A low-dose combination of two medications appears to stave off Type 2 diabetes in people at risk of developing the condition, a new Canadian study suggests.

The clinical trial appears to show the drug combo lowered a person's absolute risk of developing the disease by 26 per cent, meaning one case of Type 2 diabetes would be averted for every four people put on the regimen.

'While the concept of using low-dose combination therapy rather than high dose of either drug alone to reduce side-effects makes theoretical sense, this study doesn't actually prove it.'— Dr. Baiju Shah

Lead author Dr. Bernard Zinman said the globe is in the midst of an epidemic of diabetes, a condition which increases the risk of heart disease, stroke, blindness, kidney failure and limb amputation.

"We need to do whatever we can to stem this epidemic," Zinman said from Vancouver. "And one of the ways to do that is to prevent diabetes in the first place."

His study, called the CANOE trial — short for Canadian Normoglycemia Outcomes Evaluation — was published Thursday in the British journal The Lancet.

It was funded by pharmaceutical giant GlaxoSmithKline. GSK makes Avandia (rosiglitizone), one of the drugs used in the study. The other drug was metformin, an older medication that is no longer covered by patent protection.

This is not the first study to show that drug therapy may be able to avert or at least forestall onset of diabetes. The unique feature of this work is that it looked at using combination therapy, with two drugs administered at relatively low doses.

Heart side-effects

The idea behind the trial was that by combining lower doses of two drugs, one might get the benefit of both without the side-effects typically associated with the medications. The drugs are linked to weight gain, fluid retention and gastro-intestinal problems.

Avandia carries even more baggage. Studies suggest it raises a user's risk of heart failure and death when compared to a drug in the same class called Actos (pioglitizone). Both Avandia and Actos are seen to have higher cardiac related side-effects than metformin.

Last month a leading Toronto researcher, Dr. David Juurlink of Sunnybrook Health Sciences Centre and the U.S. watchdog group Public Citizen called on the U.S. Food and Drug Administration to scrap a large international trial comparing Avandia to Actos, saying it was unethical to proceed given Avandia's safety profile.

The FDA will hold a hearing in July to determine whether to continue the study and even whether Avandia should remain on the U.S. market.

Zinman said there was no sign of serious side-effects in people randomly selected to get Avandia and metformin in the CANOE trial.

Their results were compared to those of people given a placebo.

"We at this dose did not see any signal of concern," said Zinman, a diabetes expert at Toronto's Mount Sinai Hospital.

"But this is a very small study. It is not designed to look at cardiovascular safety. It only involves 200 individuals."

Diabetes masked?

He suggested, however, that combining metformin with Actos would probably produce the same impact.

While Zinman said the study suggested the low-dose combination therapy was as or more effective than other diabetes prevention strategies, others were not as impressed by the findings.

Dr. Victor Montori said one could look at the approach not as forestalling the development of diabetes but as speeding up the point at which at-risk individuals start getting treated as patients with diabetes.

He suggested other studies have shown that as soon as a preventative drug regime is halted the risk of developing diabetes returns to pre-treatment levels. And that suggests development of diabetes hasn't been averted, but rather masked, said Montori, an endocrinologist at the Mayo Clinic College of Medicine in Rochester, Minn.

Dr. Baiju Shah, an endocrinologist who works with Juurlink at Sunnybrook, is also not a fan of the notion of treating a lot of people for a condition they don't yet have to prevent a few of them from developing it.

Of this study, he said it's not clear the low-dose regimen works better than metformin alone or Avandia alone. That's because the combination was tested against a placebo rather than one of the other prevention options.

"Therefore, it's not clear that adding low-dose Avandia to low-dose metformin is any better or even as good as high-dose metformin by itself," Shah said in an email.

"Bottom line: This doesn't increase my enthusiasm for Avandia at all. And while the concept of using low-dose combination therapy rather than high dose of either drug alone to reduce side-effects makes theoretical sense, this study doesn't actually prove it, since that wasn't the comparison that was made."