Can Low-Dose Avandia for Diabetes Avoid Lethal Side Effects?

Jun. 3, 2010— -- Amid calls to pull the controversial diabetes drug Avandia from the market, new research suggests that a low dose of this GlaxoSmithKline drug may help prevent diabetes without undue risk.

Though the study, published Wednesday in the Lancet, showed few adverse side effects for a low-dose treatment, diabetes experts say Avandia has a history of potentially lethal side effects, and that further testing and use of this dangerous drug is questionable.

"This is a desperate attempt to salvage a dangerous drug," Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, says of the study. Wolfe urges that trials on Avandia, known clinically as rosiglitazone, be halted due to the mounting evidence that the drug brings with it significant risk of heart attack, weight gain, and other health risks.

In the study, test subjects were given a half-dose of Avandia paired with another diabetes drug, metformin, over a four-year period. They saw "very little in the way of adverse side effects," says study author Dr. Bernard Zinman of the University of Toronto. The study was not designed to test cardiovascular safety however, and the results cannot speak to the controversy surrounding the drug, Zinman says.

"I can't say that this is strong evidence that [Avandia] is safe, but it implies that at this dose it is much better," Zinman says.

Given Avandia's troubled history, complete with thousands of patient law suits and FDA recognition of its added risks, however, diabetes experts question the motivation for continuing research on this drug.

Avandia's competitor, pioglitazone (Actos), works just as well with fewer risks, and intensive lifestyle counseling has been shown to work as well with no side effects, so, Wolfe asks, why continue to play with fire?

A Safe Future for Avandia?

The drug combination in the Lancet study reduced the relative risk of developing type 2 diabetes by 66 percent among those patients at risk when compared to placebo.

Past studies have shown that intensive lifestyle counseling can reduce diabetes risk by nearly 60 percent, but Zinman says that this type of regular coaching is difficult to implement without society-wide changes in diet and exercise habits.

While all participants in the study received one-on-one coaching on diet and exercise changes in the first year, nearly forty percent of those who received only this counseling and a placebo went on to develop diabetes while only 14 percent of those treated with drugs did.

Avandia's Safety Questionable, Even at Low Dose

"Studies show that metformin and Avandia can be effective; the problem is you get significant side effects -- weight gain, bone fractures, [increase in] heart attack risk, " Zinman says. The researcher's goal was to find an effective dose at which side effects would not be as risky, something he says these findings suggest is possible.

Weight gain, fluid retention, and bone fractures were not significant side effects at the lower dose, though the study is too small to gauge the cardiovascular safety of this treatment, Zinman says.

But can these "enticing" results, as Zinman dubs them, stand up against the firestorm of liability lawsuits and criticism that has been leveled at Avandia?

Calls to Pull Avandia From the Market

Avandia's safety was called into question in 2007 when an analysis by Dr. Steven Nissen, chair of Cardiovascular Medicine at Cleveland Clinic, showed those on the drug had a 43 percent higher risk of heart attacks and a 64 percent higher risk of dying from heart disease.

In February 2010, the U.S. Food and Drug Administration's associate director of drug safety, David Graham, echoed these concerns, recommending in a public report that Avandia be removed from the market.

The report said the drug could be linked to about 500 additional heart attacks and 300 additional cases of heart failure each month than would occur if its comeptitor, Actos, were used exclusively.

This call to pull Avandia off the market was given amid thousands of lawsuits brought against GlaxoSmithKline by patients alleging that the drug caused heart attacks.

The company has faced an estimated 13,000 claims for damages involving Avandia, according to The Associated Press. thousands of which were settled Tuesday. Some 700 Avandia cases were settled in May for $60 million.

Concerns Remain Over Avandia

What's more, a Senate Finance Committee report in April suggested that GlaxoSmithKline may have withheld information concerning the dangers of the drug -- a claim that the company denies in a written response on its website.

Even if Wednesday's study offers hope of a safer treatment, as Zinman says, some diabetes specialists say that there would have to be overwhelming evidence -- something that this single study cannot offer.

"Any drug used for prevention must be even safer that [those used for] treatment," says Dr. David Nathan, director of the Diabetes Center at Massachusetts General Hospital.

"Whether the one half dose...will avoid the safety issues that have led many physicians to stop using it is unknown."