After the Headlines, What Is the Real Avandia Story?

Findings on the safety of the diabetes drug has doctors locked in debate.

July 2, 2010, 3:22 PM

ORLANDO, Fla., July 4, 2010— -- Controversy continues to surround Avandia -- a drug used to treat type 2 diabetes that has been linked to heart failure. As a result, a question that emerged here at the American Diabetes Association meeting was whether the class of drug, called "thiazolidinediones," which includes Avandia and its cousin, Actos, should be prescribed at all.

But contradictory studies on the drugs' effects have complicated the issue. During a single day here at the ADA meeting, one researcher linked Avandia with cardiovascular harm, another with cardiovascular benefit, and a third suggested Actos was better.

In an update to his 2007 study that prompted concerns about the drug, Dr. Steven Nissen of the Cleveland Clinic reported a 28 to 39 percent relative risk for heart attacks in patients taking Avandia. Those numbers, published online in the Archives of Internal Medicine, stemmed from a review of 56 previously published studies, also known as a meta-analysis.

This update supports the "totality of information" against Avandia, Nissen said. But not everyone saw it as an end to the debate.

The ADA, the American College of Cardiology and the American Heart Association have refused to take sides. They would rather let the U.S. Food and Drug Administration decide what to do, but acknowledge that clinicians may be uncomfortable prescribing Avandia.

"Why would we use a drug that might be harmful, even though it's not conclusive when there are so many other choices?" said Dr. David Nathan of Massachusetts General Hospital in Boston.

The package insert for Avandia warns about dose-related edema (swelling), an average weight gain of 3.5 kg after four years and anemia -- problems that have plagued Avandia and Actos users along with increased fracture risk. Both drugs also carry a black-box warning about the risk of heart failure.

"The first question is not whether to switch someone from Avandia to Actos, but whether they should be on either one at all," said Dr. Lee Green of the University of Michigan in Ann Arbor, who called the evidence convincing enough for him.

Despite the intense debate over Avandia, the drug remains a billion-dollar-per-year seller. Actos continues to garner support, with profits that have progressively risen since even before the controversy over Avandia arose.

Despite the drugs' downfalls, they do control blood sugar levels in a high-risk patient population with type 2 diabetes, said Dr. Joel Zonszein of Montefiore Medical Center.

This generally obese group has a more aggressive form of diabetes that sets in at an earlier age and is associated with liver disease and even liver failure, Zonszein explained in an email.

While not an FDA-approved indication, Actos and Avandia also fight fatty liver disease, said Dr. Robert H. Eckel of the University of Colorado Denver, a former president of the American Heart Association.

"It's an impact that's been published and seen by many of us," Eckel said.

Eckel said he considers Actos a good third or fourth add-on drug for patients who aren't at risk for heart failure. He also said he continues to treat patients with Avandia who come to him already taking the drug.

Given that there may be unique, albeit limited, circumstances in which the thiazolidinediones work best, the drugs should continue to be available for use at the physician's discretion, Zonszein advocated.

"Avandia is already rarely prescribed," he said. "Let the free markets work following science not politics."

However, the numbers from IMS Health show that Avandia continued to be prescribed to 2.6 million Americans in 2009--no small number, though smaller than the blockbuster drug once saw.

What the FDA will actually do is anyone's guess. While some had strong opinions about what the agency should do, no one at the ADA meeting was willing to hazard what would actually happen.

Eckel reported having a pending preclinical research grant with GlaxoSmithKline for an unrelated drug.

Nissen reported having received research support from AstraZeneca, Atherogenics, Eli Lilly, Novartis, Pfizer, Resverlogix, Takeda, Daiichi-Sankyo, and Sanofi-Aventis through the Cleveland Clinic Center for Clinical Research within the last five years and having consulted for a number of pharmaceutical companies but with all fees paid directly to charity.

Nathan reported no conflicts of interest.

Zonszein reported being on an advisory board for Takeda, which makes pioglitazone, and on the speakers bureau for Takeda, Eli Lilly, Novo Nordisk, Merck and many other companies that make diabetes medications, although not GlaxoSmithKline.