Introduction: Addressing the Sex Gap in Peripheral Artery Disease
Peripheral artery disease (PAD) represents a significant manifestation of systemic atherosclerosis, affecting millions of individuals globally, particularly those with type 2 diabetes (T2D). Historically, PAD was often characterized as a male-dominant condition, leading to an underrepresentation of women in clinical trials and a subsequent lack of sex-specific evidence. However, contemporary epidemiological data suggest that the prevalence of PAD is similar, if not higher, in women than in men, especially as populations age. Furthermore, women with PAD often present with more atypical symptoms, faster functional decline, and poorer quality of life compared to their male counterparts.
The STRIDE trial recently established that semaglutide 1.0 mg, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), improves functional outcomes and health-related quality of life in patients with early symptomatic PAD and T2D. Given the known sex-based differences in cardiovascular disease presentation and response to pharmacotherapy, a critical question remained: Does the efficacy of semaglutide in PAD vary between men and women? A recent post hoc analysis of the STRIDE trial, published in the Journal of the American College of Cardiology, provides essential insights into this query.
Study Design and Methodology
The STRIDE trial was a randomized, double-blind, placebo-controlled study designed to evaluate the impact of once-weekly semaglutide 1.0 mg on functional status in individuals with T2D and early symptomatic PAD (Fontaine stage II). This post hoc analysis specifically examined the baseline characteristics and therapeutic efficacy categorized by sex.
The primary endpoint was the ratio to baseline in maximum walking distance (MWD) at week 52, measured using a constant-load treadmill test. Confirmatory secondary endpoints included the change in MWD at week 57 (after a 5-week washout period), the change in pain-free walking distance (PFWD) at week 52, and changes in the PAD-specific Vascular Quality of Life Questionnaire-6 (VascQoL-6) total score. The analysis utilized interaction P-values to determine if the treatment effect significantly differed between males and females.
Baseline Characteristics: A Tale of Two Profiles
Out of the 792 participants in the STRIDE trial, 195 (24.6%) were female and 597 (75.4%) were male. This distribution highlights the ongoing challenge of female recruitment in cardiovascular trials, yet it provided a sufficient cohort for meaningful analysis. The researchers observed significant differences in the clinical baseline profiles between the two groups:
Demographics and Comorbidities
Females in the study were generally younger than the males. Interestingly, they exhibited lower rates of traditional cardiovascular risk factors such as smoking and had a lower prevalence of concomitant coronary artery disease (CAD) and heart failure. Despite this seemingly lower systemic atherosclerotic burden, their functional impairment at baseline was comparable to men, with a geometric mean MWD of 187.3 m in females versus 191.5 m in males.
Treatment Disparities
A notable finding was the difference in baseline medical management. Females were less likely to receive antiplatelet therapies compared to males. This disparity reflects a broader trend observed in real-world registries where women with PAD are often less aggressively treated with guideline-directed medical therapy (GDMT) than men.
Key Findings: Consistent Efficacy Across the Sex Spectrum
The core finding of this analysis is the consistency of semaglutide’s benefit regardless of the patient’s sex. The data demonstrated that semaglutide 1.0 mg improved all measured functional and quality-of-life parameters in both men and women.
Maximum Walking Distance (MWD)
At week 52, semaglutide treatment favored an improvement in MWD in both sexes. The P-interaction value was 0.65, indicating no significant difference in the magnitude of benefit between males and females. This improvement was sustained even after the 5-week washout period at week 57 (P-interaction = 0.53), suggesting potential durable changes in vascular or muscular function.
Pain-Free Walking Distance (PFWD)
One of the most clinically relevant outcomes for patients with claudication is how far they can walk before the onset of pain. Semaglutide demonstrated a consistent improvement in PFWD across both sexes at week 52 (P-interaction = 0.80). This suggests that the medication helps delay the ischemic threshold during physical activity for both men and women.
Quality of Life (VascQoL-6)
PAD profoundly impacts daily activities and mental well-being. The study used the VascQoL-6 questionnaire to assess PAD-specific health-related quality of life. The improvements observed with semaglutide were consistent with the overall trial results for both sexes, reinforcing the idea that functional gains translate into perceived symptomatic relief and better daily functioning for all patients.
Expert Commentary and Mechanistic Insights
The consistent results across sexes are particularly encouraging given the historical disparities in PAD outcomes. Experts suggest that the benefits of semaglutide in PAD may extend beyond simple glycemic control or weight loss. While weight reduction can reduce the mechanical load on the lower extremities, GLP-1 RAs are known to exert direct pleiotropic effects on the vasculature.
Biological Plausibility
Mechanistically, GLP-1 RAs have been shown to improve endothelial function, reduce systemic inflammation, and potentially enhance skeletal muscle microcirculation. In the context of PAD, these effects might mitigate the ischemia-reperfusion injury and oxidative stress that occur during walking. The fact that women responded as well as men—despite having different baseline risk profiles—suggests that the underlying pathways of vascular improvement targeted by semaglutide are universally applicable.
Clinical Implications
The finding that women were less likely to be on antiplatelet therapy at baseline, yet still derived significant benefit from semaglutide, underscores the need for more vigilant screening and comprehensive management of women with PAD. Clinicians should be encouraged that semaglutide offers a potent tool to improve limb-specific outcomes in a population that has traditionally faced poorer functional trajectories.
Study Limitations
As a post hoc analysis, these findings should be interpreted with the understanding that the trial was not primarily powered to detect sex-specific differences. Furthermore, the 25% female representation, while substantial, still reflects a male predominance. Future studies should aim for a 50/50 sex split to more definitively characterize sex-specific responses, particularly regarding safety and long-term major adverse limb events (MALE).
Conclusion: A Universal Step Forward
The post hoc analysis of the STRIDE trial confirms that semaglutide 1.0 mg is an effective therapy for improving walking capacity and quality of life in both women and men with T2D and early symptomatic PAD. While women present with different baseline characteristics and are currently subject to treatment disparities, their response to semaglutide is robust and comparable to men. This evidence supports the broad implementation of GLP-1 RAs in the management of PAD, ensuring that both sexes benefit from these therapeutic advances.
Funding and Registration
The STRIDE trial was funded by Novo Nordisk. ClinicalTrials.gov Identifier: NCT04560998.
References
1. Verma S, Catarig AM, Houlind K, et al. Sex Differences in Effectiveness of Semaglutide in Patients With Peripheral Artery Disease: The STRIDE Trial. J Am Coll Cardiol. 2025;86(20):1843-1857. doi:10.1016/j.jacc.2025.08.046.
2. Bonaca MP, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Peripheral Artery Disease. Circulation. 2024.
3. Hirsch AT, et al. ACC/AHA 2005 Practice Guidelines for the Management of Patients With Peripheral Arterial Disease. J Am Coll Cardiol. 2006.
