Academic takes a well-aimed swipe at cholesterol drug ezetimibe

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I am not particularly enthusiastic about cholesterol management. I don’t believe that the role cholesterol has in cardiovascular disease is as is popularly stated. But more importantly, when we use drugs to manage cholesterol the results are, by and large, disappointing. For example, treatment with statins does not save lives in people without a prior history of heart attack or stroke. Even in people at higher risk of cardiovascular disease, the great majority of treated individuals over a few years will not benefit. And then we have the problems of side effects.

The popularity of cholesterol management strategies in many way hinges on the idea that (LDL) cholesterol is bad, and lowering it is good. Yet, the scientific literature is littered with evidence that does not support either of these contentions. For example, we have evidence linking higher cholesterol levels with improved health outcomes and longevity in the elderly. We also have plenty of evidence which shows that cholesterol reduction will not always benefit health, and may in fact pose hazards here.

A case in point here concerns the drug ezetimibe. This medication reduces cholesterol, but unlike statins (which reduce cholesterol production in the liver), ezetimibe blocks the absorption of cholesterol from the gut. It’s generally very effective at reducing cholesterol levels, and because of this, the Food and Drugs Administration (FDA) licensed ezetimibe for use in the treatment of raised cholesterol in 2002. Since then, ezetimibe has gone to rack up sales in the order of $4 billion dollars annually.

Ezetimibe was licensed on the basis of its ability to lower cholesterol. At this time, no study has been published that it had benefits on health. So, what’s happened since? Well, there’s been a few studies that have looked at ‘clinical’ endpoints or disease processes (such as the build-up of plaque in the arteries), and the results have been far from encouraging.

For example, 2008 saw the publication of the so-called ENHANCE study which found that adding ezetimibe to simvastatin (a statin) led to an increase in the thickness of artery walls in the neck compared to simvastatin alone (though the difference was not statistically significant). The results of this trial were delayed by 2 years and had to be forced out of the manufacturers by the US Government.

Other studies have not only found no benefit, they’ve revealed worsening outcomes. In one study, treatment with ezetimibe was associated with (statistically significant) worsening of the narrowing of the arteries in the legs [1]. And then we have the inconvenience of the trials which link ezetimibe use to an increased risk of dying from cancer [2], which some researchers (in the pay of ezetimibe’s manufacturers) put down to ‘chance’, even though the data shows that the association is highly unlikely to be due to chance, and in all likelihood is a real effect.

Casual conversations with members of the medical profession reveal to me that the issues with ezetimibe are largely unrecognised, though there have been signs in the scientific literature that we are at last seeing some awareness of the issues. I came across a piece published recently in the journal Expert Opinion in Pharmcotherapy written by Dr Sheila Doggrell of the University of Queensland in Australia [3]. Dr Goggrell has reviewed the evidence and concludes this:

“…ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on atherosclerosis or cardiovascular morbidity and mortality. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes and should not be used routinely in everyday practice.”

It is perhaps relevant that Dr Doggrell is an academic, which perhaps gives her the tools to take a cool hard look at the data and come to her own conclusions. Despite not being a clinician she is acutely aware that the only important thing is the impact ezetimibe has on health (not cholesterol levels). It’s an approach that I think more clinicians could do with adopting.


1. West AM, et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis. 2011;218(1):156-62

2. Peto R, et al. Analyses of cancer data from three ezetimibe trials. NEJM 2008;359(13):1357-66

3. Doggrell SA. The ezetimibe controversy – can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin Pharmacotherapy 2012;13(10):1469-80

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