FDA panel backs diabetes pill linked to heart risk

GAITHERSBURG, Md. -- Avandia, once the world's top-selling diabetes pill, should remain on the market, federal advisers said yesterday, but many recommended that the drug carry stronger warnings about its heart risks.

The Food and Drug Administration advisory panel's vote in favor of continued Avandia sales, which the agency does not have to follow, was 22 to 1. That's good news for GlaxoSmithKline PLC.

The bad news is the panel also wanted more serious warnings added to the label, which could further erode market share for the drug and provide more ammunition to members of Congress who seek to boost FDA funding and its powers to monitor drug safety.

Since a New England Journal of Medicine article in May questioned the heart safety of Avandia, sales have plummeted by 22 percent. In the article, Dr. Steven Nissen, a prominent Cleveland Clinic cardiologist, said he had combed dozens of studies and found that the drug raises heart attack risks by 43 percent.

A few panel members endorsed adding the agency's strongest warning label, contained within a bold black box, to discourage Avandia use by high-risk patients -- including those with established heart disease or who take the drug in combination with insulin. Other members suggested Avandia's safety should be studied more closely in high-risk diabetics. Many expressed frustration with the small, short-term, and contradictory studies they were asked to review and said larger clinical trials now underway are unlikely to clearly prove whether Avandia is harmful to the heart.

"We're being asked today to take a very Draconian action based on studies that have significant weaknesses," said Rebecca Killion, a Maryland woman representing diabetics.

Glaxo argued before the panel that Avandia poses no unique heart risks.

"None of these drugs are perfect, but all of them are important," Dr. Ronald L. Krall, Glaxo senior vice president and chief medical officer, said of diabetes treatments now on the market.

Panel member Arthur Levin, director of the Center for Medical Consumers, was the only adviser to recommend that Avandia be removed from the market. "In the face of uncertainty, I think you have to protect the public health," he said after the hearing.

Dr. David Graham, an associate director for science and medicine at the FDA, testified before the panel that Avandia sales should be halted. Part of his reasoning included an epidemiological study of 2 million diabetics he recently completed. The unpublished review indicated that two other diabetes treatments -- metformin and Actos -- were safest for hearts while Avandia posed the highest heart risks. In the nearly eight years that Avandia has been sold, it has caused roughly 80,000 additional sudden cardiac deaths and nonfatal heart attacks, said Graham, or one serious cardiovascular event for every 114 patients taking Avandia.

The FDA had planned to convene a panel in November to sort through the conflicting evidence, but after the New England Journal article, which was quickly followed by a congressional hearing, the agency altered its schedule.

Since the FDA approved Avandia in 1999, it has been used by 15 million people to help their bodies better respond to natural insulin, reducing their blood sugar levels. Last year, the drug generated $2.24 billion in US sales for Glaxo, according to IMS Health, a healthcare information company.

The sales come as the nation experiences a diabetes epidemic with 4,100 cases diagnosed daily, said Dr. Robert Ratner, vice president of scientific affairs at MedStar Research Institute.

For the 18 million Americans with type 2 diabetes, the most common form, when blood sugar rises so do complications, including heart attacks and strokes. Each day, 230 diabetics undergo amputations, 55 are diagnosed as being legally blind, 120 suffer kidney failure, and 810 die, according to Ratner.

But despite such high health risks, only 50 percent of diabetics religiously take medication to control the disease. Those who stop treatment sometimes do so because of cost, inconvenience, or such side effects as cardiovascular problems and "substantial" weight gain, Ratner said.

Charles E. Steele, a New York City resident, told the advisory panel that Avandia was the only diabetes medicine that did not cause side effects for his 84-year-old mother. Still, she was so frightened by the "hype and overreaction" to the New England Journal article that she stopped taking it, he said.

Steele, a 61-year-old amputee due to diabetes complications, said he was "fine" with any decision by the FDA, as long as the process is fair. "Please let good science and common sense influence your decision," said Steele, who received travel assistance from Glaxo to attend the hearing.

The FDA has struggled to gauge the significance of a growing number of contradictory studies on Avandia -- its own, Nissen's, Glaxo's, and analysis by the drug maker Takeda Pharmaceutical Co., whose Actos medication works the same way as Avandia but appears to cause fewer heart attacks.

"The one consistent thing about [this] class of drugs is they increase weight gain and they can cause congestive heart failure," said Dr. Clifford J. Rosen, a senior staff scientist at the Maine Center for Osteoporosis in Bangor. He said they should not be prescribed to patients with congestive heart failure.

But Chris Viehbacher, president of Glaxo US Pharmaceuticals, a GlaxoSmithKline subsidiary, said steering diabetics away from Avandia could cause more problems.

"If you put too harsh a warning on Avandia and you drive patients into other medications about which you know less, you could actually cause greater harm," he said. "I think the FDA has a fine line to walk."

Diedtra Henderson can be reached at dhenderson@globe.com.