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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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November 16, 2009

Zetia Takes Another Torpedo

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Posted by Derek

Over the weekend, the results in a small cardiovascular trial came out that compared Merck's Zetia (ezetimibe/simvastatin) (correction - ezetimibe alone) against Abbott's Niaspan (time-release niacin). Niacin's an underappreciated therapy in the field - it has tolerability problems, mainly irritating and uncomfortable hot flushing, but it really does seem to help normalize lipid numbers. (And that's why Merck itself, among others, have taken cracks at the market).

This latest trial was a small one, but people have been starved for data on Zetia ever since it took a surprising hit (in the ENHANCE trial) suggesting that it might not be very efficacious. There's an ongoing larger trial that should answer this question once and for all, but those numbers won't be showing up for another two years. For now, anything that can help clarify what's going on is of great interest to Merck, its investors, and to cardiologists and their patients.

And Matthew Herper at Forbes is right: these latest numbers are disastrous. The study (funded by Abbott) isn't the greatest piece of clinical research in the world - it didn't study nearly as many patients as it was designed to, since it was halted early. (Here it is in the NEJM). But it still shows Niaspan as clearly superior to Zetia, and it makes a person wonder if taking Zetia is basically an expensive way to take a possibly-inadequate dose of simvastatin. In a way, the relatively small size of the study actually helps it a bit - getting numbers that definitive without having to go to much larger sample sizes isn't so easy in cardiovascular trials, so the feeling is that there much be something here.

As Herper's article details, Merck is trying to spin this as a big win for their competition, not a big loss for their own drug. But that comes close to being logically impossible: cholesterol lowering, like many other therapeutic areas, is nearly a zero-sum game. If patients take Niaspan (or any other competing drug), they're not going to be taking Zetia. This one was certainly a victory for Abbott (and generic niacin, for those who can take it), but it was a loss for Merck as well.

The FDA's not coming out of all this looking very good, either:

"How is it possible for a drug to have $4 billion in sales without any evidence of benefit?" says Harlan Krumholz, a cardiologist at Yale University. He said that the small size of the two imaging studies mean they couldn't render a clear verdict on Zetia. "But they don't instill any confidence in it either. " Douglas Weaver, head of cardiology at the Henry Ford Hospital in Detroit says: "We've used Zetia without sufficient amounts of clinical data to support it. Using it may be right, it may be wrong, but we don't know right now."

But it's worth remembering that Zetia's mode of action made perfect sense, and that it really does lower cholesterol to what you'd think would be a very beneficial degree. But it probably has several other effects beyond simple LDL lowering, and just looking at that number is clearly (in hindsight) not enough of a clinical surrogate marker. As the study authors put it:

If viewed properly, this hypothesis-generating finding is not an indictment of the overall importance of reducing LDL cholesterol for the purpose of preventing cardiovascular events, as illustrated by therapies based on statins or nonstatins (e.g., bile acid sequestrants). Rather, this adverse relationship may be attributable to the net effect of ezetimibe, a drug with diverse actions, not all of which are measured through its effects on intestinal cholesterol absorption and LDL cholesterol level. Taken together with a preexisting concern regarding the clinical effectiveness of ezetimibe, our findings challenge the usefulness of LDL cholesterol reduction as a guaranteed surrogate of clinical efficacy, particularly reduction achieved through the use of novel clinical compounds.

But as I recall, statins themselves were first approved based largely on lowered LDL, with better outcome data only showing up later. In that case, the surrogate marker paid off, but not this time. What all this is telling us, then, is that we don't know nearly as much about cholesterol and cardiology as we thought we did. And if we don't understand that area well enough, after all these years and all this effort, what parts of medicine do we really understand?

Comments (31) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials


1. Lucifer on November 16, 2009 10:41 AM writes...

I am shocked.... not.

Have any "cholesterol lowering" drugs, other than statins, been shown to reduce morbidity and mortality caused by coronary arteriosclerosis in large clinical trials?

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2. pharmagossip on November 16, 2009 11:04 AM writes...

Hopefully this (third) torpedo will sink Zetia!

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3. pharmagossip on November 16, 2009 11:06 AM writes...

On Friday, Senator Charles E. Grassley, Republican of Iowa, wrote to the Department of Health and Human Services, asking its director, Kathleen Sebelius, what action she intended to take in light of the study results.

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4. lynn on November 16, 2009 12:31 PM writes...

Zetia is ezetimibe alone. Vytorin is the combination with simvastatin.

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5. petros on November 16, 2009 12:35 PM writes...


