Effect of insulin secretagogues on major cardiovascular events and all-cause mortality: A meta-analysis of randomized controlled trials

In 2019, the Italian Society of Diabetology and the Italian Association of Clinical Diabetologists nominated an expert panel to develop guidelines for drug treatment of type 2 diabetes. This expert panel, after identifying the effects of glucose-lowering agents on major adverse cardiovascular events (MACEs) and all-cause mortality as critical outcomes, decided to perform a systematic review and meta-analysis on the effect of insulin secretagogues (sulfonylureas and glinides) with this respect. A MEDLINE database search was performed to identify all RCTs, up to January 1st, 2020, with duration≥52 weeks, in which insulin secretagogues (glibenclamide, gliclazide, glimepiride, glipizide, chlorpropamide, repaglinide, nateglinide) were compared with either placebo or active comparators. The principal endpoints were MACE (restricted for RCT reporting MACEs within their outcomes) and all-cause mortality (irrespective of the inclusion of MACEs among the pre-specified outcomes). Mantel-Haenszel odds ratio (MH–OR) with 95% Confidence Interval (95% CI) was calculated for all the endpoints considered. Fourteen RCTs were included in the analysis for MACEs (919 in insulin secretagogues and 1,087 in control group). Insulin secretagogues were not significantly associated with an increased risk of MACEs in comparison with controls (MH–OR 1.08 [95% CI 0.96, 1.22], p = 0.20). When considering the 48 RCTs fulfilling criteria for inclusion in the analysis on all-cause mortality, insulin secretagogues were associated with a significantly increased risk of all-cause mortality (MH–OR 1.11 [1.00, 1.23], p = 0.04). This meta-analysis suggests that insulin secretagogues are associated with an increased risk of all-cause mortality when compared with placebo or other anti-hyperglycaemic drugs. •The effects of glucose-lowering agents on major cardiovascular events (MACEs) and mortality are critical outcomes.•The cardiovascular safety of insulin secretagogues (IS) is debated.•The results of the present metanalysis do not support any relevant association with an increased risk of MACEs for IS.•IS seem to be associated with an increased risk of all-cause mortality.•The increased risk of all-cause mortality with the use of IS (11%) is clinically relevant, with a high quality of evidence.