Hey! Look! Science works! Zetia, not so much.

ResearchBlogging.orgI love this story because it shows how evidence-based medicine works, even in the face of corporate greed.

A while back I told you about a cholesterol study with negative results; that is, it failed to show a drug to be helpful. Intimately entwined with the study design was a potential conflict of interest on the part of the drug company, but science won out—data, after all, is data.

Then, few months ago, another set of (preliminary) cholesterol data was released by Merck and Schering-Plough, after much prodding, regarding their drugs Vytorin and Zetia.

Zetia has been quite popular. A certain number of patients do not tolerate “statin” cholesterol medicines, and are put on Zetia as an alternative. Zetia lowers cholesterol, but it has never been shown to improve important outcomes such as mortality, heart attack, stroke. That isn’t to say it might not do these things, it just hadn’t been studied. Statin cholesterol drugs have been studied, and have an excellent effect on outcomes.

Now, interesting new data is emerging. First, according to a study in the New England Journal of Medicine (NEJM) the companies’ marketing campaign appears to be working, at least in North America. Prescribing patterns have changed, with an increase in Zetia prescribing and in costs.

Second, at last week’s American College of Cardiology (ACC) meeting, more ENHANCE data were released, and consensus crystallized around experts in the field—there is no data to support the use of Zetia or Vytorin to improve important outcomes.

This is very interesting. It has been hypothesized for a number of years that statins do not simply lower cholesterol, but also prevent vascular events by other means, probably by reducing blood-vessel inflammation.

An important piece of information here is that medical science actually works. A hypothesis is formed (based on a scientific idea, and some economic interests), it is tested, and even if it fails, it adds to our knowledge. Huzzah for science! In this case, the use of Zetia will probably change significantly.

A counter example would perhaps be the mercury militia. Several recent studies added to the already conclusive database that thimerosal does not cause autism. Despite this, the wackos insist on looking for some other hidden connections between vaccines and autism, despite this having also been disproved.

A real scientist would say, “hey, I had a hypothesis, it didn’t pan out—I’ll move on to a new hypothesis.” Not so the wackos. They hold onto an idea whether or not there is any rational reason to do so.

Well, at least it gives me something to write about.


Kastelein, J.J., Akdim, F., Stroes, E.S., Zwinderman, A.H., Bots, M.L., Stalenhoef, A.F., Visseren, F.L., Sijbrands, E.J., Trip, M.D., Stein, E.A., Gaudet, D., Duivenvoorden, R., Veltri, E.P., Marais, A.D., de Groot, E. (2008). Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia. New England Journal of Medicine, 358(14), 1431-1443. DOI: 10.1056/NEJMoa0800742
Jackevicius, C.A., Tu, J.V., Ross, J.S., Ko, D.T., Krumholz, H.M. (2008). Use of Ezetimibe in the United States and Canada. New England Journal of Medicine DOI: 10.1056/NEJMsa0801461


  1. Perhaps it’s unintended, or perhaps it’s my misinterpretation, but your post seems to imply that Zetia doesn’t really work (either alone, or in combo with Zocor as Vytorin). However, we still don’t know if it does or does not provide clinical benefit, right? We only know that it improves one marker (LDL levels) but not another (plaque formation in people with familial hypercholesterolemia.)

    There’s an ongoing study to look at Zetia’s effect on morbidity/mortality, but it won’t be done until 2012. At least, that’s my understanding.

    Note: I completely agree that under the circumstances, docs should strongly prefer the statins over Zetia, since statins do have good evidence of clinical benefit. But at this point, I don’t think we really have the right data to say whether Zetia works or “not so much.”

    (In case anyone wonders: No, I don’t have any stake in any of these drugs or any other aspect of this issue.)

  2. The preliminary ENHANCE data made available earlier this year, in addition to the newly released data, so far show no outcomes benefits to Zetia (other than decreased LDL). The full data set is due to be released in 2012 (it was supposed to be 2011).

    So at this point, there is no evidence to support the use of Zetia in most situations. That’s the ACC/AHA’s position at this point. Nissen agrees, but despite that, it seems reasonable.

    There is no clear evidence of harm, other than to the wallet.

  3. chezjake

    I appreciate your coverage of this paper and the related story on the success of evidence based medicine. I think you’ve made a positive addition here at Denialism Blog.

    However, in one major respect your coverage is no better than the AP news story. Neither you nor the AP identified either drug by generic names. I know you know the generic names, because that’s all that are used in the NEJM papers. Any reference to a drug should be first by generic name and secondarily by brand name, for several reasons.
    1. Searching the literature must be done by generic name.
    2. Sometimes different brand names are used in other countries, and blogs/the internet are world wide.
    3. Use of brand names caters to big pharma’s desire to reduce generic prescribing, thus increasing their bottom lines.

    I realize that typing out generic names is often difficult; simvastatin isn’t that bad, but ezetimibe is just asking for multiple pronunciations. I think that big pharma is deliberately establishing generic names that are hard to pronounce, spell, and remember. Nonetheless, it’s important to provide generic names in any blog post (or other writing) that refers to a specific drug.

  4. Mongrel

    I think that big pharma is deliberately establishing generic names that are hard to pronounce, spell, and remember.

    Whilst I’m sure you’re only joking….

    The names are created from guidelines laid down by the World Health Organisation to conform to their International Nonproprietary Name..

    In theory this should cut down on the confusion between countries, now if only you guys would accept Paracetamol

  5. Since Zetia is not available in a generic form, and most if not all patients will know it by it’s brand name, I chose to use that.

    When drugs are available generically, I usually use the generic name. Just one way of doing things.