Your are correct in your comment about the statins. It was some years after Mevacor was launched before any CV benefits were shown. If I remember correctly this led to a delay in UK approval

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6. Curt Fischer on November 16, 2009 1:03 PM writes...

The FDA's not coming out of all this looking very good, either:
"How is it possible for a drug to have $4 billion in sales without any evidence of benefit?"

...erm, neutraceuticals, anyone? The market size there seems to be ~$10 billion, and for most products, evidence of efficacy, is mild at best.

This question is only semi-rhetorical: why does the FDA get blamed when people spend zillions on a possibly-ineffective drug but not when people spend zillions on almost-definitely-ineffective herbal homeopathic remedies?

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7. ralphbon on November 16, 2009 1:04 PM writes...

The key question in my mind is, How would ezetimibe plus niacin performed? My guess is that this combination would also have performed better than ezetimibe+simvastatin, possibly even just as well as niacin+simvastatin.

After all, 20 years ago in the CLAS trial led by David Blankenhorn, niacin plus another cholesterol-absorption inhibitor -- the bile acid binder colestipol -- was shown to regress atherosclerotic lesions to a degree detectable by the much less sensitive measure of coronary arteriography. Colestipol and ezetimibe are very different classes of agent, but they both work by blocking cholesterol absorption from the intestines. So the likelihood that ezetimibe would have had at least a degree of that old-timey synergy with niacin seems pretty plausible.

Why didn't the researchers include a niacin+ezetimibe arm? I think because there was too great a risk of additive benefit. And since Merck/Schering still holds the patent on ezetimibe, why should Abbott risk finding such as result?

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8. Hap on November 16, 2009 1:17 PM writes...

Because the FDA doesn't regulate nutraceuticals, the expectations for a drug by the users and the people that pay for them (insurance companies, employers) are far higher than for snake oilXXXXXXXXXXnutraceuticals, supplements, etc. Supplements have only users and payers who are the same - thus no one with any money is going to bang on the FDA's door to demand that they actually regulate them. Why people buy stuff that can basically claim the sun and the moon but then say "well, yeah, we could be talking out of our lower intestinal orifice, and this stuff may not work better than your mom's brownies, but you're suckers, and you'll buy anything" I don't know. Blind hope works better when it isn't being delivered by sleazy people with a sneer.

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9. alig on November 16, 2009 2:32 PM writes...


Statins have already been proven to reduce cardivascular events and death in this patient class. It would be unethical to include an arm to the study which denies patients a standard of care which has been proven to work.

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10. Kismet on November 16, 2009 3:56 PM writes...

Hard, clinical endpoints still rule the day..

I am sure some "sceptics" will spin the story to imply that the "lipid hypothesis" is wrong. Although, it *is* suprising that - AFAIK - other than statins no cholesterol lowering drug has benefits on (CVD) mortality?

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11. FactCheck on November 16, 2009 4:20 PM writes...

Before just throwing out random statements, some folks might want to look into the scientific literature. A cursory glance will reveal the bile acid sequestrants. As a class these drugs lower cholesterol, have limited/no systemic exposure and *gasp* reduce heart attacks. See Am J Ther. 2007 Nov-Dec;14(6):567-80. for a review.

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12. Lucifer on November 16, 2009 4:28 PM writes...

Could the 'lipid hypothesis' folks tell me why rates of heart disease in northern France are about 1/2 to 1/3rd of those in southern UK?

Genetics? unlikely.. Fat intake? French eat more saturated fats than pretty much anyone in Europe.. Mediterranean Diet? hint: Northern france... Income levels?.. about the same

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13. Kismet on November 16, 2009 4:37 PM writes...

Cross-cultural comparisons are basically worthless. AFAIK the Japanese smoke more and get less lung cancer.
That's epidemiology 101.

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14. Kismet on November 16, 2009 4:40 PM writes...

...although in this case it's more cross-sectional/ecologic than cross-cultural crap, but it's a far cry from good, well-controlled prospective epidemiology if you get what I mean.

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15. Lucifer on November 16, 2009 4:54 PM writes...


Did you realize why I chose Northern France and Southern UK. Hint: Look at HLA typing and read a little history.

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16. dearieme on November 16, 2009 5:02 PM writes...

Lucifer: you are referring to two bunches of Gauls, I suppose? Anyway, surely "we don't know nearly as much about cholesterol and cardiology as we thought we did" is spot on. Or as I like to say: "All medical research is rubbish" is a better approximation to the truth than almost all medical research.

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17. milkshake on November 16, 2009 6:18 PM writes...

For MI you need to have fat deposits in blood vessels, which need to become hardened by inflammation, crusted-over with calcium and unstable.

