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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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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March 13, 2006

The Big Statin Pillow Fight

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Posted by Derek

The American College of Cardiology meeting in Atlanta is the source of all those news headlines today on cholesterol-lowering drugs. It can hard to make sense of all the studies that are being reported - my favorite confused headline so far is "Merck Says Vytorin Beats Zocor", to which the appropriate response is "It had damn well better". Beating Zocor is the whole reason that Vytorin exists, since it's Zocor (simvastatin) plus Schering-Plough's dietary cholesterol absorption inhibitor Zetia (ezetimibe).

The cholesterol-lowering market has long been vicious, but it's getting more so. There's a simple reason: Zocor's going generic this summer. Many managed-care organizations are looking forward to moving patients to the new, cheaper statin as soon as that happens, and companies are trying to come up with reasons to keep that from happening. Merck needs to show that they've got something better than their old drug, and other companies with their still-patented statins want to show that they do more than the generic will, too.

Thus AstraZeneca's big splash with their results for Crestor (rosuvastatin), where they showed arterial plaques actually reversing and getting smaller. I realize that drug-company-sponsored results aren't exactly in the highest standing these days. But the lead investigator on this study was Steve Nissen of the Cleveland Clinic, who is not exactly a tool of the drug industry, unless someone's updated the master list without telling me.

And that's clear from his own comments on the results, as opposed to those in the AstraZeneca press release. While impressed with Crestor's efficacy, Nissen did a good job putting things in perspective.

For example, he points out that he doesn't think that much more plaque shrinkage is even theoretically possible - most of the lipid content of the plaques has probably been taken out by this point. And he also mentions that no, this trial wasn't powered to say whether this effect actually improves long-term morbidity and mortality in patients (although you'd have to think it would, at least a little bit). Most tellingly, he makes the observation that everyone else's statins probably do the same thing if dosed to give a similar degree of cholesterol lowering.

AstraZeneca's argument has long been that gosh, nothing can lower cholesterol like Crestor, and I'm sure that much more in this line is coming. And Merck and Schering-Plough will continue to beat the drum for Vytorin, while Pfizer will never be known for their coyness about the benefits of Lipitor. But the Zocor patent expiration is just a coming-attraction trailer for this market. Its run as the cheapest effective statin in town will go on, arguments and advertising blaring all around it, for about three or four more years. And that's when Lipitor starts going off patent. You can bet that studies are already under way to try to show why people shouldn't switch to its generic when the time comes. . .

Comments (7) + TrackBacks (1) | Category: Cardiovascular Disease


1. Jabley on March 14, 2006 8:05 AM writes...

You have a badly outdated Toolroll. Dr. Nissen has in recent years garnered a reputation for conducting industry-sponsored studies with very obvious red flags and less than admirable statistical designs. For example, take a look at AtheroGenics' probucol analog, AGI-1067. They conducted an IVUS study of 1067's effects on plaque regression, then sent the data to the Montreal Heart Institute for analysis. They didn't like what they saw, so they sent it to Nissen who "fixed" it for them by way of inexplicably tossing out more than half of the patients in the study; the stock more than doubled in response to his shenanigans. It was one of the biggest red flags I've seen in recent years. AtheroGenics then got sued for what amounted to investor fraud after Cleveland Clinic Dept. of Cardiovascular Medicine chairman Dr. Eric Topol (Nissen's boss) found out about the $500M stunt Nissen pulled and, in response, published an article in Forbes entitled "How Not to Do a Clinical Trial." Seems to me as if Nissen has a spot on Topol's Toolroll as well; perhaps he should be on yours.

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2. Derek Lowe on March 14, 2006 9:41 AM writes...

Jabley, I'm not familiar with that AtheroGenix trial, and I'll look into it. But you could ask Merck if they think that Nissen is a shill, since he was the first person to blow a loud whistle about Vioxx, or Bristol-Myers Squibb after what he had to say about the cardiovascular risks of Pargluva.

And, if I'm not mistaken, Nissen has publicly stated that he does not take any money from the pharmaceutical industry, under any circumstances. Am I mistaken about this? There's room to argue about his approach to risk and efficacy, but if he's in the pocket of my industry, it's news to me.

