleveland Clinic Journal of Medicine
Allen J. Taylor, MD
Author and Disclosure Information

Allen J. Taylor, MD
Department of Medicine and Chief, Cardiology Service, Walter Reed Army Medical Center, Washington DC, and the Uniformed Services University of the Health Sciences, Bethesda, MD

Address: Allen J. Taylor, MD, Chief, Cardiology Service, Walter Reed Army Medical Center, 6900 Georgia Ave., NW, Building 2, Room 4A34, Washington, DC 20307-5001; e-mail allen.taylor@na.amedd.army.mil

The opinions or assertions herein are the private views of the authors and are not to be construed as reflecting the views of the US Department of the Army or the US Department of Defense.

The author has disclosed that he has received grant support for research and honoraria for teaching and speaking from Abbott Laboratories.

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.

See related commentary

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).

These trends are particularly worrisome, given that the ezetimibe/simvastatin group achieved a greater reduction in C-reactive protein levels, which typically has resulted in superior outcomes in atherosclerosis3 and clinical effects4 in combination with LDL-C reduction.

In view of these findings, should clinicians stand firm and continue to use ezetimibe? Or should we reevaluate our position and await more data about this unique, first-in-class compound?

WISHFUL POST HOC HYPOTHESES

In this issue of the Cleveland Clinic Journal of Medicine, Dr. Michael Davidson,5 a respected lipid expert but one invested in ezetimibe’s development, assures us that all is in order and that the results of ENHANCE can be explained away by several arguments, most notably that most of the trial’s participants had previously received lipid-lowering treatment, which obscured the effects of ezetimibe. Moreover, he argues that ezetimibe’s mechanism of action is well understood and that the drug is safe and well tolerated and thus should remain a first-line treatment for hyperlipidemia.

These arguments may eventually prove to be correct, but as of now they are merely wishful post hoc hypotheses awaiting more data apart from ENHANCE. Negative clinical trials do occur as a matter of chance, but we should be cautious in any attempts to explain away a trial that was designed, executed, and reported as conceived simply because the results do not match our expectations.

Confronted with ENHANCE, the astute clinician should ask three questions: Do we really understand ezetimibe’s mechanism of action? Do other lines of evidence indicate the drug is beneficial? And how reliable is the arterial thickness as a surrogate end point?

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