The U.S. Food and Drug Administration on Nov. 14th forced GlaxoSmithKline to add a stronger, though somewhat confusing, warning to the prescribing label of widely used diabetes drug Avandia (rosiglitazone), cautioning type 2 diabetics that it may increase their risk of heart attacks.

"We are announcing an update to the existing box warning on Avandia," Dr. Janet Woodcock, acting director of the FDA's Center for Drug Evaluation and Research, said on a teleconference. "A black box is the strongest form of warning, and we are adding another warning to that black box."

But the FDA said the evidence for the increased heart-attack risk is not conclusive, and said it was not seeking at this time to have one of the world's largest selling type 2 diabetes drugs withdrawn from the market.

The new warning, which in lay terms cautions about an increased risk of chest pain or heart attack, states:

"A meta-analysis of 42 clinical studies (mean duration 6 months; 14,237 total patients), most of which compared Avandia to placebo, showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction. Three other studies (mean duration 41 months; 14,067 patients), comparing Avandia to some other approved oral antidiabetic agents or placebo, have not confirmed or excluded this risk. In their entirety, the available data on the risk of myocardial ischemia are inconclusive."

The update adds to the black-box warning that the FDA ordered in August for both Avandia and a competitor, Actos (pioglitazone), informing patients and doctors that all of the thiazolidinedione class of antidiabetic drugs may cause or worsen heart failure.

The FDA did not require the update, however, to be added to the warning for Actos, and its manufacturer Takeda Pharmaceutical Company Ltd. announced it planned to immediately launch a large advertising campaign for its drug in an effort to encourage doctors to switch patients from Avandia.

Both the FDA and GlaxoSmithKline, manufacturer of Avandia, continue to say that the evidence for the risk of heart attack with Avandia is inconclusive.

"Avandia remains a safe and effective medicine for most patients with type 2 diabetes when used appropriately," said Dr. Ronald Krall, GlaxoSmithKline's chief medical officer. "Given the severity of this disease and the importance of Avandia in helping patients manage their diabetes, we will continue to work with the FDA to conduct more studies about the safety and benefits of our medicine."

A new long-term study comparing Avandia with other type 2 diabetes drugs is expected to start in 2008 and full results are not expected to be available until 2014.