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3. tango on March 14, 2006 10:33 AM writes...

In the head-to-head (PRECISION) trial that Nissen is running to compare the safety and efficacy of Celebrex with NSAIDs, no researcher on the team can accept any honoraria, consulting fees or any other monies from not just Pfizer but also any other COX2 selective inhibitor manufacturer. Also, the entire trial database will be put in the public domain one year after the trial is completed. There may be questions raised over whether there should be a Tylenol cohort, or whether this trial is just a way to buy Pfizer more time, but seems clear that Nissen is going out of his way to avoid being in the pocket of the industry.

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4. Mark Senak on March 14, 2006 10:50 AM writes...

I agree - Dr. Nissen is no tool Also very much appreciate this perspective on the Crestor blitz, which seemed to be everywhere I looked for the past two days.

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5. John Casey on March 15, 2006 12:09 AM writes...

My HMO has already notified me that they are moving Lipitor from Schedule II (moderately expensive copay) to Schedule III (most expensive copay), due to the availibility of a generic statin. I'm not switching, because my numbers are very good on Lipitor (especially in light of my bad habits), and I can afford the increase. But it's nice to see that their thinking of me.


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6. S. Chander on March 16, 2006 12:16 AM writes...

I was at the ACC and so can give a first-hand view of everthing that happened (I also had the opportunity to speak to Dr. Nissen briefly, between sessions)

He is most definitely not in the pockets of the companies; he makes it clear to all of his team that all honoraria and funding is to be directed to charity. As far the issue with Topol, that may have been more politically motivated.

In regards to his perspective regarding rosuvastatin, he didn't quite state the any statin could achieve the same result, but rather indicated that it would be up to each of the other companies to step up and continue the same research. It is interesting to note that the initial funding request was made to Merck/Schering, but they turned it down, so he then went to AstraZeneca. (I doubt this is supposed to be well known.)

He also made it a point of stating several times that based on the results of REVERSAL he didn't expect to see regression but only cessation of progression. (REVERSAL was atorvastatin vs pravastatin; atorvastain 80mg demostrated no progression but no regression either in a similar population - final LDL was 79 in that study). In fact the study was designed in such a way that it would either demonstrate regression, or demonstrate that we have hit the maximal benefit of statin therapy. He went out of his way to explain both the advantages, and the holes in the study design. He also pointed out that the statistical analysis (independently verified) allowed for "worst-case scenario" analysis with no change in the direction and significance of the results.

Later, in another session, he did also suggest that the data was probably driven by the patients with the higher initial LDL values. In addition, he suggested that those with the more lipid-laden lesions were more likely to show regression (which makes sense; you can't take away the cellular and/or fibrous components of the plaque).

He also addressed the safety issue, noting that there really wasn't an issue (at present, the safety statistics for rosuvastatin are actually better than atorvastatin on a mg basis as well as on a %-lowering basis). His quote at the press conference was "I guess Sid was wrong", referring to Sidney Wolfe, from the Public Action Committee.

The bottom line is this: our natural LDL is probably around 60 (or 1.5 for those of us in Canada) based upon data from hunter-gatherers, and primitive tribes. At this level, there really shouldn't be much atherosclerotic lesion progression due to LDL deposition. This study simply supports that theory. This study gives us evidence that rosuvastatin regresses (and would probably then stabilize) plaque. If you don't want to take that particular drug then take another statin, as long as you can find another statin to get you down to an LDL of 60. But he stressed that this doesn't give us any support for other lipid lowering therapies (i.e. ezetimibe/Zetia/Ezetrol/etc). He also pointed out that 70 is just not low enough to regress, and that while this study didn't provide M&M data, we do have sufficient evidence to begin making the link between IVUS and morbidity/mortality. He then questioned whether going even lower would have even greater impact; as far as I know several companies (Novartis? Pfizer? Merck?) have "superstatins" in early development.

Sorry for the long post, but that's the whole story, straight from Atlanta (ACC).


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7. martin640b on November 4, 2006 4:26 PM writes...

How does Torcetrapib fit into into the scheme? Is it improved m&m outcomes through greater plaque reduction (is that even possible), or is it other effects of HDL boosting?

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