MONDAY, May 21, 2007 (HealthDay News) -- Avandia, a pill widely prescribed by doctors to treat type 2 diabetes, actually increases users' risk for heart attack by 43 percent, U.S. researchers reported Monday.
The U.S. Food and Drug Administration responded by issuing a safety alert Monday for the drug, but stopped short of a stronger warning label, saying more analysis was needed.
The findings on Avandia (generic name rosiglitazone) will appear in the June 14 issue of the New England Journal of Medicine. The journal's editors released the findings early on Monday due to their public health importance.
"The Food and Drug Administration is aware of a potential safety issue related to rosiglitazone," Dr. Robert J. Meyer, director of FDA's Office of Drug Evaluation II, said during an afternoon teleconference. But, he added that "at this point we have not reached a definitive conclusion on the data. We don't feel there is consistent enough data to make a decision from a regulatory standpoint. We are not ready to make an action."
Meyer added that while some data indicate a risk for heart attack with the drug, other published and unpublished studies show the opposite. The FDA received data indicating the increased risk in August 2006, Meyer said.
The FDA is continuing to analyze the research, he said. "FDA has not confirmed the significance of the reported increased risk in the context of other studies," he said. "Further, the FDA doesn't know whether other approved treatments in the same class of drugs have the same or greater risks."
More than 2 million people worldwide take Avandia for type 2 diabetes, generating $3.2 billion in annual sales for its maker, GlaxoSmithKline, according to The New York Times. The drug was first approved for the treatment of type 2 diabetes in 1999.
For the new study, Dr. Steven Nissen and his colleague Kathy Wolski at the Cleveland Clinic evaluated 42 studies that compared patients taking Avandia with patients not using the drug. The studies included almost 28,000 patients, 15,560 of whom were taking Avandia.
The researchers found the risk of a heart attack was increased 43 percent among those taking Avandia, and there was a 64 percent increased risk of dying from cardiovascular causes, compared with patients not taking the drug.
Among patients taking Avandia, 86 had heart attacks compared with 72 among patients not on the drug. In addition, 39 patients taking Avandia died from cardiovascular causes compared with 22 patients not receiving the drug, Nissen and Wolski found.
"Rosiglitazone was associated with a significant increase in the risk of myocardial infarction [heart attack] and with an increase in the risk of death from cardiovascular causes that had borderline significance," the authors wrote.
"Until more precise estimates of cardiovascular risk of this treatment can be delineated in patients with diabetes, patients and providers should carefully consider the potential of rosiglitazone in the treatment of type 2 diabetes," they concluded.
Dr. Sue Kirkman, vice president for clinical affairs at the American Diabetes Association, called the findings "somewhat concerning."
"People with diabetes are at increased risk for cardiovascular disease, so anything that raises the possibility that something might worsen that risk is concerning," she said.
But Kirkman said there's no need for patients to panic, either. "We recommend that patients speak with their physician about the appropriate form of treatment," she said. "We don't think that this is an emergency that requires drastic action."
The FDA's Meyer agreed that patients and their doctors may want to discuss the new findings. "What the FDA would say to patients at this point is that if they are taking rosiglitazone, and particularly if they have underlying heart disease or are otherwise at high risk for a heart attack, they should talk to their doctor about these data," he said.
Other experts said the study's results raise questions about Avandia's usefulness and safety.
"In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic [blood sugar] control, the rationale for prescribing rosiglitazone at this time is unclear," concluded Drs. Bruce M. Psaty, of the University of Washington, and Curt D. Furberg, of Wake Forest University, two diabetes experts who co-authored an accompanying editorial in the journal.
Psaty and Furberg also said that, barring any new data to the contrary, the U.S. Food and Drug Administration should take regulatory action to restrict access to Avandia.
"The primary problem here is that studies that were needed early on about the health benefits of this drug were never done," Psaty said in an interview. "As a result of the failure of the sponsor to do long-term clinical trials to show health benefits, as a result of the failure of the FDA to insist on it, we have data that are weak."
Accordingly, the editorial notes that the Cleveland findings aren't conclusive either. "A few events either way might have changed the findings for [heart attack] or for death from cardiovascular causes. In this setting, the possibility that the findings were due to chance cannot be excluded. In their discussion, the authors properly emphasize the fragility of their findings."
GlaxoSmithKline responded by issuing a strongly worded press release defending the safety of the drug. In the statement, company officials said GSK "strongly disagrees with the conclusions reached in the New England Journal of Medicine article, which are based on incomplete evidence and a methodology that the author admits has significant limitations."
The company said several large scale, long-term clinical trials, overseen by safety monitoring boards, have yet to uncover any threats to patient safety. "GSK's long-term, landmark study ADOPT [A Diabetes Outcome Progression Trial] -- one of the longest clinical trials in people with type 2 diabetes to date -- directly compared both the safety and effectiveness of Avandia with other oral anti-diabetic medicines in over 4,300 patients studied for up to six years," the statement said.
"Data from ADOPT showed that the overall risk of serious, cardiovascular events [CV death, myocardial infarction, and stroke, or MACE endpoint] for patients on Avandia was comparable to metformin and sulfonylurea (glyburide) -- two of the most commonly used medicines to treat type 2 diabetes," the statement said.
A second long-term study, DREAM, which followed more than 5,200 patients at high risk of developing type 2 diabetes for a period of three to five years, found that "Avandia monotherapy showed no increase in cardiovascular risk when compared to placebo," according to the statement.
In their editorial, Psaty and Furberg said the new data about Avandia highlights the failure of the FDA's drug-approval process.
"During the market life of rosiglitazone, tens of millions of prescriptions for the drug have been written for patients with type 2 diabetes," they wrote. "Insofar as the findings of Nissen and Wolski represent a valid estimate of the risk of cardiovascular events, rosiglitazone represents a major failure of the drug-use and drug-approval process in the United States."
Consumers Union said the news about Avandia "underscores the urgent need for Congress to pass strong drug-safety reform legislation this year.
"Today's New England Journal of Medicine analysis is yet another example of the FDA's lax post-market safety oversight system, and vividly illustrates the need for Congress to pass reforms to more quickly detect -- and act on -- safety problems with drugs already on the market," the group said in a prepared statement.
But GlaxoSmithKline strongly refuted the study's claims.
"The totality of the data show that Avandia has a comparable cardiovascular profile to other oral anti-diabetic medicines," the company said. "GlaxoSmithKline stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks."
For more information on type 2 diabetes, visit the U.S. National Institute of Diabetes and Digestive and Kidney Diseases.