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Diabetes drug investigation yields unclear decision from FDA committee

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This week, a federal advisory committee of 33 experts convened to review data on the controversial type 2 diabetes drug, Avandia, and debated whether the drug should remain on the market. The meeting was prompted by recent studies suggesting that patients on the drug have an increased risk of heart attack. The U.S. Food and Drug Administration (FDA) committee's recommendation, issued July 14, is unclear. Whereas a strong majority (21 of 33) of the panelists agreed that available data shows Avandia increases the risk of heart attack compared to other diabetes drugs, their opinion on whether or not to remove it from the market depends on how their vote is interpreted.

Given the choice of five options, one to completely remove Avandia from the market and four to keep the drug on the market under various stipulations, 12 panelists voted to ban sales of Avandia outright. This choice received more votes than any other single option. When votes for the remaining four options are added together, however, the majority voted to keep the drug on the market under certain conditions. Importantly, 10 of the panelists who voted in favor of keeping Avandia on the market chose the option to limit its use to only select patients. What the FDA will ultimately decide remains to be seen, but the committee recommendation suggests that, should Avandia remain on the market, its sales may become more restricted.

In response to the committee's decision, Avandia's manufacturer GlaxoSmithKline (GSK) asserted in a press release that results from six clinical trials, released subsequent to a 2007 FDA review of Avandia, "show that Avandia does not increase the overall risk of heart attack, stroke or death. As a result, we believe that when used in the appropriate patient and in accordance with labeling, Avandia is a safe and effective treatment option for type 2 diabetes."

Avandia was approved for sale by the FDA in 1999, and quickly became one of the leading treatments for diabetes. It also became one of the best-selling drugs for GSK with more than $2 billion in sales in 2006. Avandia belongs to a class of drugs known as thiazolidinediones (TZDs), which help to manage diabetes by making the body more sensitive to its own insulin. Actos, a different TZD manufactured by Japanese pharmaceutical company Takeda, is also frequently prescribed for diabetics but has not been associated with increased heart attack risk.

Safety concerns regarding Avandia arose in 2007 when a meta-analysis, published in the New England Journal of Medicine by Cleveland Clinic physician Steve Nissen and colleagues, suggested that Avandia use is associated with 43 percent greater risk of heart attack as compared to placebo or other diabetes drugs.

Later that year, the FDA assembled the first advisory committee to review available data on Avandia's safety. The committee overwhelmingly agreed that the evidence indicated that Avandia increases heart attack risk, but voted at that time to keep the drug on the market, a recommendation that the FDA later adopted. The FDA further required that a warning label be added to the drug alerting consumers to the potential heart risks.

In the meantime, GSK agreed to conduct its own postmarket study of Avandia's safety—that ongoing trail, Thiazolidinedione Intervention With Vitamin D Evaluation (TIDE) compares the safety of Avandia with the related drug, Actos, and is set to be complete in 2015.

In a recent letter to the FDA, Sidney Wolfe of Public Citizen, a Washington, D.C.-based citizens' advocacy group, and David Juurlink, a researcher at Sunnybrook Health Sciences Centre in Toronto whose recent study found Avandia-associated health risks, called the TIDE trial "unethical" and urged the FDA to halt the study. They insist that Avandia offers no advantage over Actos, yet comes with significantly greater health risks.

This February, the Senate Finance Committee issued a report further raising concerns over Avandia's safety, and suggested that GSK "was aware of the possible cardiac risks associated with Avandia years before such evidence became public…" The report's authors state that "GSK executives intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that the rival drug ACTOS (pioglitazone) might reduce cardiovascular risk."

The New York Times confirmed these allegations in an article published July 12. A GSK spokesperson told the newspaper that the company did not release their internal study findings to the public because they "did not contribute any significant new information."

So far, GSK has paid approximately $460 million to resolve lawsuits alleging Avandia can cause heart attacks and stroke. Sales of the drug have declined since 2007, with sales in 2009 of approximately $250 million.

In light of this week's review of Avandia, many patient groups are concerned that diabetics may suddenly decide to stop taking the drug. "It's especially important that patients not change or stop medications without consulting their healthcare provider," American Heart Association (AHA) President Ralph Sacco said in a prepared statement commenting on the FDA advisory committee's recommendation.

Type 2 diabetes affects approximately 23 million Americans, and 220 million individuals worldwide, according to estimates from the National Institutes of Health and the World Health Organization, respectively. Aside from the TZD-class of drugs, other pharmaceutical options are available to treat diabetes, including Metformin, a drug the AHA generally recommends as the first choice treatment. Metformin helps to lower blood sugar levels by telling the liver to release less sugar and prompting muscle and fat cells to absorb sugar. The disease can also be managed by non-pharmacological strategies, including dietary changes, increased physical activity and weight loss.

Image courtesy of iStockPhoto

The views expressed are those of the author and are not necessarily those of Scientific American.

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