Commissioner Andrew C. von Eschenbach announced for the first time that the FDA had instructed the manufacturers of the two diabetes drugs known as TZD’s to label them with a so-called black box warning “to more prominently address the risks of congestive heart failure associated with the use of these drugs in certain patients.” He said that doctors were prescribing both Avandia and Actos to people with diabetes “with significant heart failure.”
The timing of the announcement is strange. Dr. von Eschenbach told the House committee that it was on May 23 that the FDA issued letters to GlaxoSmithKline, the manufacturer of Avandia, and Takeda Pharmaceuticals, which makes Actos, to warn people with diabetes about the danger of their drugs. That was just two days after The New England Journal of Medicine published the results of a meta-analysis (which pools data from previous studies) that found that Avandia raises the risk of heart attack by 43 percent. But until yesterday nobody outside the FDA or the companies knew.
We have been able to get both Avandia and Actos since 1999, when the FDA approved them. At that time the FDA’s medical reviewer for Avandia recommended post-marketing studies, Committee Chairman Henry Waxman said yesterday. But nobody did the studies.
Actos got caught in the crossfire even though the authors of the meta-analysis that set off the frenzy exonerated it. The hearts of people taking Actos actually benefited from it, Dr. Steven Nissen and Kathy Wolski wrote. But Actos is in the same class of drugs as Avandia, and so-called class effects happen. Now it seems the FDA is bending the other way, indicating that heart failure can sometimes result when people take Actos too.
The FDA is getting most of the blame for subjecting us to this danger. The story is still coming out, but already a supervisor in the FDA’s drug safety office said this week that the FDA had reprimanded her in March 2006. Why? Because she had pushed for the same black box warning on Avandia and Actos that will now appear on their labels. The FDA ordered her to retract her approval of the warning and stripped her of her power to approve such assessments. Now, she no longer supervised reviews of the safety of Avandia and Actos.
But Avandia’s manufacturer is also getting heat for its heavy-handed behavior. One story comes from Dr. John Buse. He is one of the country’s most prominent endocrinologists and is the incoming president of the American Diabetes Association.
He told the House committee yesterday that when he spoke out about his fears that Avandia might increase heart risks, people at Glaxo threatened him. They “felt that my actions were scurrilous enough to attempt to hold me liable for [the company’s] loss in market capitalization.”
A lot more of this story is certainly to come. Both the FDA and Glaxo look suspect. But what about those of us with diabetes, particularly people who take Avandia or Actos?
The black box warning, as severe as it sounds, is actually just a slap on the wrist. Even the most commonly prescribed diabetes drug, metformin, has carried a black box warning on its label for years.
But note that Avandia and Actos are the two surviving members of one class of diabetes drugs. Until 2000 doctors were able to prescribe another member of the same class, Rezulin. Then, under pressure from the FDA, the manufacturer pulled Rezulin from the market. But only after it killed at least 63 of us.