Risk of lower extremity complications with GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors in peripheral artery disease.
Hong. Alexander T AT; Lin. Forest F; Luu. Ivan Y IY; Shin. Laura L; Han. Sukgu M SM; Armstrong. David G DG; Tan. Tze-Woei TW
Key Findings
- GLP‑1RAs lowered major amputation risk by about 21% (HR 0.79) versus SGLT2 inhibitors.
- GLP‑1RAs reduced lower‑extremity revascularisation risk by about 18% (HR 0.82).
- All‑cause mortality was reduced by roughly 29% (HR 0.71) with GLP‑1RAs.
- Benefits held true in symptomatic PAD and in patients who had prior revascularisation.
- Semaglutide and tirzepatide showed the strongest protective effects.
Practical Outcomes
- For biohackers and self‑experimenters, adding a GLP‑1RA such as tirzepatide could be a strategic move to protect leg health and improve survival in the context of PAD and diabetes. Consider discussing with a clinician to assess eligibility, dosing (often weekly injections), and monitor for typical GLP‑1RA side effects. This evidence supports using tirzepatide not just for glucose control or weight loss, but also for vascular protection.
Summary
In people with peripheral artery disease (PAD) and type‑2 diabetes, drugs that activate the GLP‑1 receptor—especially semaglutide and tirzepatide—cut the risk of major leg amputations, need for leg re‑vascularisation, and overall death compared with other diabetes meds like SGLT2 inhibitors or DPP‑4 inhibitors.
Abstract
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. 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. 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. GLP-1RAs were associated with lower limb complication and mortality risks in PAD, supporting a potential vascular benefit that warrants prospective evaluation.
Study Information
pubmed
2025
2025-11-01T00:00:00.000Z
10.1016/j.diabres.2025.112982
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