Differential Effect of GLP-1 Receptor Agonists and SGLT2 Inhibitors on Lower Extremity Amputation Outcomes in Type 2 Diabetes: A Nationwide Retrospective Cohort Study

OBJECTIVE

To compare the risk of lower extremity amputations (LEA) between new users of glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus sodium-glucose cotransporter-2 inhibitors (SGLT2i).

RESEARCH DESIGN AND METHODS

This retrospective cohort study utilized TriNetX, a federated electronic health records network, including adults with type 2 diabetes who initiated GLP-1 RA or SGLT2i between May 2013 and March 2025. Propensity score matching (1:1) balanced demographics, comorbidities, medications, and laboratory values. Major amputation-free survival was evaluated using Kaplan-Meier curves, while risks of major and minor LEA, diabetic foot ulcers (DFUs), and mortality were estimated by hazard ratios (HRs) with 95% confidence intervals (CIs).

RESULTS

The matched cohorts included 180,740 GLP-1 RA and 180,740 SGLT2i recipients. At 3 years, the GLP-1 RA cohort was associated with greater major amputation-free survival (99.69% vs. 99.64%, p=0.001) compared to SGLT2i cohort. Additionally, GLP-1 RA cohort was associated with lower risk of major LEA (HR 0.77 [95% CI 0.66, 0.90]), minor LEA (HR 0.73 [95% CI 0.63, 0.84]), DFU (HR 0.92 [95% CI 0.87, 0.96]), and mortality (HR 0.66 [95% CI 0.63, 0.69]). Risk reduction for major LEA remained significant in individuals with peripheral artery disease (HR 0.68 [95% CI 0.56, 0.82]) and DFUs (HR 0.70 [95% CI 0.58, 0.84]) at enrollment.

CONCLUSIONS

GLP-1 RA treatment was associated with greater major amputation-free survival compared with SGLT2i in people with type 2 diabetes, particularly in high-risk subgroups. Prospective studies are needed to confirm findings and inform selection of glucose-lowering therapies for people at risk of diabetes-related amputations.