An article in a leading medical journal yesterday raised serious safety questions about the widely used diabetes pill Avandia and renewed skepticism about the vigilance of federal drug regulators.
The analysis, based on a review of more than 40 existing clinical studies involving nearly 28,000 patients, showed that Avandia significantly increased the risk of heart attacks, compared with other diabetes drugs or a placebo.
Both the study’s lead author and the editors of The New England Journal of Medicine, in which the article appeared, cautioned that the research method used left the findings open to interpretation. But they said the study nevertheless raised important concerns.
And the publication of the study on the journal’s Web site prompted the Food and Drug Administration to issue a public safety alert and advise users of the drug — an estimated million people in this country and two million worldwide — to consult their doctors about the potential cardiovascular risks.
The journal’s editor in chief, Dr. Jeffrey M. Drazen, said: “We view this as the best publicly available data on a very important question. It shows what we regard as a preliminary, but worrisome, signal about cardiovascular toxicity of this drug.”
The drug’s maker, GlaxoSmithKline, issued a news release defending Avandia’s safety and saying it “strongly disagrees” with the conclusions of the journal article, which it said was based on incomplete evidence.
Glaxo’s stock fell by nearly 8 percent on the news.
While the analysis took Wall Street and many doctors by surprise, Glaxo and the F.D.A. disclosed yesterday that they had known about the signs of potential cardiovascular risk since last August, when the company, on its own initiative, submitted a similar analysis to the agency. That disclosure prompted questions on Capitol Hill about why patients and doctors had not been informed earlier.
Explaining its delay, the F.D.A. said the significance of the studies had not been confirmed and in fact was contradicted by some other studies of the drug.
“We decided we needed to reanalyze the complex dataset ourselves to make a better informed decision,” Dr. Robert J. Meyer, a director of the agency’s office of drug evaluation, said in a news conference yesterday.
Dr. Meyer said that the agency was close to completing its analysis and would convene an advisory panel as soon as possible to review the drug. The F.D.A. is conducting an estimate of excess heart attacks that might be attributed to the drug, but Dr. Meyer said that the results were not final, declining to disclose the number. He noted that Avandia’s label already carries a warning of cardiovascular risks.
Meanwhile, the F.D.A. advised Avandia patients to check with their doctors.
“We’re expecting dozens if not hundreds of phone calls tomorrow,” said Dr. John B. Buse, chief of endocrinology at the University of North Carolina in Chapel Hill. “I’ve told our staff to tell people who call that this is not cause for panic. We can discuss it further at their next visit.”
But Dr. Buse, a president-elect of the American Diabetes Association, said he would not be surprised if some doctors ultimately switched patients to an alternative drug unless additional details were released supporting Avandia’s safety.
The New England Journal of Medicine posted the paper on its Web site, ahead of its planned print publication on June 14. Early Web postings are made by the journal’s editors in matters that they consider to have public health importance.
The study was not supposed to be released until 5 p.m. yesterday, after the closing bell on Wall Street, but it was inadvertently published yesterday morning by two wire services. The company’s stock began falling almost immediately and was down more than 8 percent by midafternoon, before finishing down 7.85 percent, at $53.18.
The research method employed by the lead author, Dr. Steven E. Nissen of the Cleveland Clinic, was a so-called meta-analysis, which combines the data of various studies. Such analyses, generally used to develop hypotheses, are seen as less reliable than uniform controlled studies.
In an interview, Dr. Nissen said that the average diabetic has a 20.2 percent risk of a heart attack over a seven-year period. A diabetic taking Avandia has a 28.9 percent risk during that same seven-year period, according to his analysis.
“It’s a huge risk,” he said, estimating that “tens of thousands of people” had heart attacks as a result of taking the drug.
