Effect of semaglutide in patients with type 2 diabetes and peripheral artery disease: an analysis of the STRIDE trial stratified by disease severity and age

Abstract Introduction Peripheral artery disease (PAD) is a prevalent atherosclerotic condition in people with type 2 diabetes (T2D) which impairs perfusion in the lower limbs. Disease progression can lead to exercise-induced pain (intermittent claudication) and severe functional impairment. Disease severity at presentation, along with age, may inform prognosis for the affected limb, thereby guiding subsequent treatment strategies. Ankle-brachial index (ABI) is commonly used to screen for lower extremity PAD. In people with T2D, however, vessel incompressibility due to medial arterial calcification may result in a falsely normal or elevated ABI. The alternative toe-brachial index (TBI) is less susceptible to incompressibility artefacts from medial calcification in the digital arteries. Guidelines recommend TBI 0.7 as a diagnostic cutoff for PAD in patients with incompressible ABIs. The STRIDE trial demonstrated that semaglutide improved functional parameters, symptom status and haemodynamic measures in patients with PAD. Whether these benefits were consistent across measures of PAD severity and age is not known. Purpose To investigate whether the benefits of semaglutide in STRIDE were consistent by baseline PAD severity and age. Methods STRIDE enrolled 792 participants with PAD and T2D who were randomised to receive either once-weekly s.c. semaglutide 1.0 mg or placebo for 52 weeks. The primary and a confirmatory secondary endpoint were change in maximum walking distance (MWD) and pain-free walking distance (PFWD) on a constant load treadmill (fixed speed: 3.2 km/h and fixed inclination: 12%), respectively, at week 52. These endpoints were measured as ratio to baseline and presented as estimated treatment ratios, a ratio of the endpoints in semaglutide vs placebo groups. Analyses were stratified according to age (65 and ≥65 years) and median TBI status (0.52 and ≥0.52). A mixed model for repeated measures analysis, with an interaction term between the treatment and relevant subgroups adjusted for baseline of the endpoint, was performed. Results Participants had a mean (SD) age of 66.6 (9.4) years and a baseline geometric mean (CV) TBI, MWD and PFWD of 0.48 (0.4), 190.5 (0.6), and 116.2 (0.6), respectively. At Week 52, MWD ratio to baseline (geometric mean) in semaglutide vs placebo groups were 1.35 vs 1.14 in the 65-year group and 1.2 vs 1.08 in the ≥65-year group, respectively, and 1.24 vs 1.1 in the TBI 0.52 group and 1.3 vs 1.11 in the TBI ≥0.52 group. Similar trends were observed for PFWD. No significant interactions were observed with TBI or age groups for treatment effects on MWD and PFWD (Figure). Conclusions These analyses demonstrate a consistent benefit of semaglutide across different levels of lower limb perfusion deficit, as assessed by TBI recordings, in individuals with T2D and PAD. Additionally, the benefit of semaglutide persists across age groups, for functional outcomes, which are often negatively impacted by age.