Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis

Abstract

Introduction: New antidiabetic drugs are required to demonstrate safety in cardiovascular outcome trials. However, they are rarely compared with each other. We therefore performed a network meta-analysis to compare new antidiabetic drug classes with respect to cardiovascular outcomes. Methods: We searched for cardiovascular outcome trials involving glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose co-transporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM) using major adverse cardiovascular events (MACEs) and mortality as endpoints. Network meta-analysis was performed using random-effects model in R. Results: Ten trials with altogether 81 825 patients with T2DM were eligible to be included. Glucagon-like peptide-1 receptor agonists and SGLT-2 inhibitors significantly reduced MACEs (odds ratio [OR]=0.86, 95% confidence interval [CI]=0.78-0.94 and OR=0.86, 95% CI=0.76-0.96) when compared with placebo. Sodiumglucose co-transporter 2 inhibitors significantly reduced cardiovascular mortality and all-cause mortality when compared with DPP-4 inhibitors (OR=0.77, 95% CI=0.61-0.98 and OR=0.77, 95% CI=0.64-0.92) and placebo (OR=0.76, 0.63-0.92 and OR=0.79, 95% CI=0.68-0.91), respectively. Glucagon-like peptide-1 receptor agonists lowered the risk of MACEs (OR=0.87, 95% CI=0.77-0.99) compared with DPP-4 inhibitors, and showed a trend towards a lower risk of non-fatal myocardial infarction (OR=0.87, 95% CI=0.76-1.00) when compared with placebo. No significant differences were found in the risk of non-fatal stroke. Conclusion: Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors both reduce MACEs when compared with placebo. Sodium-glucose co-transporter 2 inhibitors are the most beneficial in reduce mortality while GLP-1 RAs reduce cardiovascular events the most. Dipeptidyl peptidase-4 inhibitors do not worsen cardiovascular outcomes, but are inferior to GLP-1 RAs and SGLT-2 inhibitors. Our findings support SGLT-2 inhibitors and GLP-1 RAs as the preferred treatment for patients with T2DM to reduce cardiovascular risk.