How do researchers end up recommending a drug they concede has no benefit?

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Although medical practice has a sheen of being ‘evidence-based’, you don’t have to look to far to find a lot of what we do as doctors to be either untested or proven ineffective. I wrote about this recently here where I highlight an initiative by the British Medical Journal entitled ‘Too Much Medicine’ which seeks to draw attention to the issue. A very good idea, I think.

I believe one prime candidate for ‘Too Much Medicine’ is the cholesterol-reducing drug ezetimibe. It blocks cholesterol absorption from the gut and does a generally good job of dropping blood cholesterol levels, but as I am pains to point out, none of this matters a jot. The question we need to ask is: “What effect does taking ezetimibe have on health?”

Some researchers recently did us a huge favour by summarising the evidence on ezetimibe to date [1]. The review gives a loads of information on ezetimibe’s mechanism of action and how effective a cholesterol reducer it is, but things only get interesting (for me, anyway) once we get to the section entitled ‘Clinical outcome trials’.

Here’s how it starts:

The clinical efficacy of ezetimibe treatment was evaluated in the SEAS study, where 1873 subjects with mild to moderate aortic stenosis without indication for lipid-lowering therapy were randomized to ezetimibe 10 mg/day plus simvastatin 40 mg/day or placebo. The primary end point was a composite of need for aortic valve surgery and cardiovascular events. After 4 years of therapy, combination therapy with ezetimibe reduced LDL-C by 61% as compared to placebo. While there was no significant difference in the primary end point, major cardiovascular events with fatal and nonfatal myocardial infarction were significantly reduced by 41% in the simvastatin plus ezetimibe group (Figure 3).

This study compared taking simvastatin and ezetimibe together with taking nothing (placebo), and because of that, we cannot judge what, if any, benefits, ezetimibe had on the people who took it in this study.

The authors go on to write:

Similar evidence supportive of a cardiovascular benefit in using statin plus ezetimibe treatment was noted in the SHARP trial. In SHARP, subjects with chronic kidney disease with and without dialysis dependence were randomized to simvastatin 20 mg/day plus ezetimibe 10 mg/day or placebo. After 5 years of therapy, there was a significant 17% reduction in major atherosclerotic events in the ezetimibe groups as compared to placebo (P = 0.0021). Risk reduction was again found to be proportional to magnitude of LDL-C reduction.

Again, this study suffers from the same study design as the one before (SEAS). It simply is useless for judging the effects of ezetimibe on clinical outcomes. The authors also refer to other ‘positive’ studies: SANDS and VYCTOR. In neither of these studies was ezetimibe given on its own and outcomes compared with placebo. Also, clinical outcomes (like heart attack) were not assessed. Again, these studies fail to answer critical questions about the effectiveness of ezetimibe.

To their credit, though, the authors do tell us about two trials with ‘negative’ outcomes (ENHANCE and ARBITER 6). However, to be fair, these trials did not look at clinical outcomes either, and in neither study, again, was ezetimibe given alone.

The authors then concede this point:

Also, to date, no randomized trial has shown a significant reduction in clinical events with combination therapy using ezetimibe plus statin versus statin alone.

So, not only has ezetimibe not be found to be of benefit when given alone (because for some reason, this has not been tested), it has not been found add any benefit that statins have on their own.

The authors go on to tell us about a trial that is underway called IMPROVE-IT, in which the effect of ezetimibe is being tested on 18,000 people when given on top of statin therapy (again). The results are ‘highly-anticipated’ according to the authors. However, it seems the authors do not want to get out hopes up by telling us that:

Given the already low LDL-C levels and reduced cardiovascular events with simvastatin-only therapy in this population, the further reduction of cardiovascular events with the addition of ezetimibe will likely be of modest value…Ideally, a trial comparing ezetimibe monotherapy versus placebo in hypercholesterolemic subjects would provide the best answer on ezetimibe’s ability to lower LDL-C and subsequently affect cardiovascular events. But unfortunately, given the long-established benefit of statin therapy, a cholesterol trial without statin therapy would not be possible today, particularly in subjects with [coronary heart disease].

Can I paraphrase: “The IMPROVE-IT results are unlikely to be anything to write home about (just like all the other studies), and what’s really required is a study where ezetimibe is tested on its own. This study is not going to be done, and we can justify that too.”

And then after all this, the authors write:

Results from IMPROVE-IT are forthcoming and may help to guide better the use of ezetimibe in very high-risk CHD populations. Until that time and based upon the current available data, ezetimibe should remain a viable adjunct to statin therapy in the treatment of hypercholesterolemia.

Anyone with any degree of objectivity would have to concede the ‘evidence base’ for ezetimibe is, well, pretty much non-existent. But, according to the authors we should still use it for the ‘treatment of hypercholesterolemia’. Nice choice of words, and perhaps a clever way of diverting our attention again from the fact that ezetimibe has never been shown in any study to improve health outcomes in any person – ever.

So, how do we end up with a conclusion which, in my view, simply cannot be supported in terms of the clinical evidence we have on ezetimibe. Here’s the conflicts of interest disclosure that comes with this paper:

[box style=”rounded” border=”full”]Disclosure
Binh An Phan is a speaker for Abbott. Thomas Dayspring consults for Abbott, GSK, Health Diagnostic Labs, Kowa Company, Eli Lilly, Merck, Genentech, The Roche Group, Genzyme, and Omthera. He is on the Lecture Bureau for Abbott, GSK, Health Diagnostic Labs, Kowa, Eli Lilly, LipoScience, Merck. Peter P Toth is a speaker for Abbott, AstraZeneca, Amylin, Boehringer-Ingelheim, GSK, Kowa, Merck and consults for Abbott, Aegerion, AstraZeneca, Atherotech, Genzyme, Genentech, Kowa, and Merck.[/box]

So, all the authors have links with drug companies that make cholesterol-reducing agents, and that two of them have multiple such links, including with the company that makes ezetimibe (Merck). If you feel deeply cynical about this, then I think you can be forgiven.


1. Binh An P Phan, et al. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag. 2012; 8: 415–427.

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