Glycemic Control For Fun And Litigation
May 26, 2014 - 11:51:45 AM
The latest bad news concerns one more of the ill-fated thiazolidinediones (TZDs). This class of drugs was introduced in the late 1990s, and includes Avandia, Actos, and Rezulin. TZDs are PPAR-gamma agonists, meaning that they activate peroxisome proliferator-activated receptors, especially the "gamma" receptor. Such activation affects certain metabolic processes, and among other things, insulin resistance is reduced.
Rezulin--notoriously fast-tracked by FDA--was withdrawn from the market in 2000, in the wake of scores of liver failures and deaths. Pfizer, the manufacturer, was on the hook for upwards of $750 million in damages. At the time, Dr. Janet Woodcock, director of FDA's drug evaluation center, said that Avandia and Actos, "[O]ffer the same benefits as Rezulin without the same risk. We are now confident that patients have safer alternatives."
The next to fall would be Avandia, taken off the market in 2011, after being suspected of increasing the risk of heart attacks. GlaxoSmithKline, the manufacturer, has already paid out more than $200 million in settlements. This leaves Actos, and it is noted that the 2007 study promoting further inquiry into Avandia was paid for by Takeda, manufacturer of Actos. Conflict of interest anyone?
Alas, Actos' day would also come. Early on, the drug was implicated in increased risk for bladder cancer, and was taken off the market in France and Germany in 2011. Yet, the FDA approved a generic version in 2012, after issuing its own bladder cancer warning on the proprietary drug in 2011! Yes, you read that correctly. Nonetheless, the lawsuits began to pile up for Takeda.
Fast forward to April 7, 2014. Takeda and its partner Eli Lilly & Co. were ordered to pay a combined $9 billion in punitive damages after a federal court jury found they hid the cancer risks of Actos. The extreme damages derive from Takeda's systematic efforts to destroy incriminating e-mails and other documents--going back many years. Leave it to canny plaintiff's attorneys to still be able to find a smoking gun.
It seems that in 1993, Takeda was negotiating with Upjohn (now owned by Pfizer) to partner with them on the development of Actos. Based on correspondence obtained from Upjohn, its president declined, expressing concerns over Actos' "margin of safety." Takeda replied, asking Upjohn to change its reason to Actos not showing sufficient glucose reduction.
Ironically, earlier this year, Takeda stopped development of another diabetes drug when research linked it to liver damage.
Needless to say, this entire matter stinks to high heaven. Although the three proprietary drugs differ in chemical structure, their mode of action is essentially identical, and associating one with liver damage, the next with heart issues, and the final one with bladder cancer could have more to do with the luck of the draw than anything more definitive. Indeed, the science behind the Avandia withdrawal is the most suspect--and not only because there were contradicting studies.
Heart attacks (myocardial infarcitons) are not a particularly useful endpoint when studying an anti-diabetes drug. The majority of type 2 diabetics, and thus the majority of those taking the drug, are overweight, which is itself a key risk factor for MI's. Moreover, it is likely that a significant number of these patients would emphasize drug therapy over lifestyle change. As such, you are looking at a cohort of overweight people, who, yes, are more inclined to MI's. I daresay that this finding could be duplicated with Rezulin, Actos, insulin, and even metformin--the so-called safest of all the oral diabetes drugs.
At any rate, the thiazolidinediones are now 0 for 3. Perhaps the worst part of this is that--as we pointed out last week--the need for glycemic control with strong drugs in type 2's is dubious at best.
You might also ask what the FDA was doing when it approved these drugs, or why it is held harmless when its approved drugs go sour. Heck, you could go even further. Inasmuch as the FDA could be instantly replaced with a random board of experts from academia and the private sector, you might well ask why the FDA exists at all.
Michael D. Shaw
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