New research has suggested that several commonly prescribed drugs for type 2 diabetes may not be as effective at preventing death and cardiovascular diseases, such as myocardial infarctions and stroke, as the oral anti-diabetic drug, Metformin ( Glucophage ).

Insulin secretagogues, such as Glimepiride ( Amaryl ), Glibenclamide ( known as Glyburide [ Micronase ] in the USA and Canada ), Gliclazide ( Diamicron ) and Tolbutamide ( Orinase ), have been used to treat type 2 diabetes since the 1950-1970s. Nevertheless, the long-term risk associated with these drugs has largely been unknown.
Metformin is the first drug of choice in type 2 diabetes, but, until now, there have not been studies investigating the long-term risk of individual insulin secretagogues compared with Metformin.

A study followed a large, unselected group of everyone living in Denmark, aged over 20, who had been treated with either an insulin secretagogues or Metformin ( monotherapy ) between 1997 and 2006 – a total of 107,806 people. It found that, compared to Metformin treatment, monotherapy with most insulin secretagogues, including Glimepiride, Glibenclamide, Glipizide and Tolbutamide, was associated with a greater risk of death from any cause, and a greater risk of myocardial infarctions, stroke or death from cardiovascular diseases. This was the case both for patients who had already suffered a heart attack and for patients who had not. Two other insulin secretagogues, Gliclazide and Repaglinide ( Prandin ), showed no significant difference to Metformin in their effectiveness in patients with and without a history of myocardial infarctions.

Compared to Metformin, patients who had not suffered a heart attack had approximately a fifth to a third higher risk of death from any cause if they were taking Glimepiride, Glibenclamide, Glipizide or Tolbutamide. In patients with a history of heart attacks, the risk was approximately a third to a half higher.

The researchers, led by Tina Ken Schramm, at the Heart Centre at the Rigshospitalet Copenhagen University Hospital ( Copenhagen, Denmark ), have stressed that the findings may not mean that these insulin secretagogues actually cause harm, but only that they appear to be less effective than Metformin.

Previous studies have shown that insulin secretagogues, in particular sulphonylureas, are associated with a reduction in long-term risk. Therefore, the increased risk from insulin secretagogues shown in the study presumably has more to do with the beneficial effects of Metformin, Gliclazide and Repaglinide, than the detrimental effect of the other insulin secretagogues.
This is the first study to compare all insulin secretagogues with Metformin despite a wide debate on the possible cardiovascular risk associated with insulin secretagogues for about three decades.

In an accompanying editorial, Odette Gore and Darren McGuire of the University of Texas Southwestern Medical Center ( Dallas, Texas, USA ), have wrote that the study’s findings are among the most robust published, and it is of key importance to note that the observation of less benefit with most sulphonylureas in the study compared with Metformin should not be interpreted as causing harm.
Patients taking Metformin had the best outcomes, supporting prior evidence of Metformin benefit and making it the first-line drug recommended for almost all patients with type 2 diabetes. Compared against this beneficial drug, most of the insulin secretagogues were associated with worse outcomes, but they would almost certainly be similar to, or better, had the comparison been made against placebo treatment, with the added benefit on kidney, eye, and nerve disease of the glucose control they yield. So patients should not stop their medications based on this study.
These are observational analyses and not randomised comparisons, so it is impossible to tease out what if any of the difference in outcomes is due to the drugs compared versus differences in the patients – those taking insulin secretagogues might have an increased risk to begin with.

In conclusion, the study has supported previous studies demonstrating that Metformin may be less hazardous or more beneficial than most insulin secretagogues. This suggests that Metformin should be the first drug of choice in type 2 diabetes in most patients. The study has shown there are important differences in the risk associated with different insulin secretagogues, suggesting that Gliclazide and maybe Repaglinide are preferable, although in patients who have had a previous myocardial infarction the most beneficial agents are Metformin and Gliclazide.

Source: European Heart Journal, 2011

XagenaMedicine2011