Female participation in cardiovascular trials of antidiabetic medications: a SAGER-Guided systematic review

Abstract Abstract Cardiovascular disease (CVD) is the leading cause of mortality worldwide. There is evidence that antidiabetic medications reduce major cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death. However, females remain underrepresented in randomized controlled trials (RCTs) on CVD, despite growing evidence that males and females respond differently to antidiabetic medications, which may influence both the efficacy and safety of treatment. Understanding the differences is important to optimize therapeutic strategies. The Sex and Gender Equity in Research (SAGER) guidelines provide recommendations for reporting sex and gender in study design and analysis. This review assessed how these considerations are incorporated in CVD outcome RCTs of antidiabetic therapies. Purpose To evaluate female participation and integration of sex and gender in RCTs of antidiabetic medication based on the SAGER guidelines. Methods We systematically reviewed the literature (PubMed, OVID) for RCTs evaluating antidiabetic medications in adults (aged ≥18 years) with or at risk of diabetes mellitus that reported CVD outcomes. We followed the search strategy suggested by Ghosh-Swaby et al., which included RCTs up to November 2019 and updated the search until March 2025. The primary outcome of interest was MACE. Studies focusing solely on non-CVD outcomes were excluded. To ensure the inclusion of high-quality studies, we only included RCTs with ≥1,000 participants, ≥12 months follow-up, ≥0.01% difference in HbA1c between baseline and follow-up, and ≥20 CVD events. Results Thirty-seven RCTs with 269,169 participants were eligible for inclusion. The RCTs investigated various interventions including GLP-1 RAs (n=11), SGLT2i (n=6), DPP-4 inhibitors (n=5), thiazolidinediones (n=5), and other glucose-lowering strategies such as weight loss, diet, exercise (n=9). Overall, 36% of participants were female (range 2.9%-59.5%). While all trials reported sex or gender at baseline, 57% presented sex- or gender-stratified efficacy outcomes, and only 8.1% reported sex- or gender-disaggregated adverse events data. None of the RCTs mentioned sex or gender in the introduction and 10% discussed implications of sex- or gender-specific findings. No improvement in adherence to the SAGER guidelines over time was observed. Overall, sex and gender considerations was low and inconsistent. Conclusion In CVD outcome RCTs on antidiabetic medications, sex- and gender-specific analyses are inconsistently reported despite global efforts towards equity in clinical research. Greater adoption of the SAGER guidelines is recommended to enhance applicability and equity of evidence informing CVD risk reduction in individuals with or at risk of diabetes.