GLP ‐1 Receptor Agonist Therapy Is Associated With Lower Risk of Lower Extremity Amputation in Adults With Type 2 Diabetes and Foot Ulcer Without Coded Peripheral Arterial Disease: A Hypothesis‐Generating Real‐World Cohort Study

Aims To compare lower extremity amputation (LEA) risk in adults with Type 2 diabetes and diabetic foot ulcer (DFU) treated with glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) versus other glucose‐lowering therapy, and to test whether coded peripheral arterial disease (PAD) modifies this association and replicates across comparator classes. Materials and Methods This new‐user, active‐comparator retrospective cohort study used the TriNetX Global Collaborative Network (queried 11 July 2026). Adults with Type 2 diabetes and DFU were propensity‐score matched 1:1 on 22 covariates, giving 21 325 pairs for the primary comparison. Effect modification by coded PAD (ICD‐10 I70.2) was examined in independently matched subgroups. Six sensitivity analyses were pre‐specified: 30‐ and 180‐day landmarks, all‐cause mortality, background‐therapy balancing, limb‐severity adjustment and a broadened PAD definition. Results GLP‐1 RA use was associated with lower 5‐year LEA risk than all non‐GLP‐1 RA therapy (hazard ratio [HR]: 0.60, 95% CI: 0.54–0.67). The association was confined to the no‐PAD stratum (HR: 0.21, 0.13–0.33) and absent where PAD was coded (HR: 0.97, 0.78–1.20); ratio of hazard ratios 0.21 (0.13–0.36; p < 0.001). All‐cause mortality was also lower (HR: 0.48, 0.45–0.50). The insulin no‐PAD estimate persisted under background‐therapy balancing (0.14), limb‐severity adjustment (0.16) and 30‐ and 180‐day landmarks (0.28, 0.33). Broadening the PAD definition attenuated the no‐PAD association without abolishing it (HR: 0.34, 0.17–0.65). Conclusions In Type 2 diabetes with DFU, GLP‐1 RA use was associated with lower LEA risk, surviving six pre‐specified sensitivity analyses. These observational findings are hypothesis‐generating and require prospective confirmation.