Sex differences in the efficacy of GLP ‐1 receptor agonists: A systematic review and meta‐analysis of cardiovascular and renal outcome trials

Type 2 diabetes mellitus (T2DM) is a well‐established risk factor for cardiovascular disease (CVD), yet emerging evidence indicates that its impact may differ between sexes. Women with T2DM appear to have a higher relative risk of adverse cardiovascular (CV) events compared to men, potentially due to biological, hormonal, and pharmacokinetic differences.1, 2 The 2022 American Diabetes Association (ADA) Standards of Medical Care recommend glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) as first‐line therapies for individuals with T2DM who either have or are at high risk for atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or chronic kidney disease (CKD).3 Recent clinical trials have examined sex‐based differences in the effects of GLP‐1RAs on CV and renal outcomes. The FLOW trial (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease) reported a 21% reduction in composite kidney outcomes among females and a 30% reduction among males.4 Recent randomised controlled trials (RCTs) have reported mixed findings regarding sex‐specific CV benefits of GLP‐1RAs in reducing major adverse cardiovascular events (MACE). The AMPLITUDE‐O trial (Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes) demonstrated a significant 44% reduction in MACE among females, suggesting potential cardioprotective benefits of GLP‐1RAs in women.5 In contrast, the SUSTAIN‐6 trial (Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes) reported a significant reduction in MACE primarily among males by 32%, highlighting possible sex‐based differences in therapeutic response.6 These contrasting findings raise uncertainty about the extent to which these effects differ between men and women.

Despite the higher relative CVD risk in female T2DM patients, they remain underrepresented in RCTs, limiting the generalisability of findings. For instance, the SELECT and HARMONY trials included only 27.8% and 30% females, respectively.7, 8 Existing meta‐analysis has faced constraints due to the limited number of RCTs available, as well as the absence of data on renal outcomes and other key CVD indicators such as stroke. This raises concerns about statistical power and the applicability of current evidence to broader populations.9 To address these gaps, the present systematic review and meta‐analysis aim to synthesise the latest evidence on sex differences in the cardiovascular and renal effects of GLP‐1RAs, providing insights that may help inform precision medicine approaches in diabetes care.

This systematic review and meta‐analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines (PROSPERO REGISTRATION ID: CRD420251031670).9, 10 The literature search was conducted up to February 2025. Since the analysis was based on publicly available data, Institutional Review Board approval was not required.

The PRISMA flow chart (Figure S1) summarises the search and trial selection. From a total of 4739 initial results, 11 trials were found to meet the eligibility criteria.4, 5, 6, 7, 14, 15, 16, 17, 18, 19, 20 Secondary analyses of these trials that reported relevant subgroup data were also shortlisted.21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 All included trials had a low risk of bias (Table S2). In total, 11 trials were included, which constituted 85,273 patients (n = 43, 339 receiving GLP‐1RAs; n = 41, 934 receiving placebo). Baseline characteristics of patients in each included trial are presented in Table 1.

This meta‐analysis of 85, 273 patients identifies several important findings. First, GLP‐1RAs reduce the risk of MACE by 14% in men and 18% in women, with consistent benefits observed for stroke mortality indicating important protective effects for both sexes. While no individual trial demonstrated a statistically significant reduction in stroke mortality, this effect became apparent when the data were pooled (Figure 6). Second, GLP‐1RAs lowered the risk of the composite kidney outcome by 20% in men and 31% in women, with no evidence of treatment effect heterogeneity across the available data. However, GLP‐1RAs did not show significant benefits for CV death, MI, or HHF in both sexes. These outcomes were reported in a relatively limited number of studies, indicating that the absence of statistical significance may reflect insufficient statistical power rather than a genuine lack of effect.

GLP‐1RAs have demonstrated consistent cardiovascular and renal benefits across diverse populations.32, 33, 34, 35 These effects are attributed to multiple mechanisms, including attenuation of atherosclerotic progression, enhancement of endothelial function, promotion of weight loss, and suppression of pro‐inflammatory cytokines.35, 36, 37, 38, 39 These agents have also demonstrated efficacy in stroke prevention, with findings from the REWIND trial indicating that reductions in HbA1c accounted for 54% of the observed decrease in stroke risk, alongside a linear association between HbA1c improvement and stroke reduction across trials.20, 40 They also help improve renal outcomes by enhancing natriuresis and lowering glomerular hyperfiltration.41

Our findings are consistent with prior analyses; however, previous studies were based on smaller effect sizes and a limited number of outcomes, potentially restricting generalisability and precluding a comprehensive assessment.9 Moreover, a separate meta‐analysis investigating sex‐specific effects of GLP‐1RAs employed odds ratios, which do not account for event timing and may overestimate risk, rendering them less suitable for time‐to‐event analyses.9, 43 In contrast, the present study exclusively utilises HRs, offering a more precise and dynamic estimation of risk.

