The Vytorin Data At The ACC: No Smoking Gun?
14 CommentsBy Ed Silverman // March 28th, 2008 // 8:34 am
That’s what one Wall Street analyst posits this morning in an investor note. As you may know, the complete Enhance trial - that controversial study of Vytorin - will be unveiled and dissected at the American College of Cardiology conference on Sunday. The lead investigator, John Kastelein, will make his first public remarks since the release of preliminary data in January engulfed Schering-Plough and Merck in controversy and embarassment.
The results found that the cholesterol pill failed to show any benefit over the much cheaper Zocor in reducing plaque in the carotid artery, and even showed a statistically insignificant buildup, although it did a better job of lowering LDL. A debate then ensued about the merits of using Vyotrin, which includes Schering-Plough’s Zetia and Merck’s Zocor. But does the full study, which will be dissected on Sunday, contain still more damaging info?
Probably not, writes Tim Anderson of Sanford Bernstein, “the results will very likely contain no smoking gun” on either primary or secondary endpoints. “We think the prevailing opinion will be that the trial showed what it did - no difference in artery wall thickening between the two treatment arms - due to the fact that trial participants had surprisingly healthy arteries to begin with. (And this was) probably related to intense pre-treatment with cholesterol reducers prior to enrolling in Enhance, making it difficult to show a difference between the two arms of the trial.”
However, he throws in a caveat: “It cannot be said for certain that this is why Enhance failed to show a benefit for Vytorin. Alternate possibilities will certainly continue to be discussed, raising the possibility that there were other factors at play that potentially question the clinical value of Vytorin/Zetia as treatment options. One view says…statins offer benefits for reasons not solely related to their ability to reduce LDL cholesterol levels. The data supporting pleiotropy has been mixed, however, and many have moved away from this theory.
Congress, meanwhile, is investigating the way the drugmakers handled the trial - a two-year delay in releasing the data; a brief change in the primary endpoint without consulting the lead investigator, and huge stock sales by some Schering-Plough execs. More recently, the probe was widened to include a Schering-Plough schmoozefest, called the 49 Plan, to wine and dine Zetia docs. Look for a Congressional progress report shortly.
MKM
Interesting that he says data supporting statin pleiotropy has been mixed. That is not what I have heard. In addition, there is data supporting the view that ezetimibe does not have the same pleiotropic effects as statins. It is even possible that ezetimibe counteracts some of the pleiotropic effects of statins.
Marilyn
HorusCat
MKM,
You seem to be remarkably fluent on this topic. It has been a long time since I sold CV drugs, and I am rusty. What is pleiotropy? Thx.
SP 2
It’s not about the study! Negative trials happen all the time in research. If you have integrity, you report it in a timely fashion and go on to the next one. It’s about the handling of the study! It was almost 2 years between study completion and any results. In the meantime, some top people profited millions by selling off stock. There’s the smoking gun!
MKM
Pleiotropic effects of statins refer to beneficial effects that appear unrelated to LDL-lowering. As you know, statins are inhibitors of HMG-CoA reductase. By inhibiting the conversion of HMG-CoA to L-mevalonic acid, statins block the synthesis of important isoprenoids. It is likely that some of the pleiotropic effects of statins are mediated via inhibition of the Rho pathway and its downstream target, Rho-kinase (ROCK). ROCK activity is often elevated in disorders of the cardiovascular system.
Ezetimibe may lack the pleiotropic effects of statins. In heart failure patients, four weeks of simvastatin treatment but not ezetimibe improved endothelial function and reduced oxidative stress, despite comparable reduction in LDL. Landmesser et al., Simvastatin versus ezetimibe: pleiotropic and lipid-loering effects on endothelial function in humans. Circulation 2005;111:2356-63. See recent articles by James Liao, MD and colleagues for more references.
Insider
SP 2 is right.
Der Waarheid
I have repeatedly stated that it is not the data, it is the (attempted) manipulation of the data that is rotten. I think that MKMs citation of sim v ezet confirms the shortcomings of V/Z. Taken in context, this just makes the delay in ENHANCE even more of a money grab. As this cited data has a release date of 2005, one could hypothesize that knowing of this earlier trial result, FH and CC could expect similar results from ENHANCE and have since enriched many insiders at the expense of patients, insurers, the US Govt, shareholders and employees. Is this idea a stetch? You decide.
MKM
Is “Der Waarheid” Afrikans? What does it mean?
Thanks Marilyn
Jack2
Insider is right about SP2.
HorusCat
Jack2 is right about Insider being right about SP2. (I couldn’t resist; but they are right.)
Thanks MKM.
MKM
Here’s another interesting study:
Birnbaum et al., Pretreatment with high-dose statin, but not low-dose statin, ezetimibe, or the combination of low-dose statin and ezetimibe, limits infarct size in the rat, Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 13, No. 1, 72-79 (2008).
Statins reduce infarct size by upregulating nitric oxide synthases and PGI2 production. In this article, the infarct size-limiting effect of low-dose simvastatin + ezetimibe, ezetimibe, and high-dose statins were compared. Rats received 3-day water, atorvastatin (10 mg/kg/d), simvastatin (10 mg/kg/d), simvastatin (2 mg/kg/d), simvastatin (2 mg/kg/d) + ezetimibe (1 mg/kg/d), or ezetimibe. Rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Atorvastatin and simvastatin 10 reduced infarct size, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. Atorvastatin and simvastatin 10 increased nitric oxide synthases activity, whereas simvastatin-2, ezetimibe, and simvastatin-2 + ezetimibe had only a small effect. Atorvastatin and simvastatin 10 significantly increased myocardial 6-ketoprostaglandin F1 levels, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. High-dose statin is required to decrease infarct size, upregulate myocardial nitric oxide synthases activities, and increase 6-keto prostaglandin F1 levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.
HorusCat
MKM,
You’re great. Poor rats.
Doc
Statin pleiotropy is an unproven wish.
HorusCat
Doc,
Maybe so, but with my family history and lipid profile, I am wishing away.
Doc
HC,
I take statins and other lipid drugs as well, but the pleitrophy data is virtually all in vitro and in rat-o.