Taking half a dose of Glaxo's combination pill reduced by two-thirds the risk that patients would go from having high blood sugar -- pre-diabetes -- to full type-2 diabetes, the researchers reported in the Lancet medical journal.

Fourteen percent of the patients treated with the drugs developed diabetes after four years, compared to 39 percent of those given placebo, the researchers found.

The effect would likely be the same with Avandia's rival drug in the same class, Takeda's Actos, said Dr. Bernard Zinman of Mount Sinai Hospital at the University of Toronto, who led the study.

I think it is a class effect, Zinman said in a telephone interview.

Actos, known generically as pioglitazone and Avandia, known generically as rosiglitazone, belong to a class of drugs called thiazolidinediones, which help the body better use insulin.

Type-2 diabetes is caused as the body gradually loses its ability to respond to insulin, a condition called insulin resistance. Overeating, a lack of exercise, genes and other factors all play a role.

As insulin works less and less well, levels of glucose rise in the blood, damaging blood vessels and organs. The beta cells in the pancreas begins to lose their ability to make insulin.

SIDE-EFFECTS

Avandia and Actos work well to help and even prevent diabetes. But they have side-effects, including fluid retention, heart failure and, possibly, heart attacks.

Glaxo said this week it had settled more lawsuits alleging Avandia caused heart attacks.

The U.S. Food and Drug Administration is reviewing data on possible heart risks from the drug.

Glaxo, which will be looking to save its faltering market for Avandia, paid for the study. Sales of Avandia topped $3 billion in 2006, but fell to $1.2 billion in 2009.

Metformin is an older drug that also helps the body use insulin, but it can cause upset stomach.

So Zinman decided to try a half-dose of both to see if that would be effective and cut back the side-effects.

His team recruited 207 patients with pre-diabetes and gave them either two pills a day of combined Avandia and metformin or placebos. They followed them for almost four years.

The side-effects were not there -- the weight gain, fluid retention, the gastrointestinal side-effects, Zinman said.

The study has not lasted long enough to tell whether heart failure or heart attack rates would rise measurably, but Zinman said fluid retention often points to future potential heart effects.

Both Avandia and Actos will soon be available generically, and metformin has long been, meaning a potentially inexpensive way to prevent diabetes, he said.

Lifestyle changes like exercising and losing weight also work to prevent diabetes, but people do not follow them well, he noted.

The concept of combining submaximum doses of effective drugs to maintain efficacy and reduce side-effects is an attractive one, Dr. Thomas Buchanan of the University of Southern California wrote in a commentary.

The International Diabetes Federation estimates that 300 million people worldwide have pre-diabetes and 230 million have diabetes.

Medicine