Meta-Analyses of Semaglutide Trials Report Differential Cardiovascular Risk Reduction Between Men and Women

Meta-Analyses of Semaglutide Trials Report Differential Cardiovascular Risk Reduction Between Men and Women

Meta-analyses of semaglutide and other GLP-1 receptor agonist cardiovascular outcome trials (CVOTs) have found consistent relative reductions in major adverse cardiovascular events (MACE) for both men and women, with no statistically significant treatment-by-sex interaction in pooled data. Pooled analyses of the STEP trials identified greater mean weight loss among women than men. These findings derive from post-hoc and pooled evaluations of randomized trials conducted primarily in populations with type 2 diabetes or overweight/obesity [1, 2, 3].

The syntheses add context to an established class effect while underscoring that absolute cardiovascular event rates remain higher in men across most trials. Regulatory documents cite supporting subgroup data without recommending sex-specific adjustments to dosing or indications [4].

What this means

The compiled evidence indicates that relative risk reductions for MACE linked to GLP-1 receptor agonists occur similarly in men and women, while women in the examined trials achieved larger percentage body-weight reductions. Absolute event rates for cardiovascular outcomes were typically higher among male participants. Data on secondary endpoints such as heart-failure hospitalization and stroke show directional consistency without clear evidence of sex dimorphism. The analyses do not alter existing regulatory labeling, which applies the same cardiovascular risk-reduction language to both sexes.

Cardiovascular outcome consistency across sexes
A 2023 meta-analysis of seven CVOTs evaluating GLP-1 receptor agonists reported an overall hazard ratio for 3-point MACE of 0.86 and confirmed the absence of sex-based heterogeneity, with an I² of 0% for the treatment-by-sex interaction [1]. The REWIND trial of dulaglutide similarly showed MACE hazard ratios of 0.85 in women and 0.90 in men (interaction p=0.62) [3]. Subgroup data from the SUSTAIN-6 trial included in the FDA approval package for semaglutide injection align with these patterns of consistent directional benefit [4].

Weight loss and cardiometabolic markers
Pooled analysis of the STEP 1–4 trials found that once-weekly semaglutide produced mean weight loss of −15.4 kg in women versus −12.8 kg in men (P<0.001) [2]. The analysis associated these reductions with greater relative improvements in several cardiometabolic markers among female participants, although the trials were not designed to test whether weight-loss differences translate into differential long-term cardiovascular outcomes.

Secondary endpoints and broader trial synthesis
Subgroup forest plots from REWIND and data referenced in the SUSTAIN-6 labeling indicate that reductions in stroke and heart-failure hospitalization occurred in both sexes without meeting thresholds for significant interaction [3, 4]. Larger meta-analyses encompassing LEADER, EXSCEL, and other CVOTs report directionally consistent MACE reductions across male and female subgroups, supporting a class-level observation that relative efficacy does not differ meaningfully by sex in the studied populations [1].

Limitations

Most data come from underpowered post-hoc sex subgroups of trials not designed to detect sex interactions [1, 3]. Women are typically underrepresented (≈40% of participants) in CVOTs, which narrows the precision of female-specific estimates. Hormonal status, menopausal stage, and sex-specific pharmacokinetics are rarely stratified, leaving potential modifiers unexamined. Real-world evidence and longer-term (>5 yr) safety data by sex remain sparse. The syntheses therefore show consistent relative benefit across sexes in the available randomized data but do not establish whether outcomes would differ in populations with different demographic balances or in dedicated prospective sex-stratified trials.