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Diabetes drug's future unclear

GlaxoSmithKline disagreed with a study that found Avandia might increase the risk of heart attack.

Steven Nissen, cardiologist and coauthor of the Avandia study.
Steven Nissen, cardiologist and coauthor of the Avandia study.Read more

A day after a new study suggested that the widely prescribed diabetes drug Avandia might increase the risk of heart attack and death, the prognosis for the medicine and its manufacturer, GlaxoSmithKline P.L.C., remained unclear.

London-based GlaxoSmithKline, with U.S. headquarters in Philadelphia and North Carolina, stood by its statement Monday that it "strongly disagrees with the conclusions reached" in the New England Journal of Medicine article.

At the same time, critics of the Food and Drug Administration continued to raise the specter of Vioxx, the Merck & Co. Inc. pain reliever that was pulled from the market three years ago after studies raised similar concerns and critics accused Merck of withholding other evidence of Vioxx's risks.

"We need to know if this is another Vioxx, where the FDA sat on its hands and endangered lives," said Sen. Charles E. Grassley (R., Iowa), who has pushed for changes in how the agency monitors prescription drugs.

After knocking down GlaxoSmithKline's share price by $4.53, or 8 percent, on Monday, investors showed a more measured response yesterday. By the close of trading, GlaxoSmithKline's stock had regained a small fraction of the previous day's loss, closing at $53.93, up 75 cents.

Avandia, one of GlaxoSmithKline's top-selling drugs, generates about $3 billion in annual sales, mostly in the United States. It's among a new generation of medicines in a growing market for Type-2 diabetes treatments.

Some analysts and doctors said the uncertainty reflected acknowledged limitations in the New England Journal study, a "meta-analysis" of 42 mostly small-scale clinical studies that together examined Avandia's effects on a total of 15,560 patients. The study found that Avandia appeared to raise the risk of heart attack by 43 percent when compared with alternative drugs or placebos.

"This paper does nothing more than raise a question. It is very far from definitive," said Brian Strom, a professor and chairman of biostatistics and epidemiology at the University of Pennsylvania Medical School. "The real question is what else is out there? What else is the FDA privy to?"

On Monday, the FDA issued a safety alert on Avandia, even as it said that "published and unpublished" data and analyses presented some "contradictory evidence." To support its new alert, it cited a parallel meta-analysis, which it said had been submitted "recently" by GlaxoSmithKline and showed that Avandia users might face a 30 percent to 40 percent greater risk of heart attack and related events than patients taking placebos or other diabetes drugs.

The FDA's warning said: "Safety data from controlled clinical trials have shown that there is a potentially significant increase in the risk of heart attack and heart-related deaths in patients taking Avandia."

Steven Nissen, a Cleveland Clinic cardiologist who cowrote the New England Journal study, said he discovered the GlaxoSmithKline meta-analysis while doing a Google search as he prepared his article.

"I was extremely surprised to find that both the FDA and the company" had access to a similar analysis, he said in an interview yesterday.

One meta-analysis, submitted to the FDA in September 2005, included 37 trials. The second, an update submitted in August 2006, was based on 42 trials, though not the exact same 42 trials used in Nissen's study.

"Frankly, I was reassured that we were correct when the company's own analysis showed similar results," Nissen said.

In a note to investors yesterday, Timothy Anderson, a pharmaceutical analyst for Prudential Equity Group, said he did not expect GlaxoSmithKline or the FDA to remove Avandia from the market. But Anderson said that he expected harsher warnings about Avandia, and that sales would fall as a result of the study. Previously, Prudential had forecast 2008 Avandia sales of $2.8 billion.

Anderson also suggested the negative news for GlaxoSmithKline could help its leading rival, Merck, which has two new drugs, Januvia and Janumet, in the growing diabetes market. Merck shares closed yesterday at $54.15, up 36 cents.

To endocrinologist Mark Schutta, medical director of the Penn Rodebaugh Diabetes Center, the study results were a new warning flag but hardly a big surprise.

"People ask me, 'Are you shocked by this?' No, I'm not shocked," Schutta said.

He said that both Avandia and Actos, made by Takeda Pharmaceuticals North America Inc. and the only other drug in the same class currently approved for U.S. use, could cause significant weight gain, which itself could elevate cardiovascular risk.

But unlike Actos, Schutta said, Avandia also tends to elevate LDL cholesterol, another risk factor.

"When I see this study, I think, wow, maybe this is a result of the elevation in LDL," Schutta said. "I think this is a red flag, but we need to approach it cautiously and dig into it a little more. It's too early to draw conclusions."

Nissen and his coauthor, statistician Kathy Wolski, said the effect on LDL cholesterol could help explain why Avandia's use might raise the risk of heart attack and death. But they said "the rapidity and magnitude of the apparent hazard was not consistent with an effect by lipid changes alone."

Schutta said that concerns about such side effects already had discouraged him from prescribing Avandia in most cases. But he said that he had some patients who already were stable on the drug when they came to his practice, and that he had continued their treatment.

He said patients calling with concerns were being asked to come in this week for reevaluations.

"You can't just stop the drug," he said. "You have to replace it with something else."