Singapore's Health Sciences Authority will be reviewing the widely prescribed diabetes drug Avandia and consult the US Food and Drug Administration, after US researchers reported that the drug raises the risk of cardiovascular-related death by 64 per cent and the risk of heart attack by 43 per cent.

The news about Avandia, also known as rosiglitazone, set off a clamor by consumer groups, heart experts and the US Congress -- some of whom question the safety of all drugs in this class after a number of studies that have shown liver, heart and bone side effects. It also triggered a freefall in GSK's shares, which closed off more than 5 percent on the London Stock Exchange. The stock slide continued on the New York Stock Exchange, falling $3.67 per share, or more than 6 per cent.

Writing in the New England Journal of Medicine, which was released on Monday, Dr Steven Nissen and colleagues at the Cleveland Clinic analysed 42 clinical trials involving close to 28,000 patients and said more than 65 per cent of the deaths among diabetic patients in the trials of the drug could be attributed to heart disease.

Glaxo said it strongly disagreed with the conclusions of the report, which was based on an analysis of other studies.

"Unfortunately, rosiglitazone appears to increase, rather than decrease, the most serious complication of diabetes, heart disease," Dr. Nissen, chairman of cardiovascular Medicine at the Cleveland Clinic, said in a statement.

In response to queries from AsiaOne, an HSA spokesman said Avandia, which belongs to a relatively recent class of oral antidiabetic agents which acts primarily by increasing insulin sensitivity, has been approved for marketing in Singapore since 2000 for adult-onset diabetes (Type II diabetes).

She said it is approved for use alone as an adjunct to diet and exercise to improve blood sugar control, and use in combination with older oral antidiabetic agents ( metformin and sulfonylurea) when diet , exercise and a single drug do not result in adequate blood sugar control.

"The risk of cardiac events is a known risk associated with drugs in this glitazone class. In the package insert of Avandia (R), prescribers are advised that patients should be observed for sign and symptoms of heart failures and other cardiac adverse events. Avandia(R) should be discontinued if any deterioration in cardiac status occurs," said the HSA spokesman.

"Since its approval in 2000, HSA has received isolated reports of non-fatal cardiac adverse events associated with Avandia(R). However, the causal link of these adverse events to the drug could not be confirmed because of confounding factors such as underlying medical conditions and other drugs which the patients were on.

"Based on the recent information, HSA will be reviewing all available data again in close consultation with US FDA. In the mean time, HSA advises patients who are prescribed Avandia and with specific concerns to review their individual treatment with their doctors, taking into consideration this emerging safety information."

HSA also advises doctors to monitor their patients for signs and symptoms of cardiovascular events, she added.

Meanwhile, a US consumer advocacy group, Public Citizen, said on Tuesday that U.S. health authorities were aware of heart risks linked to Avandia and another competitor nearly five years ago.

The group, citing an internal FDA documents, said that in 2002, the FDS staff scientists called for reports of congestive heart failure to be included on the label of Avandia as well as Actos, made by Takeda Pharmaceutical Co. Ltd.

The group released the memo one day after researchers reported Avandia, or rosiglitazone, raises the risk of cardiovascular-related death by 64 percent and the risk of heart attack by 43 percent.

At the same time, the FDA said an agency analysis showed a higher risk but it was not yet completed, adding other studies contradicted the latest findings. It called on patients to talk to their doctors but stopped short of taking other action.

Dr. Sidney Wolfe, head of Public Citizen's Health Research Group which has been critical of Avandia for years, said the 2002 memo showed the agency failed to take the concerns of its staff scientists seriously.

"As a result, millions of people - to the detriment of their health - are prescribed drugs whose risks are dangerously understated, instead of being prescribed safer, equally or more effective alternative drugs," he said in a statement.

In a letter to FDA Commissioner Andrew von Eschenbach, Wolfe urged the agency to impose the strongest warning possible -- a black box -- on both Avandia and Actos, or ban them outright.

"There continues to be no mention of the large and increasing number of post-marketing reports of heart failure, which was the explicit recommendation in the 2002 internal FDA memo," Wolfe wrote.

An FDA spokeswoman could not be immediately reached for comment.

Actos, also known as pioglitazone, and Avandia, are part of a class of drugs known as thiazolidinediones (TZDs) that target the PPAR-gamma gene to help the body use insulin more effectively.

FDA staff reviewers, in a memo dated July 16, 2002, said they analyzed reports of heart failure that led to patient hospitalizations in an agency post-marketing database.

"Data from this case series provides evidence that TZDs may be associated with CHF (congestive heart failure) to an extent not clearly defined in the product labels," the staffers wrote.

They added that the exact link between the drugs and the heart problems could not be established, and that increased patient monitoring may have also boosted the number of diagnoses.

Still, the reviewers concluded that reports of heart problems in patients taking Avandia and Actos existed and should be mentioned on the products' labels.

Separately, three major medical organizations have issued a joint statement saying diabetes patients should stay on their medications until they speak to their doctors. But Glaxo disagreed. "GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks," the company said in a statement.

Paul Diggle, an industry analyst at Nomura Code Securities in London, said: "Unless this can be refuted, which I rather doubt, then this is going to seriously damage one of the cornerstones of Glaxo going forward."