No Mortality Risk With Sulfonylureas, Meta-Analysis Shows

Michael O'Riordan

June 06, 2015

BOSTON, MA — The use of sulfonylureas in patients with type 2 diabetes mellitus does not increase the risk of all-cause or cardiovascular mortality, according to the results of a new meta-analysis[1]. In addition, investigators did not observe an increased risk of stroke or MI with the antidiabetic agents.

Dr Dimitris Rados (Hospital de Clinic de Porto Alegro, Brazil), who presented the data here at the American Diabetes Association (ADA) 2015 Scientific Sessions, said the results were similar when they included and excluded data from the United Kingdom Prospective Diabetes Study (UKPDS).

When analyzing the different sulfonylureas, investigators did observe a statistically significant increase in the risk of all-cause and cardiovascular mortality with glipizide, although they caution against making too much of the subgroup analysis given the small number of patients and clinical events.

Speaking with heartwire from Medscape, Rados said sulfonylureas, which are cheap, are still used in approximately 30% of patients in high-income countries and are even more frequently used in healthcare systems in poorer nations. The drugs remain a popular second-line option for the management of patients with type 2 diabetes.

There has been an ongoing, almost permanent, debate, however, over whether or not the drugs increase mortality and cardiovascular mortality. The UKPDS study was the first to suggest a potential mortality risk among patients treated with metformin plus a sulfonylurea. Since then, there have been a number of systematic reviews and meta-analyses showing conflicting results.

No Signal of Harm in Latest Analysis, But Issue Far From Settled

The researchers included 47 randomized, controlled clinical trials (>52 weeks duration) involving 37,650 patients in this latest meta-analysis. Overall, the use of a sulfonylurea as first-line or second-line therapy was not associated with an increased risk of total mortality (odds ratio [OR] 1.12; 95% CI 0.96–1.30) or cardiovascular mortality (OR 1.12; 95% CI 0.87–1.52). Similarly, there was no significant association with sulfonylurea use and the risk of MI or stroke.

Despite there being no signal of harm in the observed analysis, the safety issue with sulfonylureas appears far from settled.

Speaking during the question-and-answer session following the presentation, Dr Stephan Jacob (Cardiometabolic Institute, Villingen-Schwenningen, Germany) noted that his group, along with Dr Thomas Forst (Institute for Clinical Research and Development, Mainz, Germany), also conducted a similar meta-analysis two years ago[2]. In contrast, they found that sulfonylureas did increase the risk of all-cause and cardiovascular mortality.

Using studies that reported raw data on mortality with sulfonylurea use, the German researchers identified 19 cohort and observational registries with 551,912 patients. In 13 studies reporting all-cause mortality, patients treated with sulfonylureas alone or in combination treatment had a 92% increased risk compared with those who received treatment with a nonsulfonylurea. In five studies, individuals treated with sulfonylureas alone or in combination had a nearly threefold increased risk of cardiovascular mortality (OR 2.72; 95% 1.95–3.79).

"Our problem, in general, is that we have no really good data on this [type of] compound," Jacob told heartwire . Despite the absence of solid data, in Germany, physicians are required to prescribe a sulfonylurea as the second agent after metformin. All new agents need to compare favorably against sulfonylureas if they want to become the second drug in diabetes management, he added.

Regarding the question of risk with sulfonylureas in patients with diabetes, Jacob isn't certain meta-analyses are the best solution to the problem. "I have the impression that if you want to predict the results [of a meta-analysis], you can do so based on the selection of the trials included," said Jacob.

Regarding their own data, which was published July 2013 in Diabetes and Vascular Disease Research, Jacob said he was astonished at the observed increase in mortality with the drug class. To heartwire , Jacob said the two groups included different studies, with the Brazilian researchers including randomized, controlled trials and the German group focused exclusively on observational cohort studies.

"We took observational registries, which are, let's say, real-world data reporting raw data on mortality," he said. "I think, for the sake of getting the most information as possible, the larger the sample size, the better it is."

The researchers report no relevant financial relationships.


  1. Rados DV, Pinto LC, Remonti LR, et al. Sulfonylureas are not associated with increased mortality: Meta-analysis and trial sequential analysis of randomized clinical trials. American Diabetes Association 2015 Scientific Sessions; June 6, 2015; Boston, MA. Abstract 16-OR

  2. Forst T, Hanefeld M, Jacob S, et al. Association of sulphonylurea treatment with all-cause and cardiovascular mortality: A systematic review and meta-analysis of observation studies. Diab Vasc Dis Res 2013; 10: 302-314. Article