Avandia is used to treat Type 2 diabetes, the most common form of the disease, which is linked to obesity and afflicts 18 million Americans and 200 million people worldwide. This form of diabetes occurs when the body does not make enough insulin or cannot effectively use what it manages to produce.

Avandia, or rosiglitazone, helps sensitize the body to insulin and was considered a breakthrough medication for blood-sugar control. It also is combined with metformin and sold as Avandamet. Only one other drug like it — pioglitazone, sold as Actos and Actoplus Met by Takeda Pharmaceuticals — is sold in the United States.

Avandia had total U.S. sales of $2.2 billion in 2006, slightly trailing $2.6 million for Actos, according to IMS Health, a healthcare information company. About 13 million Avandia prescriptions were filled in the U.S. last year. A one-month supply of Avandia sells for between $90 and $170.

GlaxoSmithKline also has been testing Avandia to try to prevent diabetes in those at high risk of it, and, in separate studies, to prevent Alzheimer's disease.

However, the new analysis casts a pall on its prospects for prevention as well as treatment, many specialists said. The study was led by Dr. Steven Nissen and statistician Kathy Wolski at the Cleveland Clinic. Nissen accepts no personal fees for consulting for any drug makers.

While the analysis doesn't spell out the actual the rate of heart attacks among Avandia users, the 43 percent excess risk is in line with what a similar analysis found for lower doses of Vioxx use, Nissen said. Another context for that number: Heart attack risks are lowered about 25 percent by cholesterol-reducing statin drugs — ample reason to prescribe them.

The Avandia studies Nissen analyzed were not designed to look for heart risks and many of them were so short that risks may only appear over the longer term, he said.

Dr. David Nathan, chief of diabetes care at Massachusetts General Hospital, agreed.

"This analysis is just scratching the surface of what may be there. It needs to be taken seriously," said Nathan, who reviewed the paper for the medical journal and has no financial ties to any diabetes drugmakers.

The situation "reflects very badly on the FDA and on Glaxo," Nathan said. "It's the FDA's responsibility to be monitoring this stuff."

The drug "represents a major failure of the drug-use and drug-approval processes in the United States," Drs. Bruce Psaty and Curt Furberg wrote in an editorial in the New England Journal. Psaty is with the University of Washington in Seattle and Furberg is with Wake Forest University.

When the drug was approved, evidence of its benefits were "at best mixed," wrote the two doctors. Both have been frequent critics of the FDA's failure to spot dangers in the drug approval process and its conduct involving Vioxx.