Second line use of a sulfonylurea in type 2 diabetes treatment is associated with an increased the risk of cardiovascular and hypoglycaemic events, an observational study of UK data has found.

Published in the BMJ, the analysis of outcomes in more than 77,000 patients taking metformin suggests that increases in myocardial infarction and hypoglycaemic events are driven by switching to a sulfonylurea rather than just addition of a sulfonylurea.

The data, derived from the UK Clinical Practice Research Database covered patients with type 2 diabetes who were initially on metformin monotherapy.

During more than one year of follow up, adding or switching to a sulfonylurea was associated with an increased risk of myocardial infarction (hazard ration 1.26), all cause mortality (HR 1.28) and severe hypoglycaemia (HR 7.6).  There was also a trend towards increased risk of ischaemic stroke (HR 1.24) and cardiovascular death (HR 1.18) with second line sulfonylurea treatment.

When the researchers compared adding and switching to sulfonylureas they found that switching was associated with a 51% higher risk of MI and a 23% higher risk of all cause mortality compared to adding a sulfonylurea.

Potential mechanisms to account for the increase in risk seen with sulfonylureas might include weight gain and the hypoglycaemic propensity for arrhythmias and cardiac ischaemia, the study authors suggest.

“Thus, in line with current recommendations on the treatment of type 2 diabetes, continuing metformin when introducing sulfonylureas is safer than switching,” they conclude.

However they caution that the associations may not be causal, and the differences in risk could be due to higher doses of sulfonylureas being needed by patients who switched.

An accompanying commentary notes that data support previous findings of beneficial cardiovascular effects with metformin, by showing that the increased risk from sulfonylurea use was primarily among those who switched and completely stopped metformin.

“These data suggest that adding a sulfonylurea to metformin treatment is preferable to switching to sulfonylurea monotherapy. It also suggests that continuing metformin alone and accepting higher HbA1c targets is preferable to switching to sulfonylureas when considering both macrovascular outcomes and hypoglycaemia,” the authors say.

The BMJ‘s journal’s reviewer Dr Richard Lehmann takes a stronger viewpoint, saying in his blog that “the time has long gone for a randomised controlled trial of sufficient power to determine the cardiovascular risk of sulfonylureas in type 2 diabetes.”

“But I think the time may have come to retire sulfonylureas as a therapeutic class altogether,” he writes.