11/14/2007- The Food and Drug Administration Wednesday toughened warnings on GlaxoSmithKline PLC's diabetes drug Avandia, saying the product was linked to a potential increase in the risk of heart attacks.

The agency said Avandia would remain on the U.S. market while a "safety assessment continues."

The new black-box warning, which is the FDA's strictest drug warning, is also expected to apply to two other diabetes drugs sold by Glaxo, Avandamet and Avandaryl, because they contain the same active ingredient that is in Avandia.

The agency said it has asked GlaxoSmithKline to conduct an additional long-term safety study of Avandia that would include comparing it to a similar drug, Actos, made by Takeda Pharmaceutical Co. The details of the study, however, have not been fully worked out between the FDA and Glaxo.

The new heart-attack warning was added to an existing black-box warning that says the drug increases the risk of heart failure. The heart-failure warning, a condition in which a weakened heart muscle can't effectively pump blood, also applies to Actos. A heart attack is an injury to the heart caused by a loss of blood supply and often occurs when a blood clot blocks the flow of blood through a coronary artery.

The new heart-attack warning doesn't apply to Actos; however, the FDA said it would require makers of Actos and other oral anti-diabetes drugs to relabel their drugs to state that there is no evidence the drugs reduce the risks of cardiovascular problems such as heart attacks and strokes.

Questions about whether Avandia was linked to an increased risk of heart attacks surfaced in May when Cleveland Clinic cardiologist Steven Nissen published an analysis of 42 relatively short-term studies suggested Avandia increased risk of heart attacks by 43%. Sales of Avandia, Avandamet and Avandaryl totaled about $3 billion last year, but have fallen by almost 50% in the U.S. since May.

Indeed, the warning states that a meta-analysis of 42 studies with an average duration of six months showed Avandia to be associated with an increased risk of myocardial ischemic events, or heart attacks. However, the warning points out that three other studies that lasted for more than three years "have not confirmed or excluded this risk." The warning also says "the available data on the risk of myocardial ischemia are inconclusive."

FDA officials said there's been a split within the agency about whether to pull Avandia off the market or allow it to stay on the market with stronger warnings. The agency convened a meeting of an outside panel of medical experts in July to discuss the matter. The panel voted 22-1 to keep Avandia on the market, but several panel members also recommended the drug carry stricter warnings.

About 18 million to 20 million Americans have type-2 diabetes, a disease characterized by high blood-glucose levels that result from the body's inability to use insulin. Insulin, produced by the pancreas, is needed to take sugar from blood into cells.

Drugs such as Avandia and Actos are designed to make the body more sensitive to insulin in order to help lower blood sugar. Other drugs used to treat diabetes include sulfonylurea drugs, which work to stimulate the pancreas to release insulin, and metformin, which works on the liver to reduce blood sugar. Diabetes itself increases the risk for cardiovascular disease, kidney disease, blindness and amputations.

The FDA approved Avandia for use in treating type-2 diabetes in 1999.