An independent analysis of thousands of older people with diabetes found that those treated with the widely used drug Avandia had significantly elevated risks of heart attack and death.
The finding, published Tuesday in the Journal of the American Medical Association, could rekindle the debate about whether the controversial treatment for Type 2 diabetes should remain on the market. Earlier studies have drawn similar links between Avandia and cardiac risks.
The new study concludes that Avandia users had a 60 percent increased risk of heart failure, a 40 percent increased risk of heart attacks and a 30 percent increased risk of death, compared with patients taking other oral diabetes medicines.
"Our study suggests that, at least in this high-risk population, the harms of the drug may outweigh the benefits," said the study’s lead author, Dr. Lorraine L. Lipscombe of the Institute for Clinical Evaluative Sciences in Toronto, an independent non-profit group that evaluates treatments. The study analyzed drug use and health outcomes of 159,000 people age 65 and older treated for Type 2 diabetes in the government-run health system that provides medical care to all people in the Ontario province. Of those diabetes patients, 2,268 took Avandia.
The findings suggest that for every 100 people taking Avandia over a four-year period there would be five additional deaths, four additional heart attacks and three additional episodes of heart failure, Dr. Lipscombe said.
Because it is a retrospective observational study – one that reviews the actual medical records of real-world patients – the findings carry less weight than a placebo-controlled clinical trial in which patients have been carefully screened for comparative analysis. But the study’s conclusions mirror those observed last May in an analysis published by Dr. Steven E. Nissen and colleagues from the Cleveland Clinic.
Sales of the drug, formerly a $3.4 billion product in global sales, have declined sharply since Dr. Nissen’s article was published in the New England Journal of Medicine.
Dr. Nissen’s meta-analysis, a pooling of clinical studies of Avandia, suggested a 42 percent increased risk of heart attack among those who took Avandia. That analysis spawned a controversy, with Avandia’s maker, GlaxoSmithKline, insisting that Dr. Nissen’s findings overstated the drug’s risks.
After a review, the Food and Drug Administration in November concluded that the evidence against the drug was inconclusive. But while the F.D.A. allowed Avandia to remain on the market, it also called for the agency’s strongest caution, a so-called black box warning on the label.
Responding Tuesday to the new study, Dr. Nissen said that it could spur the F.D.A. to take additional action. "As you accumulate more and more evidence that Avandia has this problem and it involves a very serious consequence, namely heart attack and death, it puts a lot of pressure on the F.D.A. to do more."
The F.D.A. released a statement Tuesday. "This new study we have just seen today does not change FDA’s recommendations," the statement said, in part. "The information FDA provided for the most recent labeling change remains accurate – the data are inconclusive and we have added a boxed warning to the labeling to ensure that health care professionals and patients are aware of this potential risk and can take this into account as they make individual prescribing decisions."
In a statement, GlaxoSmithKline said the new analysis was flawed because the patients given Avandia in the Ontario health program are typically patients who have failed other treatments. They tend to be sicker patients facing a higher baseline risk of cardiovascular disease, Glaxo said.
"This difference is not corrected for in the analysis of the data and in the study conclusions," the company’s statement said.
Canadian authorities have also allowed the drug’s marketing to continue. But they have taken a stronger stance against the medication than the F.D.A.. They have prohibited its use except in patients who could not tolerate other oral diabetes medications or as part of a combination treatment regimen when other oral diabetes medications by themselves have failed.
Dr. Lipscombe said her group had submitted its data to Canadian health authorities in case they wanted to revise their recommendations. "We feel that our study now gives more certainty that these previous reports were, in fact, well founded," she said.