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DBL%20Hendrix%20small.png College chemistry, 1983

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: derekb.lowe@gmail.com Twitter: Dereklowe

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November 25, 2008

Avandia: Trouble, Run Head to Head

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Posted by Derek

Avandia (rosiglitazone) has been under suspicion for the last couple of years, after data appeared suggesting a higher rate of cardiovascular problems with its use. GlaxoSmithKline has been disputing this association all the way, as well they might, but today there’s yet more information to dispute.

A retrospective study in the Archives of Internal Medicine looked at about 14,000 patients on Medicare (older than 65) who were prescribed Avandia between 2000 and 2005. Now, looking backwards at the data is always a tricky business. For example, comparing these patients to another group that didn’t get the drug could be quite misleading – the obvious mistake there is that if someone has been prescribed Avandia, then they’re likely getting it because they’ve got Type II diabetes (or metabolic syndrome at least). Comparing that cohort to a group that isn’t showing such symptoms would be wildly misleading.

But this study compared the Avandia patients to 14,000 who were getting its direct competitor, Actos (pioglitazone). Now that’s more like it. The two drugs are indicated for the same patient population, for the same reasons. Their mechanism of action is supposed to be the same, too, as much as anyone can tell with the PPAR-gamma compounds. I wrote about that here – the problem with these drugs is that they affect the transcription of hundreds of genes, making their effects very hard to work out. Rosi and pio overlap quite a bit, but there are definitely (PDF) genes that each of them affect alone, and many others that they affect to different levels. Clinically, though, they are in theory doing the exact same thing.

But are they? This study found that the patients who started on Avandia had a fifteen per cent higher deaths-from-all-causes rate than the Actos group. To me, that’s a startlingly high number, and it really calls for an explanation. The Avandia group had a 13 per cent higher rate of heart failure, but no difference in strokes and heart attack, oddly. The authors believe that these latter two causes of death are likely to be undercounted in this population, though – there’s a significant no-cause-reported group in the data.

The authors also claim that the two populations were “surprisingly similar”, strengthening their conclusions. I think that that’s likely to be the case, given the similarities between the two drugs. GlaxoSmithKline, for their part, is saying that these numbers don’t match the safety data they’ve collected, and that a randomized clinical trial is the best way to settle such issues.

Well, yeah: a randomized clinical trial is the best way to settle a lot of medical questions. But neither GSK (nor Takeda and Lilly, makers of Actos) have seen fit to go head-to-head in one, have they? My guess is that both companies felt that the chances of showing a major clinical difference between the two was small, and that the size, length, and expense of such a trial would likely not justify its results. And if we’re talking about the beneficial mechanisms of action here, that’s probably true. You’d have quite a time showing daylight between the two drugs on things like insulin sensitivity, glycosylated hemoglobin, and other measures of diabetes. Individual patients may well show differences, and that's useful in practice - but that's a hard thing to show in a large averaged set of data. But how about nasty side effects? Maybe there's some room there - but in a murky field like PPAR-gamma, you'd have to have a lot of nerve to run a trial hoping to see something bad in your competitor's compound, while still being sure enough of your own. No, it's disingenuous to talk about how these questions need to be answered by a clinical trial, when you haven't done one, haven't planned one, and have (what seemed to be) good reasons not to.

This kind of study is the best rosi-to-pio comparison we're likely to get. And it does not look good for Avandia. GSK is going to have to live with that - and in fact, they already are.

Comments (4) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | Toxicology


COMMENTS

1. milkshake on November 25, 2008 6:15 PM writes...

I saw couple presentations from the group at our institute that is trying to figure out what PPAR receptors do - and the conclusion was that the range of receptor shape changes upon the ligand binding and the resulting cellular responces is quite staggering. And you have reverse partial agonists vs antagonists, etc.

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2. Steve Parker, M.D. on November 25, 2008 9:23 PM writes...

It's increasingly hard for me to justify prescribing of Avandia as opposed to Actos. Assuming that Avandia indeed increases the odds of death, it would also increase my odds of being sued for prescribing it at this point.

I'm reminded that many physicians and "experts" think all drugs in a given class are therapeutically equivalent. These two TZDs don't seem to be.

With publication of the JUPITER study, many will assume statins other than Crestor will be just as effective. Baycol, for example. Oh, that's right . . . Baycol was taken off the market because it was killing people.

-Steve (BTW, I'm not a fan of JUPITER)

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3. Morten G on November 26, 2008 8:25 AM writes...

Hmm I was really, really sceptical about the meta studies on Avandia but I'm glad to see that it lead somewhere and even more glad that someone spent the time and money to figure out what the better alternative was (since Avandia is probably better than no Avandia tbh).

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4. Alastair Parkes on November 28, 2008 8:35 AM writes...

Didn't I read a post recently referring to Ben Goldacre's summary of why relative risk is often not a good stat to use. The absolute numbers would have been more meaningful...

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