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

Abstract

Objective: To compare the risk of lower-extremity amputations (LEAs) between new users of glucagon-like peptide 1 receptor agonists (GLP-1RAs) versus sodium-glucose cotransporter 2 inhibitors (SGLT2is).

Research design and methods: This retrospective cohort study used TriNetX, a federated electronic health records network, including adults with type 2 diabetes who initiated GLP-1RAs or SGLT2is between May 2013 and March 2025. Propensity score matching (1:1) was used to balance demographics, comorbidities, medications, and laboratory values. Major (above-ankle) amputation-free survival was evaluated using Kaplan-Meier curves, while risks of major and minor LEAs, diabetic foot ulcers (DFUs), and mortality were estimated using hazard ratios (HRs) with 95% CIs.

Results: The matched cohorts included 180,740 GLP-1RA and 180,740 SGLT2i recipients. At 3 years, the GLP-1RA cohort was associated with greater major amputation-free survival (99.69% vs. 99.64%, P = 0.001) compared with the SGLT2i cohort. Additionally, GLP-1RA treatment was associated with a lower risk of major LEAs (HR 0.77 [95% CI 0.66, 0.90]), minor LEAs (HR 0.73 [95% CI 0.63, 0.84]), DFUs (HR 0.92 [95% CI 0.87, 0.96]), and mortality (HR 0.66 [95% CI 0.63, 0.69]). Risk reduction for major LEAs 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]).

Conclusions: GLP-1RA 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 for diabetes-related amputations.

Graphical abstract

Figure 1

Study cohort flow diagram.

Figure 2

Major amputation–free survival at 3 years. A: Kaplan-Meier survival analysis of major amputation–free survival among patients receiving GLP-1RA vs. SGLT2is in a 3-year follow-up. B and C: Separate analyses were conducted for patients with prior PAD or DFU.

Figure 3

Forest plot of major amputation and mortality at 3 years. Patients were followed up for as long as 3 years after the index event for both groups. HRs with 95% CIs were calculated using a Cox proportional hazards model with censoring applied. For each outcome, the groups were propensity score matched for covariates related to the outcome, and the outcome was compared between the matched groups. Each eligible individual was followed up from the index event until the occurrence of the outcomes, death, loss to follow-up, or 3 years after the index event, whichever occurred first.