Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials

First Authors: Fabio Marsico and Stefania Paolillo

Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini, 5, I-80131 Naples, Italy.

Glucagon-like peptide-1 (GLP-1) receptor agonists are recommended by European guidelines as first choice in diabetic patients with known cardiovascular (CV) disease or at high CV risk, or as second choice in patients already taking metformin. RCTs reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in diabetic patients without established CV disease are available. In this trial-level meta-analysis, we analyzed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in type 2 diabetic subjects, including an overall of 56.004 patients. We observed that in the entire population GLP-1 receptor agonists significantly reduced by 12% the risk of major adverse CV events (MACE) (HR 0.88, 95% CI 0.80–0.96) together with a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79–0.98), all-cause mortality (HR 0.89, 95% CI 0.81–0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76–0.94), and heart failure hospitalization (HR 0.92, 95% CI 0.86–0.97). No significant effect was detected for MI (fatal and non-fatal). Interestingly, no differences in efficacy on MACE were found between patients with established CV disease and patients with CV risk factors only (HR 1.06, 95% CI 0.85–1.34) (secondary vs. primary CV prevention). These data sustain the recent ESC/EASD recommendations, providing a strong support to a favorable protective effect of GLP-1 receptor agonists at earlier stages of the CV disease course in diabetic patients.