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

Jun 25, 2025Diabetes care

Different impacts of GLP-1 receptor drugs and SGLT2 inhibitors on leg amputation risk in type 2 diabetes

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Abstract

At 3 years, 99.69% of patients on glucagon-like peptide 1 receptor agonists (GLP-1RAs) remained free of major amputations compared to 99.64% of those on sodium-glucose cotransporter 2 inhibitors (SGLT2is).

GLP-1RA treatment is associated with a lower risk of major lower-extremity amputations (LEAs) compared to SGLT2is.
The hazard ratio for major LEAs in the GLP-1RA group is 0.77, indicating a 23% reduction in risk.
Minor LEAs also show reduced risk with GLP-1RAs, with a hazard ratio of 0.73.
Diabetic foot ulcers (DFUs) are less common in the GLP-1RA cohort, with a hazard ratio of 0.92.
Mortality risk is lower in patients treated with GLP-1RAs, with a hazard ratio of 0.66.
Risk reduction for major LEAs is significant in individuals with peripheral artery disease and those with DFUs.

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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.

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

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