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.