It is the latest safety-related blow for the medication after previous studies also indicated it undermined heart health and regulators in Canada and the U.S. issued safety alerts.

The new research by the Institute for Clinical Evaluative Sciences links Avandia to an extra three cases of heart failure, four heart attacks and five deaths in every 100 elderly diabetes patients taking the pills over four years.

"The magnitude of harm observed in our study may be sufficient to outweigh any potential benefits ... in an older, higher-risk population," said the paper to be published today in the Journal of the American Medical Association.

Health Canada and other regulators should re-examine the drug in light of the findings, said Dr. Lorraine Lipscombe, the lead author.

"It's not that big an increase, but when we're treating people for diabetes, we're expecting to reduce the risk of complications, not increase it," she said in an interview. "That's where the concern lies."

However, the drug's manufacturer and a leading Canadian expert say the study, which examined huge databases of Ontario patients, appears biased toward sicker patients who are more likely to suffer such complications. They cautioned against reading too much into it.

"The controversy remains, and this doesn't nail it," said Dr. Ehud Ur, head of the endocrinology department at the University of British Columbia and a scientific advisor to the Canadian Diabetes Association.

"They add to some of the flags that have already been raised about the drug [but] there is nothing conclusive here."

Canadians bought 1.2 million prescriptions of Avandia, at a cost of $151-million, in the year that ended in October, according to IMS Health, which tracks prescription drug sales. The number of prescriptions dropped somewhat in recent months amidst the safety debate.

It and others in the thiazolidinedione, or TZD, class are designed to reduce blood-sugar levels in type-2 diabetes sufferers by helping the body use its naturally produced insulin better.

However, overview studies of existing research, published earlier this year in the JAMA and the New England Journal of Medicine, found increased risks of heart attack and heart failure. Some clinical trials have shown no spike in danger, on the other hand.

In November, Health Canada issued new restrictions on Avandia's use, saying it should be prescribed on its own only when patients cannot take another diabetes drug, metfornin, and should be avoided entirely by anyone with a history of heart failure.

The ICES study looked at drug and hospital data for about 160,000 Ontario diabetes patients over age 65 between 2002 and 2005. After four years, patients on just Avandia had a 60% greater risk of suffering heart failure, 40% higher chance of a heart attack and 30% more danger of dieing than those on other treatments.

It is the first study of the drug to look at a whole population of patients and to show a heightened risk of death, said Dr. Lipscombe. The researchers found no increased heart danger with Actos, another TZD, but said that may be because relatively few Ontarians use that medication.

GlaxoSmithKline (GSK), which makes Avandia, said in a statement yesterday that the study's findings on heart attacks and death are "misleading" and contrary to actual clinical trials on the medicine's effects.

In fact, the Ontario Drug Benefit plan database used by ICES likely skewed the results, said Dr. Ur. Patients can only charge the plan for the cost of Avandia prescriptions if they have already failed treatment on other drugs, which means they would be further along in their illness and more prone to suffer serious side effects, said the physician, who has acted as a consultant to GSK and other companies serving the diabetes field.

Dr. Lipscombe said some of the patients in the database, though, took Avandia because they could not tolerate the other drugs, not because they were sicker. And those patients still faced the same risk of heart problems, she said.

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