Cardiovascular safety of DPP-4 inhibitors compared with sulphonylureas: Results of randomized controlled trials and observational studies

After failure of metformin monotherapy, another glucose-lowering agent should be added to improve glucose control. The clinician has several pharmacological choices, including the addition of a sulphonylurea (SU) or a dipeptidyl peptidase-4 inhibitor (DPP-4i). While the cardiovascular safety of SUs remains a matter of controversy, DPP-4is have proven their non-inferiority vs placebo in recent cardiovascular (CV) outcome trials. In the absence of a head-to-head CV outcome trial—the CAROLINA, comparing linagliptin with glimepiride, is still ongoing—only indirect information can be found in the literature to compare CV outcomes (major CV events, myocardial infarction, ischaemic stroke, CV death and all-cause mortality) in patients with type 2 diabetes mellitus (T2DM) treated with SUs or DPP-4is. Thus, this comprehensive review summarizes the CV outcomes (excluding heart failure) reported in meta-analyses of randomized controlled trials (RCTs) of SUs vs placebo or other glucose-lowering agents, DPP-4is vs placebo or other glucose-lowering agents and SUs vs DPP-4is in phase-II/III studies. Also, the results of observational studies reporting CV events in patients treated with either SUs or DPP-4is have been carefully examined. Overall, the CV safety of SUs appears to be poorer than that of DPP-4is in both RCTs and cohort studies. However, the results are somewhat disparate, and such heterogeneity may be explained by different patient characteristics across studies, but also perhaps by differences between various molecules in each pharmacological class. In particular, some doubt about a class effect affecting SU CV safety has been raised. The results of CAROLINA are expected to shed more light on SU CV concerns, especially compared with DPP-4is.