  6. I’m hesitant to post this, but here goes…

    If it does pan out that Zetia is useless in reducing arterial disease, and

    If Zetia does actually block cholesterol absorption in the GI tract, then

    Would it be right to conclude by inference that reducing cholesterol in your diet would not have a positive effect on arterial disease?

  7. It’s a bit of an overstep. It has been observed that lower LDL is correlated with lower rates of cardiovascular events, and that higher LDLs correlate with higher rates.

    It has also been observed that lowering markers such as LDL and HS-CRP with statins lowers risk.

    At this point, it has not been shown that lowering LDL with Zetia improves important end-points.

  8. Published on http://www.brainblogger.com:

    A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial

    While it seems that sponsors of clinical trials usually end up with results that clearly favor their meds studied in their trial, there are rare exceptions, and Merck and Schering proved that with their disappointing ENHANCE Trial, which many have heard about through the media not long ago. The drugs studied were Vytorin, which was compared with Zocor
    Vytorin is a combination med for high cholesterol and contains Merck’s Zocor, which is now generic, and Schering’s Zetia, which works differently than Zocor, which is one of many statin drugs. Both Vytorin and Zetia are co-promoted by Merck and Schering. So, several years ago, an outcomes study was initiated to prove superiority of Vytorin over Zocor as monotherapy. The trial was named the ENHANCE trial, possibly because Zocor is generic now, and not a priority from a profit paradigm of its creator.
    After several years passed, a disappointment arrived for the sponsors of this trial, which was first brought to the attention of Schering in March of 2007, yet the results existed since the spring of 2006, I believe upon information and belief.
    The disappointment is that Vytorin lacked anticipated benefit or superiority over Zocor. Since about 1 million scripts were written for both Vytorin and Zetia every week in 2007, combined with what I believe was about 5 billion in revenue for these two drugs that year, this was a problem for the drug makers, meaning a fear of shareholder reaction. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs with Schering, I understand.
    Being the responsible corporations both companies are, of course, alterations occurred after such events were discovered that fractured numerous rules and regulations with clinical trials, possibly in illegal and unethical tactics.
    The trial sponsors delayed the release of the trial results for secrecy reasons, it has been speculated. Results from the trial existed, yet were not disclosed at the time of their discovery. After several months of possessing these trial results that were only known to the manufacturers, they created or implemented some atrocious tactics to improve the trial’s unimpressive results following the original results of this ENHANCE study. At the end of 2007, the companies changed the primary endpoint of the trial, which is what the results were measured upon during the entire course of the trial. Sort of like sorting cards to make a good hand not dealt to you. Anyway, since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually as they had been anticipated for quite some time, and while such trial manipulation was occurring and results were being kept secret, Schering stated that continued data analysis from the trial results was the etiology for the delay.
    With clinical trials, case report forms are used to record data from the trials, and are created in a manner where further analysis is not normally necessary, as such forms are quite clear and often not subject to interpretation as implied by the trial sponsors, one could conclude. So at the end of 2007, both Merck and Schering got the attention of relevant government officials who contacted both companies regarding this ENHANCE trial due to such suspicions on the facts known and presented, and an investigation began into the activities of both companies regarding this trial at that point.
    This became a catalyst for the ENHANCE trial results to be finally released at the beginning of 2008, which caught the attention of major media organizations, as expected. In the spring of 2008, a very large cardiology meeting was held, where the audience was told, I understand, to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, it has been said that a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin by prescribers, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades, starting with Mevacor in the 1980s. Of course and as expected, Merck and Schering were not pleased, nor were they surprised at the review of Vytorin at this particular meeting. The following month after this cardiology meeting, Schering’s earnings dropped by 48 percent, as I recall. Also during much of this year, Schering in particular blamed the media for amplifying the situation regarding the ENHANCE trial.
    Now, these cholesterol drugs promoted by Merck and Schering, Zetia and Vytorin, were aggressively marketed in a number of ways, including investing I believe about 200million dollars in 2007 for DTC ads for these products. To add to this, and soon after both meds were launched, reps from both companies made inferences to doctors about outcomes regarding plaque accumulation and how Vytorin was superior in that area, which, of course, this ENHANCE trial proved it is in fact not the case whatsoever. It did not matter, apparently, to both Merck and Schering that such claims were is entirely void of proof, which is not unique to any pharma rep, in my opinion. No remorse or regret from the makers of these drug makers, either, which did not shock many. Yet what is known now is that these companies, as stated by other researchers, performed junk science with their deliberate manipulation of this ENHANCE trial using such tactics. Also, last year, Zetia and Vytorin had about 20 percent of the cholesterol lowering market. It does not seem that there will be an increase of this percentage because of this scandal. Possibly if they presented the truth, the future of these meds might be better than what is anticipated presently.
    Worst of all regarding this ENHANCE trial scandal is the harm caused to both doctors and patients. The ENHANCE trial concerned and confused both of these participants in the health care system. Furthermore, it’s likely they were devastated by being so clearly misled by the marketing of both Merck and Schering regarding the false benefits of Vytorin they were led to believe by the companies that promoted them- the health care providers in particular.
    This whole situation is another example of the progressively frequent discovery of corruption of the scientific method by placing profits over the well-being of patients, which harms the well being of patients. In addition, most were shocked by Merck behaving in such a way in particular because of what use to be their excellent reputation as an ethical pharmaceutical company. And this alone shows the progression and infiltration of such damaging ethical atrophy that desperately needs to be stopped and corrected for the sake of others. For the sake of everyone.
    Don’t just say something. Have something to say- to the right people, with conviction and with others who share your views.
    “Waste no more time arguing what a good man should be. Be one.” — Marcus Aurelius
    Dan Abshear

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