When taken as first-line therapy, sulfonylureas may increase the risk of death in patients with type 2 diabetes, researchers reported here.

In a retrospective analysis of U.K. data, patients who were initially treated with a sulfonylurea had a 58% higher risk of all-cause mortality than patients given first-line therapy with metformin (95% CI 1.48 to 1.68, P<0.001), Craig Currie, PhD, an epidemiologist at Cardiff University in Wales, and colleagues reported at the European Association for the Study of Diabetes meeting here.

”I’m not saying this is a smoking gun. I’m just saying that regulatory agencies and [medical] societies have got to take this seriously and insist that the drug industry commissions studies to evaluate it properly,” Currie said during a press briefing. ”At the moment, nobody is doing that.”

There has been some evidence that sulfonylureas — a class that includes glimepiride (Amaryl) and glipizide (Glucotrol) — increase the risk of adverse events in type 2 diabetics. Although the class has largely been supplanted by metformin as a first-line therapy, Currie said clinicians in the U.K. and the U.S. still prescribe it as monotherapy for the estimated 15% of patients who can’t tolerate metformin.

To assess the effects of sulfonylureas on all-cause mortality, the researchers looked at data from the Clinical Practice Research Datalink (CPRD), which includes information on about 10% of all patients treated in primary care in the U.K., from 2000 to 2012.

They included a total of 76,811 patients given metformin monotherapy and 15,687 patients given sulfonylurea monotherapy during that time, each of whom were followed for an average of 2.9 years.

Overall, they found a significantly increased risk of all-cause mortality with sulfonylurea monotherapy compared with metformin as a first-line treatment (aHR 1.58, 95% CI 1.48 to 1.68, P<0.001).

They reported similar results in propensity-matched analyses (aHR 1.90, 95% CI 1.73 to 2.09, P=0.018) and in directly matched analysis (aHR 1.34, 95% CI 1.05 to 1.70, P<0.001).

Currie and colleagues also analyzed mortality data when sulfonylureas were used as add-on second-line therapy versus DPP-4 inhibitors as add-on therapy.

Their database included information on 33,983 patients taking metformin plus a sulfonylurea, as well as 7,864 who were given metformin plus a DPP-4 inhibitor.

Again, they saw an increased risk of all-cause mortality among those on combination therapy with a sulfonylurea compared with a DPP-4 inhibitor (aHR 1.35, 95% CI 1.08 to 1.71, P=0.01).

Currie said the harmful effects of sulfonylureas may be attributable to their effects on insulin. These drugs increase levels of the hormone, upping the risk of hypoglycemia — which is, in turn, associated with adverse cardiovascular events such as arrhythmias and cardiac arrest, he said.

Andreas Pfeiffer, MD, of Charite University Hospital in Berlin, who moderated the press briefing during which the findings were presented, added that animal models have also shown that knocking out insulin is associated with increased life expectancy.

”This is something inherent to the insulin system,” which may help explain why sulfonylureas were associated with increased risk of death in these studies.

Currie cautioned that observational studies such as his do have inherent biases — for instance, patients with worse disease may get higher doses of drugs — but added that his team has done a significant amount of controlling for potential confounders.

”In my view,” he concluded, ”the safety of sulfonylureas needs urgent evaluation because we are potentially increasing the risk of all-cause mortality.”

http://www.medpagetoday.com/

European Association for the Study of Diabetes