Diabetes drug said to raise risk of heart attack

Avandia, the world's top-selling oral diabetes drug, significantly increases the risk of heart attacks, a prominent cardiologist said in an article that the New England Journal of Medicine deemed important enough to post on its website yesterday, weeks before the scheduled print publication date.

Dr. Steven E. Nissen, a cardiologist at the Cleveland Clinic and the article's lead author, pored through summaries of dozens of studies and found a 43 percent higher risk of diabetics suffering a heart attack if they took Avandia compared with other drugs or sugar pills. Nissen was unable to determine whether the risk is affected by how long Avandia is used or how much is taken.

GlaxoSmithKline PLC , which manufactures Avandia to treat type 2 diabetes, the most common form of the disease, said it stands by the drug's safety and called the findings of Nissen and a Cleveland Clinic statistician flawed. The company said other clinical trials contradict the report's conclusions, including one that examined medical records for 33,000 diabetics.

Last year, Avandia generated $3.1 billion in sales worldwide and is used by about 1 million people in the United States.

Type 2 diabetes is a life-threatening disease that affects about 20 million people in the United States and 200 million worldwide. In the United States , 1.5 million new cases are diagnosed each year. Diabetics' bodies either make insufficient insulin or cannot efficiently use the hormone, which helps regulate blood sugar levels. The metabolic disorder puts them at increased risk of suffering other ailments, especially heart disease. Avandia lowers blood sugar by helping the body to better use insulin.

"The leading cause of death in diabetes is heart disease. It causes between 65 to 80 percent of all diabetes mortality," Nissen said in an interview. "When a diabetes drug, which is intended to reduce the risk of diabetes complications, actually increases it, it has profound public health consequences."

In an accompanying editorial published by the New England Journal of Medicine, Bruce Psaty and Curt Furberg, doctors who are critics of the FDA's drug-approval process, said there is little reason for doctors to prescribe Avandia, but they said patients should not take action without consulting a physician.

Since the Food and Drug Administration approved Avandia in 1999 doctors have written tens of millions of prescriptions for the drug. The Journal released the paper in advance of its June 14 print publication date partly because of its public health impact, according to executive editor Dr. Gregory Curfman .

Investors and others, including members of Congress, yesterday reacted strongly to the article.

GlaxoSmithKline shares closed at $53.18, down 7.85 percent, in heavy trading.

Some FDA critics are already comparing Avandia to Vioxx, the painkiller pulled from the market in 2004 because studies showed it doubled the risk of heart attacks and strokes.

"My question today is do we have another Vioxx on our hands with Avandia?" Senator Charles E. Grassley , Republican of Iowa, said in remarks prepared for delivery from the Senate floor. Grassley and Democratic Senator Max Baucus of Montana , Senate Finance Committee leaders, yesterday sought documents about the drug from the FDA and GlaxoSmithKline. Grassley criticized the FDA for not reacting strongly to cardiovascular risk data concerning Avandia that the company's own analysis uncovered nearly two years ago.

"We want to understand, what did FDA know about this drug, when did it know it, and what did it do about it?" he said.

Representative Henry Waxman , Democrat of California, said he was incensed that the FDA did little after meeting with his staff in March to discuss Avandia's risks.

"It inexplicably failed to act," said Waxman, who has scheduled a June 6 oversight hearing to discuss the drug. "The American people deserve to know why the FDA failed to take action to warn doctors and patients."

The FDA said Avandia's risks are unclear and suggested that people with heart risks who are taking it talk to their doctors. Some trials point to an emerging cardiovascular problem, which the agency had already noted on the drug's label. But larger and better-designed clinical trials do not show elevated heart risks, it said.

The FDA said it was trying to "make sense" of the conflicting data, which it began receiving from GlaxoSmithKline as early as 2005 , but did not want to needlessly scare patients. Older diabetes drugs also carry heart risks, it said.

"We are internally looking at that very hard and trying to come to conclusions about what the best pathway is to come to a better recommendation -- if there is a need for specific regulatory action with this drug -- and what that might be," said Dr. Robert J. Meyer of the FDA's Center for Drug Evaluation and Research . The FDA says it will convene a meeting of outside scientists to consider the evidence.

In 2000 , the FDA hailed Avandia as being among the safer treatment options for diabetes.

But Avandia is a potent reminder that the way the FDA approves new drugs and monitors safety after they are on the market is flawed, Psaty and Furberg wrote in their accompanying editorial in the Journal. If the heightened heart risk found by Nissen is confirmed, Avandia "represents a major failure of the drug-use and drug-approval processes in the United States," they wrote.

"I don't think the drug should be used. It does not offer any benefit," Furberg, a public health sciences professor at Wake Forest University School of Medicine , said in an interview.

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