Peripheral artery disease (PAD) and diabetes are associated with high risks of limb complications and mortality. Although glucagon-like peptide-1 receptor agonists (GLP1-RAs) improve cardiovascular outcomes, their effect on limb outcomes in PAD remains uncertain.

We conducted a retrospective cohort study using the Clalit Health Services database. Adults with PAD and diabetes were classified according to GLP1-RA dispensing exposure, and inverse probability of treatment weighting was used to balance measured baseline characteristics in the primary analysis. The primary outcome was major adverse limb events (MALE), defined as lower-limb revascularization or amputation. To address potential immortal time bias, all-cause mortality was additionally evaluated using an incident-treatment risk-set approach aligned to the qualifying GLP1-RA exposure date, while sustained GLP1-RA exposure was evaluated for MALE using a time-varying persistent-use model.

Among 20,031 patients, 5,960 met the original GLP1-RA exposure definition and 14,071 were classified as non-users. In the original IPTW-weighted analysis, GLP1-RA exposure was associated with lower risks of MALE, revascularization, major amputation, and all-cause mortality. In the time-aligned risk-set analysis, GLP1-RA exposure remained associated with lower all-cause mortality (HR 0.80, 95% CI 0.73–0.88; P < 0.001). In a time-varying analysis of sustained exposure, persistent GLP1-RA use was associated with a lower hazard of MALE (adjusted HR 0.65, 95% CI 0.44–0.94; P  = 0.022).

In patients with PAD and diabetes, GLP1-RA exposure was associated with favorable clinical outcomes. Time-aligned analyses demonstrated a lower risk of all-cause mortality, while sustained GLP1-RA exposure was associated with lower MALE risk. Given the observational design, these findings should be interpreted as associations rather than causal treatment effects.