Semaglutide in peripheral artery disease and diabetes by baseline disease severity and age: the STRIDE trial

Walking limitation and claudication are defining features of peripheral artery disease (PAD), and common in persons with type 2 diabetes (T2D). Despite this burden, effective therapies for PAD remain scarce. In T2D, assessment of PAD severity is challenging as the multifactorial nature of limb symptoms and the frequent presence of atypical presentations obscure associations with functional outcomes.1 The STRIDE trial demonstrated efficacy of semaglutide for improving functional capacity in people with Fontaine IIa PAD and T2D.2 Pharmaceutical therapies for claudication may however vary in efficacy across clinical markers of PAD severity.3 Clinical history of peripheral revascularization procedures (that structurally change vessels) or presence of polyvascular disease both indicate a more progressed PAD given their association with subsequent limb and vascular events.4,5 Impaired renal function may also act as a marker of PAD severity, reflecting well-established pathological effects on vascular biology associated with hypoalbuminaemia, chronic inflammation, and the pro-calcific state of chronic kidney disease,6 with trial data suggesting semaglutide efficacy may interact with baseline estimated glomerular filtration rates (eGFR).7 Finally, polypharmacy and pharmacokinetic changes in advanced age may modify medication efficacy, but these patient populations continue to be underrepresented in clinical trials.8 In this post hoc analysis from STRIDE, we investigated the consistency of semaglutide’s efficacy across these markers of PAD severity and age. The STRIDE trial was a randomized, double-blind, placebo-controlled trial (NCT04560998), comparing once-weekly sub-cutaneous semaglutide 1.0 mg to a matched placebo in adults with PAD and T2D with intermittent claudication.2 Primary and confirmatory secondary endpoints were ratio-to-baseline in maximum walking distance (MWD) and pain-free walking distance (PFWD), respectively, on a constant load treadmill (3.2 km/h, 12% inclination) at week 52. This post hoc analysis assessed MWD and PFWD across subgroups associated with PAD severity [eGFR (