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Wednesday, June 13, 2007

Whole new ball game-case in point Avandia

The spin-off as well as the spin seems endless in regard to the Avandia issue.Nissen's NEJM article catalyzed various reactions many of which were predictable at least in direction if not in intensity. Predictable downstream effects included the reactions by GSK,by pro and anti Pharma blogs and Grass root and astro turf patient-interest groups and by plaintiff attorneys. Also expected are thoughtful posts by medical bloggers such as the one entitled "Avandia:two questions" by Dr. RW. and "The Avandia spin cycle" found at Health Care Renewal.

One of the latest developments is a class action suit by stock holders of GSK accusing the directors of withholding information about the cardiac risk of Avandia. The directors are accused of not providing adequate data to stockholders regarding the company's meta-analysis of cardiovascular deaths that was reported to the FDA.

Over thirty years ago another medical publication dealt with a purported increase in cardio vascular deaths from an oral diabetic medication. The University Group Diabetes Program (UGDP) was presented at the June 1970 meeting of the American Diabetes Association. Data presented indicated that tolbutamide increased cardiovascular deaths by over two and a half times.( R.R of 2.61, C.I.-1.29-5.27 It did not take long for the UGDP study to be referred to as the "controversial" UGDP.

The dispute over methodological issues was played out largely out of the public eye and patients and physicians alike had to largely rely on medical journal hard copy publications to follow the events that they unfolded in what would be considered slow motion in today's frenetic internet pace.Today with the Web within minutes the word spreads over the world and quickly bloggers and news sites and lawyers post messages. It is not long before a Senate hearing is held.

The UGDP study in many ways presented more robust evidence that the Nissen article.It was a randomized clinical trial ( Yes Virginia, clinical trials were done before the folks from Canada descended from the mountain with the precepts of EBM carved into stone) and the R.R. was greater than 2, a number less than which many epidemiologists put little weight as small RR's can be pushed around by small biases.Putting too much emphasis on medical analyses which derive RR's less than 2 has been a issue of interest to me for some time and I have ranted on about that before.

In time, the reputation of the class of diabetic drugs to which tolbutamide belonged was salvaged to some degree by proposing that tolbutamide might interfere with a purported pathophysiologic mechanism called "ischemic preconditioning" while others drugs in this family might not. At the end of the day, a PDR sulfonylurea family warning was issued. As new drugs have been developed to treat type 2 diabetes little discussion seems to take place about these drugs while they continue to be used with little alarm about causing heart attacks.

Sometimes controversies just die out without really being settled with apodictic medical certainty.I think that was the case with tolbutamide.Many articles critical and supportive of the UGDP were generated and for the most part probably largely unread and were it not for the internet amplified and magnified Avandia issue few would even currently think about a possible increase in c-v risk from the sulfonylureas which are still widely used in the early treatment phases of type 2 diabetes. The dogs bark and the caravan moves on.Today with the internet the dogs seem to be able to do much more than just bark.

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