Effects of once-weekly glucagon-like Peptide-1 receptor agonists on cardiovascular risks and rare events: a meta-analysis of randomized clinical trials

Objective: Exenatide, albiglutide, dulaglutide, and semaglutide are once-weekly glucagon like peptide receptor agonists (GLP-1 RAs), approved to treat type 2 diabetes mellitus (T2DM). However, there is limited evidence concerning safety levels of once-weekly GLP-1 RAs, including cardiovascular risks and rare events. The current meta-analysis was conducted to pool all relevant evidence regarding safety levels of once-weekly GLP-1 RAs. Methods: The current meta-analysis was conducted using PubMed, Embase, Cochrane Library, and the Website www.clinicaltrials.gov , aiming to identify all available trials with a duration of at least 24 weeks. For dichotomous variables, Mantel-Haenszel odds ratios (MH-OR) for incidence of major cardiovascular events (MACE), such as all-cause and cardiovascular mortality, pancreatic cancer, prostate cancer, and papillary thyroid cancer, were calculated. Cardiovascular risks were estimated according to mean differences in changes in HbA1c, body weights, blood pressure, heart rates, and lipid profiles. Results: Of the 41 included trials, 39 studies provided at least one event on MACE. Incidence of MACE was significantly reduced by once-weekly GLP-1 RAs, compared with the comparators group. Subgroup analyses suggested that a significant reduction was obtained, comparing once-weekly GLP-1 RAs and placebos (P < 0.001). Furthermore, a significant reduction was noted in all-cause mortality rates. Non-significant differences were observed in cardiovascular mortality rates, as well as incidence rates of pancreatic cancer, papillary thyroid cancer, and prostate cancer. Conclusion: Cardiovascular safety levels of once-weekly GLP-1 RAs were determined for patients with type 2 diabetes mellitus.