Drug Combo May Prevent Diabetes

Study Shows Low Doses of Avandia, Metformin Ward Off Diabetes for at-Risk Patients

From the WebMD Archives

June 2, 2010 -- Patients who have trouble controlling their blood sugar are 66% less likely to get diabetes if they take low doses of two diabetes drugs with different modes of action.

The finding comes from a four-year Canadian study of more than 200 patients with impaired glucose tolerance, a sign of impending type 2 diabetes. It's the first study to show that a low-dose drug cocktail -- Avandia plus metformin -- can prevent diabetes better than lifestyle intervention alone.

The low-dose combinationappears to reduce the risk of common side effects for each drug, says study researcher Bernard Zinman, MD, director of the diabetes center at Toronto's Mount Sinai Hospital and professor of medicine at the University of Toronto.

"Remarkably, the effect of the combination was remarkablyrobust with over 60% decrease in risk of diabetes," Zinman tells WebMD. "And the well-known side effects did not appear. There was no weight gain, no fluid retention, fractures were equal in both the treatment and placebo groups, and while there was some diarrhea, it was low intensity."

The dosages used in the study were 2 milligrams of Avandia plus 500 milligrams of metformin. Avandia daily doses usually range from 4 milligrams to 8 milligrams and metformin daily doses usually range from 500 milligrams twice daily up to a maximum of 2,000 milligrams daily.

People who have trouble controlling their blood sugar are urged to lose weight, diet, and increase their exercise. This works very well. But not everyone is able to do this.

"People should always do lifestyle change first. The problem is, this is hard to achieve," Zinman says. "We did have a very structured lifestyle intervention as part of the treatment for both the treatment and placebo group in our study."

Zinman notes that the encouraging study findings must be verified in larger clinical trials. Spyros Mezitis, MD, PhD, an endocrinologist at New York's Lenox Hill Hospital, agrees.

"This is an important study, but we need large trials to explore all the issues related to combination therapy," Mezitis tells WebMD.

Avandia: Safe at Any Dose?

Avandia is one of two approved drugs (the other is Actos) in a class known as the thiazolidinediones. Both drugs increase the risk of heart failure. But Avandia has also been linked to increased risk of heart attack, although the drug's manufacturer, GlaxoSmithKline, disputes this risk.


Steven E. Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic Foundation, was among the first to raise questions about Avandia's heart safety.

"There is no evidence whatsoever that lower doses of [Avandia] are 'safe,'" Nissen tells WebMD via email. "Any suggestion that serious cardiovascular toxicity can be avoided by using a small dose represents pure speculation at best."

Zinman agrees that his study enrolled too few patients, and was too short, to provide any information on Avandia's heart safety. However, he suggests that while it was not studied, Actos would likely have the same effect when combined with metformin in a low-dose combination.

Mezitis agrees, but he'd like to see this supported by a clinical trial.

"Yes, we can make the association that Actos would work the same way, but we don't have a study suggesting that," he says. "So I would feel more comfortable having a study first before recommending another medication."

The Zinman trial was funded by GlaxoSmithKline, and Zinman reports receiving consulting fees, honoraria, and grant support from the company. However, he says the study was free of company influence and that the study investigators initiated the study, drew their conclusions, and published their findings without any company influence.

Mezitis reports that he previously served on GlaxoSmithKline's speakers bureau but withdrew when issues about Avandia cardiovascular safety first arose.

The Zinman study appears in the June 3 online edition of The Lancet.

WebMD Health News Reviewed by Laura J. Martin, MD on June 02, 2010



Zinman, B. The Lancet, published online June 3, 2010.

Buchanan, T.A. and Xiang, A.H. The Lancet, published online June 3, 2010.

Spyros Mezitis, MD, PhD, endocrinologist, Lenox Hill Hospital; assistant professor of endocrinology, Weill Cornell Medical Center, New York.

Steven E. Nissen MD, chairman, department of cardiovascular medicine, Cleveland Clinic Foundation; professor of medicine, Cleveland Clinic Lerner School of Medicine, Case Western Reserve University.

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