Sex differences in trial representation and the cardiovascular effectiveness of newer glucose‐lowering agents in patients with and without type 2 diabetes: A systematic review and meta‐analysis of cardiovascular outcome trials

AIMS: The extent to which the cardiovascular benefits of sodium-glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) differ by sex remains unclear. This systematic meta-analysis aimed to investigate sex differences in trial representation and the cardiovascular and kidney efficacy of SGLT-2is and GLP-1RAs in patients with and without type 2 diabetes (T2D). MATERIALS AND METHODS: Cardiovascular outcome trials (CVOTs) were identified through searches in MEDLINE, Embase, and CENTRAL, and manual search of ClinicalTrials.gov up to August 2025. Sex-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Sex-differential treatment effects were assessed using the ratio of HRs and meta-regression. RESULTS: Across 47 articles from 25 unique CVOTs (n > 185 000) published between 2015 and 2025, women were less represented (approximately one-third of trial participants). SGLT-2is and GLP-1RAs significantly reduced cardio-kidney outcomes in both men and women. In individuals with T2D, SGLT-2is significantly reduced risks of major adverse cardiovascular events (MACE) 0.87 (0.80-0.95) and composite cardiovascular death or hospitalization for heart failure 0.73 (0.64-0.83) in men, with broadly similar results for women and also for both sexes in individuals without T2D. In individuals with T2D, GLP-1RAs reduced MACE risk in men 0.89 (0.82-0.96) and women 0.83 (0.77-0.91). Pooled ratio of HRs showed no significant sex differences, though some cardiovascular benefits appeared slightly greater in women; formal interactions were not statistically significant. CONCLUSIONS: SGLT-2is and GLP-1RAs provide broadly comparable cardio-kidney benefits across sexes in patients with and without T2D. The lower representation of women in CVOTs warrants attention.