Large‐scale observational studies suggest that T2DM confers a 25%–50% greater excess risk of CVD in women compared to men.44 This disparity may, in part, be attributable to a greater degree of weight loss observed in women, potentially due to higher drug exposure related to lower average body weight, which may result in improved metabolic profiles and clinical outcomes.45 However, our study observed no significant sex‐specific differences in the cardiovascular impact of GLP‐1RAs. Notably, sex‐stratified analyses of SGLT2 inhibitors demonstrated a markedly low treatment effect in women compared to men.46 The consistent improvement in cardio‐renal outcomes across both sexes and specifically in women supports the broader clinical utility of GLP‐1RAs.

Heterogeneity in outcomes may be largely attributable to variations in trial design and patient demographics. Notably, follow‐up durations differed substantially across studies, ranging from 1.3 years in the FREEDOM CVO trial to 5.4 years in REWIND, potentially impacting the ability to detect long‐term CV events.16, 20 The short follow‐up in FREEDOM‐CVO may explain the observed heterogeneity for 3‐p MACE in our analysis.16 While most trials enrolled patients with T2DM and either established CVD, CKD or associated risk factors, some studies diverged from this inclusion framework. For example, the SELECT trial focused on obese individuals without diabetes; AMPLITUDE‐O included a proportion of patients receiving SGLT2 inhibitors, introducing the possibility of synergistic effects; and ELIXA specifically recruited patients with recent acute coronary syndrome.5, 7, 14

Biological differences in men and women have important implications for disease aetiology and manifestation, treatment response, and outcomes. In contrast to previous reports, our study also identified underrepresentation of women across RCTs, limiting the ability to fully characterise sex‐specific risks (Table 1).47 The roots of this disparity are complex. In the past, researchers primarily conducted studies on male participants, and the results were generalised to women, largely to avoid dealing with the challenges posed by hormonal variations in women and the potential unknown risks to pregnancy.48 This could also be attributed to women experiencing greater GLP‐1RA‐related adverse effects leading to early discontinuation. Existing evidence suggests that women may experience higher rates of gastrointestinal side effects, including nausea, vomiting, and GI bleeding.49, 50, 51 Women have a higher risk than men of being diagnosed with depression and experiencing suicidal thoughts or attempts following GLP‐1RA therapy.52 The lack of sex‐specific data may contribute to suboptimal outcomes, highlighting the need for inclusive research to improve care for both sexes.53 Future research should prioritise increased female representation in RCTs to better delineate sex‐specific differences, characterise adverse events, assess subgroups most likely to benefit, and establish evidence‐based criteria to guide clinical decision‐making. Moreover, real‐world data assessing adherence, discontinuation rates, and treatment durability will provide insights into the long‐term viability of GLP‐1RA therapy among men and women.

Several limitations of this study should be considered. First, subgroup analyses were limited by the lack of a uniform population across the included trials, making it difficult to assess treatment effects in specific high‐risk groups. Although all trials were long‐term CVOTs, their primary inclusion criteria varied, adding to the heterogeneity. Second, while a random‐effects model was employed to account for heterogeneity, differences in trial design, GLP‐1RA type and dosage, as well as baseline patient characteristics, may affect the interpretation of results. Third, although GLP‐1RAs significantly reduced the risk of 3‐point MACE, myocardial infarction, stroke, hospitalisation for HF, CV death, and adverse events leading to treatment discontinuation, variations in follow‐up duration and patient demographics may limit the generalisability of these findings. Finally, due to insufficient data, a meta‐analysis of specific adverse events could not be performed, underscoring the need for future studies to comprehensively evaluate these outcomes.

This analysis provides substantial evidence that GLP‐1 RAs effectively reduce the risk of major clinical outcomes, including MACE, stroke, and composite kidney events, across both sexes, consistent with findings in the overall population. Additionally, GLP‐1 RAs demonstrated a beneficial impact on MI, CV death, and HHF. These findings underscore their therapeutic potential across sexes and highlight the need for further research to evaluate sex‐specific safety profiles and clinical applications.

The authors received no funds, grants, or financial support for this study.

The authors declare that they have no conflicts of interest.

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/dom.70123↗.