There was a nice paper about year ago - that implicated unusually-low levels of p38 activity in macrophages that migrate into the plaques, engorge themselves on these lipids, die off and release more pro-inflammatory signals which recruits more macrophages to migrate in and so on. (The paper raised issues about cardiovascular safety of giving a p38 inhibitor drug over a long term).

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18. Anonymous on November 16, 2009 6:24 PM writes...

so why did Merck Stock increase?

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19. Anonymous on November 16, 2009 7:04 PM writes...

The stock increased because the news was not as negative as analysts were expecting it to be.

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20. Cheapskate on November 17, 2009 12:24 AM writes...

hey! whaddya want for $30 an hour!

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21. Anonymous on November 17, 2009 11:35 AM writes...

alig @9:

If you're still looking, could you explain why the study population could not easily have been defined as one for which either a statin or Niaspan was indicated? For example, prior MI with lipids controlled to a comparable degree with either chronic statin or Niaspan monotherapy?

The Niaspan label notes, "No incremental benefit of Niaspan coadministered with simvastatin or lovastatin on cardiovascular morbidity and mortality over and above that demonstrated for niacin, simvastatin, or lovastatin monotherapy has been established."

So I don't see why there couldn't have been an ethical way to design the study to include a Niaspan+ezetimibe arm if Abbott wanted to learn the answer.

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22. Dick G on November 17, 2009 12:00 PM writes...

Taken alone, this study should not form the basis for a decision on the use of Zetia. With that said, the evidence is mounting against both cholesterol reduction and the lipid hypothesis with respect to the treatment and prevention of heart disease. There is not one clinical trial that supports the use of any cholesterol reduction drug outside of statins for the treatment of CHD. I suspect IMPROVE IT will provide the last piece of evidence required to end any speculation about the value of Zetia/Vytorin. The lipid hypothesis will be the next domino to fall.

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23. ralphbon on November 17, 2009 12:34 PM writes...

Comment 21 was mine; didn't mean to go anonymous (just lightly pseudonymous).

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24. metaphysician on November 17, 2009 5:45 PM writes...

Out of curiousity, are there any existing alternate explanations for how statins reduce heart disease?

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25. Anonymous on November 18, 2009 1:22 PM writes...

Statins have lots of known and probably even more unknown pleiotropic effects that could be more important than LDL reduction in the decrease of cardiovascular events. AFAIK, the known ones are generally anti-inflammatory in nature. I think the endpoint in this trial should be implicated more than the drug or the "LDL hypothesis." Carotid IMT is an extremely questionable surrogate and is probably much more closely related to low-level inflammation than actual plaque-forming mechanisms. Dental cleanings have been shown to meaningfully reduce carotid IMT (see NEJM last year). And the minute changes it supposedly registers over such long periods (fractions of milimeters per year) are almost implausible to either measure reliably or truly be meaningful.

Statins probably do well with carotid IMT from their anti-inflammatory effects. But this could be a little removed from other effects more closely related to its MACE-reduction. Personnally, I would not trust carotid IMT one way or the other too much: If a drug reduced it, it's maybe reassuring, but not definitive. If a drug fails to reduce it, then it seems like it is a strike against it, but there are a lot more pitches left in the at-bat...

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26. Brett on November 18, 2009 1:44 PM writes...


There is evidence that statins also have anti-inflammatory effects, which is beneficial in stabilizing plaque deposits.

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27. Matthew Herper on November 19, 2009 10:48 PM writes...

Just to answer a couple questions: It was seven years between the approval of Mevacor and 4S, which first demonstrated the hard benefits of statins, and there are studies ongoing of statin+ezetimibe+niacin as well as outcome studies of niacin+statin and statin+ezetimibe.

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28. Thomas on November 20, 2009 10:00 AM writes...

There were statins on the market before the 4S results, but they weren't used all that much until after 4S (and the primary prevention trials).

The difference with ezetimibe is that it was very widely used before there was any hard evidence as to benefit, even though statins were (for most users) available as an alternative. There's also a contrast with torcetrapib, which was developed at roughly the same time, had similarly dramatic lipid effects (raising HDL) and also didn't actually work, but where this was tested before approval.

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29. Zetia on February 20, 2010 8:43 AM writes...

If you're still looking, could you explain why the study population could not easily have been defined as one for which either a statin or Niaspan was indicated? For example, prior MI with lipids controlled to a comparable degree with either chronic statin or Niaspan monotherapy?

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30. Lose Weight on August 13, 2011 2:28 PM writes...

There is evidence that statins also have anti-inflammatory effects

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31. man and van on May 13, 2014 4:04 AM writes...

I was able to find good advice from your blog posts.

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