Benefit of Semaglutide in Symptomatic Peripheral Artery Disease by Baseline Type 2 Diabetes Characteristics; Insights from STRIDE, a Randomized, Placebo-controlled, Double-blind Trial

Objective The STRIDE trial (NCT04560998) showed that once-weekly subcutaneous semaglutide 1.0 mg significantly improved functional outcomes, symptoms, and quality of life in individuals with symptomatic peripheral artery disease (PAD) and type 2 diabetes. Whether these benefits are consistent across diabetes-related characteristics remains unclear. Research Design and Methods The primary outcome was the ratio to baseline (ETR) in maximum walking distance (MWD), with pain-free walking distance (PFWD) as a key secondary endpoint. Both were measured at 52 weeks using a constant load treadmill. Subgroup analyses were performed by diabetes duration, BMI, HbA1c, and diabetes medications. A mixed model for repeated measurements was employed, incorporating treatment, region, and subgroup as fixed factors, baseline value as covariate along with the treatment-by-subgroup interaction. Results Among 792 participants (median diabetes duration 12.2 years, HbA1c 7.1%, and BMI 28.7 kg/m²), 35.1% used SGLT2 inhibitors and 31.7% used insulin. Semaglutide significantly improved MWD regardless of diabetes duration (ETR of 1.15 vs. 1.13 for <10 vs. ≥10 years, p=0.80), BMI (1.12 vs. 1.16 for <30 vs. ≥30 kg/m², p=0.58), HbA1c (1.13 for <7% and ≥7%, p=0.99), or medication use. Semaglutide also improved PFWD across subgroups (p>0.1 for all interactions). BMI reduction correlated weakly with MWD improvements, more pronounced in the controls with higher baseline BMI. Safety outcome were consistent across subgroups. Conclusions Semaglutide improved walking function in people with PAD and type 2 diabetes, including non-obese individuals and those with well-controlled HbA1c. Benefits were consistent across BMI and HbA1c categories, supporting effectiveness beyond weight or glycemic changes.