CardioExchange Archive

A very large observational study has found an increase in death and cardiovascular risk in people taking insulin secretagogues (ISs) compared with those taking metformin. Tina Ken Schramm and colleagues, reporting in the European Heart Journal, analyzed data from the entire population of Denmark and identified 107,806  people who initiated therapy with an IS or metformin. The study, they say, is the first “to analyse major cardiovascular endpoints with all currently approved ISs monotherapies in a nationwide setting.”

The analysis found a consistent increase in deaths and cardiovascular events associated with the most commonly used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, while the risks associated with gliclazide and repaglinide were not significant.

Here are the hazard ratios and confidence intervals for mortality for the following drugs, compared with metformin, in patients without a history of MI:

• glimepiride: 1.32 (1.24–1.40)
• glibenclamide: 1.19 (1.11–1.28)
• glipizide: 1.27 (1.17–1.38)
• tolbutamide: 1.28 (1.17–1.39)

Here are the risks for mortality for the following drugs in patients with previous MI:

• glimepiride: 1.30 (1.11–1.44)
• glibenclamide: 1.47 (1.22–1.76)
• glipizide: 1.53 (1.23–1.89)
• tolbutamide: 1.47 (1.17–1.84)

In an accompanying editorial, Odette Gore and Darren McGuire write that the study is “among the most robust” due to its size, thereby giving it enough power to evaluate the individual agents studied. They warn against interpreting the study to mean that the drugs may cause harm, especially since metformin has been associated with an approximately 40% risk reduction for cardiovascular events and death compared with placebo.

Further, they write, an “important and novel finding of the present study is the variability of the estimates of hazard associated with individual insulin secretagogues, suggesting that some may be better than others with regard to the outcomes assessed.” In the absence of trial data, drug choices “remain grounded primarily on clinical judgement.”

“Ideally,” they conclude, “all drugs used to treat T2DM should undergo CV efficacy and safety evaluation, but for drugs that are already approved, and especially for those that are generic, it remains to be determined where the responsibility will fall to support such large and expensive clinical trial evaluations.”