People with diabetes are already at very high risk for cardiovascular disease, and this risk may be even greater for those with type 2 diabetes who take sulfonylureas, a medication that increases the pancreas's output of insulin.

Observational studies from Canada and Scotland have found an increase in total and cardiovascular deaths in patients with type 2 diabetes who were taking sulfonylureas (either alone or with metformin) compared with patients who were taking metformin alone.

Could the metformin have a protective effect, or is sulfonylurea the culprit? Support for the sulfonylurea toxicity hypothesis comes from the finding that both total and cardiovascular mortality increased with the dosage of sulfonylurea.

When the first of these two reports came from Canada four years ago, I tended to place little confidence in it. Now, with similar results from the larger study in Scotland published this year, I think it's time to pay more attention to the possible toxicity of sulfonylureas.

The issue is not fully resolved and probably never will be, because these observational studies do not carry the same weight as randomized controlled trials, and it is highly unlikely that such trials will ever be done.

Nonetheless, I believe that metformin is the best first choice for the treatment of people with type 2 diabetes and that sulfonylureas should be used only by those who are unwilling to take insulin or who cannot tolerate the other oral medications for type 2 diabetes.