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

Abstract

Aims Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD. Methods and results In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85–1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80–0.96) and 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 (HF) hospitalization (HR 0.92, 95% CI 0.86–0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82–1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83–1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo. Conclusion Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

GLP-1RAs and SGLT2is Reduce Cardiovascular Events Independent of Reductions of Systolic Blood Pressure and Body Weight: A Meta-Analysis with Meta-Regression

“…3 Forest plot of meta-analysis on cardiovascular death stratified by drug class by 15%, MI by 9%, and ACD by 13%. Similarly, the benefits from GLP-1RAs and SGLT2is on these cardiovascular and mortality endpoints were also observed in meta-analyses [18][19][20] of GLP-1RA trials and those [21,22] of SGLT2is trials.…”

Comparative cardiovascular safety of GLP-1 receptor agonists versus other glucose-lowering agents in real-world patients with type 2 diabetes: a nationwide population-based cohort study

“…The second and third steps above ensured that the between-group comparison derived from two groups of patients would have comparable disease severity and previous medication use patterns/extent. To minimize the computational demand for large sample size in the SU group (21,135,786 stable use sets of SU) in the matching process, we randomly sampled 30% of stable use sets of SU for matching with GLP-1ra stable users.…”

“…CVOTs have found favorable cardiovascular effects associated with GLP-1ra [11][12][13][14][15][16], and the cardiovascular benefits of GLP-1ra and underlying mechanisms (e.g., reduction in left ventricular filling pressure or systemic inflammation, effect on endothelial function) have been documented [17][18][19] and summarized in the recent review and meta-analysis literature [20][21][22]. However, there are two important caveats about the findings of CVOTs: (1) study cohorts included in these randomized controlled trials (RCTs) were highly selective, thus reflecting only a subset of the real-world T2D population, and (2) the comparator drug in these RCTs was a placebo instead of an active GLA.…”

GLP1 agonists beyond glycemic control—redefining their role

“…A systematic review and metaanalysis published in 2019 concluded that GLP1 agonists have beneficial effects on cardiovascular, kidney, and mortality outcomes in patients with T2DM. A more recent meta-analysis in 2020 showed significant reduction in major adverse CV events, CV and total mortality, stroke, and hospitalization for heart failure, with a trend for reduction of myocardial infarction in patients with T2DM with and without established CV disease [7,8]. These findings have led to a paradigm shift in the management of T2DM with guidelines recommending that those with established cardiovascular disease should use either a GLP1 agonist (or SGLT2 inhibitor) with established cardiovascular benefit as the first add-on therapy to metformin irrespective of their glycated hemoglobin level [9].…”