An article in a leading medical journal Monday 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 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 to advise users of the drug – an estimated 1 million people in this country and 2 million worldwide – to consult their doctors about the potential cardiovascular risks. “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 Monday. 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 FDA is conducting an estimate of excess heart attacks that might be attributed to the drug, but Meyer, saying the results were not final, declined to disclose the number. He noted that Avandia’s label already carries a warning of cardiovascular risks. Meanwhile, the FDA 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 Buse, a president-elect of the American Diabetes Association, said he would not be surprised if some doctors ultimately switch patients to an alternative drug unless additional details are 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 they consider to have public health importance. Information on the study was not supposed to be released until 5 p.m. Monday, after the closing bell on Wall Street, but it was inadvertently published Monday 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. 160Want local news?Sign up for the Localist and stay informed Something went wrong. Please try again.subscribeCongratulations! You’re all set! 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 strongly disagreeing 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 FDA disclosed Monday 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. Regarding the delay, the FDA said the significance of the studies had not been confirmed and in fact was contradicted by some other studies.