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

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:

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.

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.

References:

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

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

  1. Jonathan Bagley 28 March 2013 at 2:19 pm #

    Hi John,

    You say of ezetimibe

    “It blocks cholesterol absorption from the gut and does a generally good job of dropping blood cholesterol levels,……”

    Unless these two effects are independent, this suggests high blood cholesterol level follows from high cholesterol in food. I thought this wasn’t true and found this quote,

    ‘In Framingham, Massachusetts, the more saturated fat one ate, the more cholesterol one ate, the more calories on ate, the lower people’s serum cholesterol.’ Dr William Castelli, Director of the Framingham study. 1992.

    Please can you clarify. All the best,

    Jonathan Bagley

  2. Ben 29 March 2013 at 11:00 am #

    Hi John,

    I have just been put on Ezetimibe for my Familial HYpercholesterolemia, as the statins have ruined my health. I don’t really want to go any of these drugs, could you offer me any advice on what to do please, as I feel a bit lost and slightly worried at the moment. My cholesterol is now 12.4 and I am only 33. Any advice you can offer will be very welcome.

    KInd Regards,

    Ben

  3. John Walker 29 March 2013 at 12:22 pm #

    I’m given to understand that cholesterol has no effect on atherosclerosis. I hear it doesn’t cause blockages,m but that these are caused by the body trying to repair a weakness in artery walls. I’m no Doctor, but that’s what I read. Maybe it’s cholesterol the body uses for this purpose. But, if cholesterol doesn’t have any effect, what is there to be examined and measured? Doesn’t make sense to me. I think the drug companies don’t want to find cures. They just want to find drugs that can manage certain common conditions; that way there’s a never ending market for their drugs. Find a cure for hypertension, and ‘Shazam!’ No more need for beta-blockers and down go the shares. (There is a cure for most cases of hypertension of course; lose weight, by eating properly.) Which is why I have to go and see my GP, to check if I can drop the beta-blockers. But statins? It was suggested i take them. I refused.

  4. tony kerstein 29 March 2013 at 12:41 pm #

    Why is lowering cholesterol (actually LDL- so-called bad cholesterol?) considered beneficial when the real evidence shows that low cholesterol levels have the real adverse end points-i.e. more people suffer or die with this condition than with normal or what the medical profession considers high cholesterol.

  5. NM 29 March 2013 at 1:38 pm #

    Ah. I see Dr Dayspring on that list. That solves a particular puzzle: I always wondered why someone who “gets” so much of this (that sat fat is benign etc, that glycating carbs are metabolically problematic and so on) nevertheless is such a fan boi for any new lipid medication. He’s basically a a gun for hire.

  6. Gill w 29 March 2013 at 1:46 pm #

    Recently the Welsh Assembly asked all GPs in Wales to take people off ezitembe if possible because of cost. I have atherosclerosis with a totally occluded Rt internal carotid artery and a bad family history. I agreed to stop it for a trial period of 6weeks. I also take 10mg simvastatin ( the highest dose I can tolerate) my cholesterol rose from 4 to 5.2.
    40 mg of statins made me ill and weren’t as effective as the lower dose and ezitembe
    For me it is proven to work.

  7. Dr John Briffa 29 March 2013 at 2:36 pm #

    Gill W

    Leaving the possibility of the placebo effect aside, you have completely missed the major point of this blog post: the impact exetimibe has on your cholesterol is irrelevant – it’s the impact it has in your health that counts. So, what evidence is there that exetimibe benefits health (including cardiovascular health)? Answer: there is none.

  8. pat 29 March 2013 at 3:14 pm #

    after having a stroke post-operatively (carotid endarterectomy) I was put on statins, none of which suited me, so I now take fenofibrate – whats the low-down on this? Thanks, Pat

  9. Deane Alban 29 March 2013 at 3:49 pm #

    If I may add a note for Ben…

    Get a copy of The Cholesterol Myth by Dr.’s Bowden and Sinatra. Your cholesterol is not a good indicator of heart disease. It’s much more complicated than that. You need to measure your particle size not just your cholesterol levels. Ask your doctor for a VAP test. He may or may not know what that is. At least in the US, you can order this test for yourself online.

    You are way too young to spend the rest of your life on these devastating drugs. Keep looking and you’ll find your answer.

  10. david manovitch 29 March 2013 at 4:42 pm #

    Cholesterol in food does not lead to cholesterol in the blood. Cholesterol is anyway good in the same way that oxygen or water is. They are all essential for life, but too much of any of these can cause problems. There are some families who have what we call congenital hypercholesterolaemia and without medical intervention they tend to get heart attacks in in their 40s and rarely reach the age of 60. I would view this group as a special case, and that relatively high levels of cholesterol in other people are probably less toxic. I believe that they are most likely due to eating a highly processed, high carbohydrate, high sugar Western diet and if that is avoided then any health problems associated with a relatively high cholesterol can be avoided.

    When I was at medical school in the 1970s the upper limit of normal for cholesterol was claimed to be 7.0, but now is around 5.5. However nobody really knows what a normal or optimal level of cholesterol is or how variations in it affect health. If as somebody posted above, one has a cholesterol of 12.3 then my advice would be to try a statin but to radically alter your diet if you have not done so already to emulate a hunter gatherer or paleo diet and take plenty of exercise, keep alcohol consumption low and avoid tobacco.

    As for the studies quoted, they are quite useless. If it is felt unethical to omit a statin from the equation then they should be comparing ezetimibe plus statin, against a statin alone, not placebo. One has to wonder if these studies was sponsored by pharmaceutical companies.

  11. Stacie 29 March 2013 at 5:59 pm #

    To NM: I also have wondered why Dr. Dayspring, who does appear to “get it”, is so gung-ho about statins and reducing cholesterol. Now I know why. As you say, he is a”‘gun for hire.” I will henceforth discount anything he says. Also, if people understood exactly how statins work and what they really do, they would run for the hills. That such a toxin is legal and approved for use is mind boggling to me. I highly recommend “How Statins Really Lower Cholesterol and Kill You One Cell at a Time”, by the Yosephs. I really appreciate and agree with Dr. Briffa’s stance on these drugs, that it is the effect on health, not cholesterol levels that counts. Of course, most people, doctors, etc. are only looking at the soft, surrogate endpoints.

  12. Gus Fagan 29 March 2013 at 10:13 pm #

    I agree with your comments pointing out that eztimibe made no difference. But does it follow then that the statin on its own was effective in that it ‘significantly reduced [major cardiovascular events] by 41% in the simvastatin plus ezetimibe group (Figure 3).’ In the interests of not confusing those of us who agree with you on statins, you ought to make some comment on this claim.

  13. Ian Day 30 March 2013 at 2:26 pm #

    “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].”

    To what extent is “long-established benefit” better than “received wisdom” ? We all “know” the benefits because they keep telling us. Now we see that such benefits are so great that trials without the benefits of statins are likely to be considered “unethical.”

  14. DAVORIN PILJIC 13 April 2013 at 10:52 am #

    Dr Briffa, you are a rebel! Be careful that they will visit you late at night!

    Doctors should treat lifestyles, not just individual ailments.

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