Treatment with metformin for three years produced a marked reduction in macrovascular complications and mortality compared with glipizide in patients with type 2 diabetes and coronary artery disease (CAD), a recent trial has shown.

The study was a randomised, double-blind, placebo-controlled trial of 304 type 2 diabetes patients with established CAD. Patients had been diagnosed with diabetes for more than five years and with CAD for three years. They were randomly assigned to glipizide (30 mg daily) or metformin (1.5 g daily) for three years.

The primary end points were time to the composite of recurrent cardiovascular events including death from a cardiovascular cause, death from any cause, nonfatal MI, nonfatal stroke, or arterial revascularisation.

Both drugs produced a significant decrease in HbA1c. At a median follow-up of five years, a total of 103 primary events had occurred in 91 patients; 52 patients in the glipizide arm and 39 in the metformin arm.

In the glipizide group, there were 11 deaths from cardiovascular causes and three sudden deaths, six MIs,15 nonfatal strokes, and 25 arterial revascularisations. In the metformin group, there were seven cardiovascular deaths, five MIs, ten nonfatal strokes, and 21 revascularisations. This represents a relative risk reduction of 46%, hazard ratio 0.54 (95% CI: 0.30-0.90; P = 0.026).

With respect to secondary end points, there was no difference between the two groups in terms of new or worsening heart failure, new cardiac arrhythmias, new or worsening angina, or new peripheral vascular events. There was also no significant difference in hypoglycaemic episodes.

The authors conclude that treatment with metformin substantially reduced major cardiovascular events compared with glipizide. ‘Our results indicated a potential benefit of metformin therapy on cardiovascular outcomes in high-risk patients,’ they say. They point to potential anti-atherogenic properties of metformin such as reducing endothelial dysfunction and vascular adhesion molecules.

Furthermore, sulfonylureas result in weight gain which may contribute to increased mortality despite producing similar improvements in HbA1c to metformin. The authors also point out that these results were achieved in the face of lower statin use in the metformin group compared with the glipizide group (59.5% vs 73.7%;P = 0.013).

These findings lend further support to the notion that the benefits of metformin appear to extend beyond glucose lowering.

Dr Peter Savill