Risk of lower extremity complications with GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors in peripheral artery disease.

Nov 2, 2025Diabetes research and clinical practice

Impact of Diabetes Medications on Leg Complications in Peripheral Artery Disease

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Abstract

GLP-1 receptor agonists (GLP-1RAs) were associated with a 79% reduced risk of major amputation compared to sodium-glucose cotransporter-2 inhibitors (SGLT2i).

GLP-1RAs showed a 18% lower risk of lower extremity revascularization compared to SGLT2i.
All-cause mortality was 29% lower in patients using GLP-1RAs compared to those on SGLT2i.
Similar reductions in risks were observed for GLP-1RAs compared to dipeptidyl peptidase-4 inhibitors (DPP-4i).
SGLT2is and DPP-4is presented comparable risks for major amputation and mortality.
Benefits of GLP-1RAs were consistent in patients with symptomatic peripheral artery disease (PAD).
Semaglutide and tirzepatide were associated with the greatest benefits among GLP-1RAs.

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AIMS: To compare the association of glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), and dipeptidyl peptidase-4 inhibitors (DPP-4i) therapies on lower extremity vascular complications and mortality in PAD.

METHODS: We conducted a retrospective cohort study using a nationwide U.S. electronic health records database. Adults with PAD and type 2 diabetes who initiated GLP-1RA, SGLT2i, or DPP4i therapy (May 2013-January 2025) were included. Propensity score matching (1:1) balanced baseline characteristics. Cox models estimated hazard ratios (HR) with 95 % confidence intervals (CI) for major amputation (primary outcome), lower extremity revascularization (LER), and all-cause mortality over 3 years follow-up. Subgroup analyses included symptomatic PAD, prior LER, and drug-level comparisons.

RESULTS: GLP-1RAs were associated with lower risks of major amputation (HR 0.79 [95 % CI 0.70-0.90]), LER (HR 0.82 [0.76-0.88]), and mortality (HR 0.71 [0.68-0.73]) compared with SGLT2i (n = 77,393 each). Similar reductions were seen versus DPP-4is (n = 39,907 each); SGLT2is and DPP-4is showed comparable risks (n = 42,924 each). GLP-1RA benefits remained significant in symptomatic PAD (p < 0.05) and were associated with lower mortality in LER patients (p < 0.05). Semaglutide and tirzepatide showed the greatest benefit.

CONCLUSION: GLP-1RAs were associated with lower limb complication and mortality risks in PAD, supporting a potential vascular benefit that warrants prospective evaluation.

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Risk of lower extremity complications with GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors in peripheral artery disease.

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