Network meta-analysis of cardiovascular outcomes in randomized controlled trials of new antidiabetic drugs

Randomized controlled trials (RCTs) directly comparing cardiovascular outcomes of new antidiabetic drugs are lacking. We used network meta-analysis to compare new antidiabetic drug classes with respect to major adverse cardiovascular events (MACE) and mortality. We searched MEDLINE, EMBASE, the Cochrane database, and ClinicalTrials.gov up to 30 December 2016 for RCTs involving SGLT-2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors in diabetic patients that reported MACE and deaths. Outcomes were compared with frequentist and Bayesian methods using R statistics. Seven RCTs with altogether 62,268 patients were included in the network meta-analysis. The SGLT-2 inhibitor and GLP-1 RAs reduced MACE (OR 0.85, 95%CI 0.73–0.99 and 0.89, 0.82–0.97, respectively) and all-cause mortality (0.67, 0.55–0.81 and 0.89, 0.80–0.99, respectively) compared to placebo. Furthermore, the SGLT-2 inhibitor reduced all-cause mortality compared to GLP-1 RAs (0.76, 0.61–0.94). In contrast, DPP-4 inhibitors did not reduce MACE or mortality compared to placebo and were associated with higher all-cause mortality compared to the SGLT-2 inhibitor (1.53, 1.24–1.89) and GLP-1 RAs (1.16, 1.01–1.33). All-cause mortality and MACE were reduced by the SGLT-2 inhibitor and GLP-1 RAs, but not DPP-4 inhibitors. The SGLT-2 inhibitor had the most beneficial impact on all-cause mortality. DPP-4 inhibitors showed no cardiovascular benefit and were inferior to the other two drug classes in preventing deaths. •SGLT-2 inhibitor and GLP-1 RAs reduce mortality and MACE.•SGLT-2 inhibitor has a larger effect on reducing mortality.•DPP-4 inhibitors show no cardiovascular benefit.•SGLT-2 inhibitor is the evidence-based second-line treatment after metformin.