A leading diabetes doctor sent the Food and Drug Administration a letter seven years ago that warned of the heart risks of the drug Avandia. And in the next year, the F.D.A. reprimanded the drug’s maker for playing down safety concerns, according to documents from 2000 and 2001.
The documents, found in a reporter’s search of the F.D.A.’s database, indicate that the agency had been warned of safety concerns with the Type 2 diabetes treatment Avandia, and that the drug’s maker, GlaxoSmithKline, was seeking to minimize Avandia’s risks, before some of the same cardiovascular concerns were brought to public attention on Monday in an article and an editorial in The New England Journal of Medicine.
The F.D.A. has acknowledged that the company alerted the agency to concerns about a cardiovascular risk as early as 2005, based on the company’s analysis.
Glaxo has challenged the significance of the data cited in the medical journal. And, along with the F.D.A., the company has said that it was too soon to draw conclusions that Avandia raises a Type 2 diabetes patient’s risk of heart attacks. But the documents from 2000 and 2001 indicate that concerns about the drug’s safety are by no means new.
The letter in 2000 to the F.D.A. was written by Dr. John B. Buse, chief of endocrinology at the University of North Carolina in Chapel Hill, who is about to become the president of the American Diabetes Association. His letter from seven years ago sounded an alarm about Avandia, citing “a worrisome trend in cardiovascular deaths and severe adverse events” among patients using the drug.
In a telephone interview yesterday, Dr. Buse said that his opinion of Avandia had not changed since he wrote that letter. But he added yesterday that regulators should not rush to judgment by withdrawing Avandia from the market. Instead, he said, they should wait for the results of a larger study now being conducted by Glaxo that is meant to study the drug’s cardiovascular risks.
Avandia has been used by an estimated six million people in the United States since the agency approved it 1999. At the time, the company promoted Avandia as a safer alternative to a similar diabetes drug, Rezulin, which was withdrawn from the market in 2000 because it caused serious liver damage in some patients.
A Harvard professor who is a critic of the nation’s drug approval process, Dr. Jerome L. Avorn, yesterday drew parallels between the regulatory histories of Avandia and Rezulin, which had been a popular drug in its day.
With both drugs, “there were signals of a very dangerous side effect that were ignored,” he said. “Then massive marketing created a tremendous uptake of the drug.”
Last year, worldwide sales of Avandia exceeded $3 billion, making it one of Glaxo’s top-selling drugs.
The New England Journal of Medicine article, by the influential Cleveland Clinic heart specialist Dr. Steven E. Nissen, warned that the use of Avandia might significantly increase the risk of heart attacks. The extent of those possible risks had not been previously identified to the public.
Dr. Nissen has said that, according to his analysis, any person with Type 2 diabetes has a 20.2 percent chance of having a heart attack during a seven-year period. But with Avandia, he says, that seven-year risk would increase to 28.9 percent.
Glaxo has challenged the significance of Dr. Nissen’s analysis, which was developed by combining the results of more than 40 studies of the drug. Dr. Nissen has acknowledged that such studies, called meta-analyses, have limitations and are not as valid as controlled clinical trials.
As a result of Dr. Nissen’s article, the F.D.A. issued a safety advisory on Monday, suggesting that patients taking the drug consult their doctors. The agency also said that it planned to hold a meeting of outside advisers to review the drug’s safety. Among the options would be leaving it on the market with an even stronger warning — the drug’s label already alludes to the possibility of heart risks — or blocking its sale.
Even before Dr. Nissen had started working on his paper, Glaxo alerted the agency in 2005 and in 2006 that internal analyses had shown an increased risk of heart attacks. But the company also submitted a study of patients that it said showed Avandia was no riskier than other diabetes drugs. None of this analysis was specifically communicated to the public or doctors, although the company posted it on a Web site.
On Capitol Hill yesterday, agency officials explained their handling of Avandia to more than a dozen House and Senate staff members.
The briefing did little to settle concerns among some in Congress that the F.D.A. had been slow to alert patients about the drug’s potential risks to the heart, according to several staff members who were present and who spoke on condition of anonymity because the briefing was confidential.
