GlaxoSmithKline's worries about Avandia -- the diabetes drug that has been linked to increased risk of heart attacks -- goes beyond the $3 billion the drug generates in sales each year.

The British drug maker, which has a U.S. headquarters in Research Triangle Park, is testing in humans 11 drugs in the same family as Avandia. All of those drugs could end up tainted if the suspicion about the cardiovascular risk rises. GSK scientists in RTP are working on at least three of the drugs, including a promising treatment for Alzheimer's disease.

Investors, doctors, patients and medical malpractice lawyers are watching closely what steps legislators and regulators will take.

"Depending on the outcome, it could change our estimates for the [drug development] pipeline," said Linda Bannister, a pharmaceutical analyst with Edward Jones.

Bannister expects more clarity from a Food and Drug Administration advisory panel, which is expected to meet in June to review whether Avandia's benefits outweigh its risks. At least once before, the FDA's advisory panel advised against approving a new diabetes drug that increased cardiovascular risk, Chris Schott, a pharmaceutical analyst with Bank of America, wrote in a research note to investors.

More information is expected to come out of a congressional hearing on Avandia on June 6, and GSK might address its work on diabetes drugs during a research and development update on cancer drugs on June 18.

For now, Bannister said, "it's too soon to jump to any conclusions."

GSK's American depositary receipts, which are like stock, continued on a downward slide in higher than average trading for the fourth day in a row Thursday. Shares closed at $52.59, down 73 cents. Since the New England Journal of Medicine published the study Monday saying that Avandia increases the risk of heart attacks by 43 percent, GSK's stock has lost $5.12, about 9 percent.

GSK strongly disagreed with the study findings, which reflected data from 42 of the more than 100 Avandia studies that had been conducted previously, most of them by GSK.

Signs of the increased risk emerged during late-stage testing of Avandia, which was approved for sale in 1999. In 2000, Dr. John Buse, director of the UNC Diabetes Care Center, wrote a letter to the FDA expressing concerns about the cardiovascular safety of the drug and the way in which it was being marketed.

The next year, FDA scientists recommended that packaging information include the cardiovascular risks. The company changed the label to show that there was an increased risk of heart problems for patients taking the drug in combination with insulin. Study results that GSK submitted to the FDA last year refreshed the concerns. But other studies found no increased cardiovascular risks.

"The important thing is, it's not new data," said Mary Anne Rhyne, a GSK spokeswoman in RTP.

Avandia is the first drug approved by the FDA that stimulates a receptor deep inside a cell's center. This receptor is called the peroxisome proliferator-activator receptor or PPAR. As a stimulant, Avandia lowers the blood sugar level, but the drug also has multiple effects on the cell's genes, most of which are not yet understood.

Except for Actos, the best-selling diabetes drug made by Takeda Pharmaceuticals, all other PPAR stimulants have failed because of serious side effects.

Of the 11 PPAR drugs that GSK is testing in humans, six are new.

GSK is deeply invested in PPAR research. A group of Glaxo Wellcome scientists in RTP discovered PPAR's significance in the treatment of diabetes. A paper outlining their research was published June 1995 in the Journal of Biological Chemistry.