Safety concerns cloud Type 2 diabetes treatments

At the same hearing, the FDA revealed plans for a black box warning on both rosiglitazone and pioglitazone-but not for heart attacks or other ischemic cardiac events. Instead, the new box warns of increased risk for congestive heart failure (CHF), a move the agency's own safety reviewers had recommended more than a year earlier.

The split in FDA ranks surfaced again in July. The agency asked its Endocrinologic & Metabolic Drugs and Drug Safety & Risk Management advisory committees to review rosiglitazone. FDA officials spoke both for and against banning the product.

"Pharmacists have been aware of these cardiac risks for some time, but to have them highlighted so quickly was a surprise," said Marcie Bough, director of federal regulatory affairs for the American Pharmacists Association. "This really highlights the concern we should all have about the risks and the benefits of these medications."

The sudden controversy over TZDs also emphasizes the concern that pharmacists should have about FDA oversight, said Larry Sasich, acting chairman of pharmacy practice at Lake Erie College of Osteopathic Medicine (LECOM) School of Pharmacy and a longtime public health advocate. "Cardiac ischemia is a new concern in the United States," he said. "The British warn about it, but we don't. The FDA chose not to emphasize this issue as strongly as it should have. I have real doubts as to whether rosiglitazone should stay on the market."

Safety concerns brewing

Safety concerns surrounding TZDs surfaced in the 1990s. One of the first TZDs to be approved, Rezulin (troglitazone, Parke-Davis), was suspended by British health authorities in 1997 pending review of hepatic safety data. It was later withdrawn from the U.K. market.

Parke-Davis withdrew Rezulin from the U.S. market in 2000 after a series of increasingly restrictive label changes and safety warnings imposed by the FDA.

Rosiglitazone and pioglitazone were approved for the U.S. market in 1999. The potential for edema and CHF was known at the time, Sasich noted, and was included in labeling.

An FDA advisory committee recommended that Glaxo be required to submit long-term postmarketing data as a condition of approval. The committee advised that the rosiglitazone study use cardiovascular end points. The required trial, ADOPT (A Diabetes Outcome Progression Trial), was conducted, but the study looked at glycemic durability, not cardiovascular events.