Sex differences in the efficacy of <scp>GLP</scp> ‐1 receptor agonists: A systematic review and meta‐analysis of cardiovascular and renal outcome trials
Hasan Fareed Siddiqui, Dua Ali, Maryam Sajid, Shaheer Qureshi, Hibah Siddiqui, Ali Hasan, David P Ripley, Raheel Ahmed, Saad Ahmed Waqas
Abstract
Sex-based differences in the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on cardiovascular, renal, and cerebrovascular outcomes remain unclear. This systematic review and meta-analysis evaluated sex-specific effects of GLP-1RAs in patients with type 2 diabetes mellitus and related comorbidities. Randomised controlled trials and secondary analyses comparing GLP-1RAs with placebo and reporting sex-stratified data were included. Outcomes assessed included composite kidney outcomes, 3-point major adverse cardiovascular events (MACE: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke), individual components of MACE, and hospitalization for heart failure (HHF). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Eleven trials comprising 85,273 patients (43, 339 receiving GLP-1RAs; 41, 934 placebo) were analysed. GLP-1RAs significantly reduced the risk of composite kidney outcomes by 20% in males (HR: 0.80; 95% CI: 0.69-0.92) and 31% in females (HR: 0.69; 95% CI: 0.54-0.87), with no significant sex interaction (p = 0.31). The risk of 3-point MACE was reduced by 14% in males (HR: 0.86; 95% CI: 0.79-0.93) and 18% in females (HR: 0.82; 95% CI: 0.75-0.90; p = 0.47). Stroke risk decreased by 21% in males and 25% in females. No significant sex-based differences were observed for cardiovascular death, myocardial infarction, or HHF. GLP-1RAs reduce the risk of major cardiovascular, kidney, and cerebrovascular outcomes in both sexes, with consistent benefits across men and women. While variations between sexes were observed in certain outcomes, these differences did not reach statistical significance for interaction. Future trials should improve female representation and explore sex-specific effects further.