Glucagon-like peptide-1 (GLP-1) receptor agonists — including semaglutide (Ozempic, Wegovy), liraglutide (Victoza), and dulaglutide (Trulicity) — are well established for glycaemic control, cardiovascular protection, and weight loss in type 2 diabetes. Now, a growing body of peer-reviewed evidence published between 2018 and 2026 suggests these agents may also meaningfully reduce diabetic foot ulcer (DFU) complications, amputation risk, and mortality.
Why the Diabetic Foot Remains a Critical Challenge
Diabetic foot ulcers affect an estimated 15–25% of people with type 2 diabetes across their lifetime and are the leading cause of non-traumatic lower-extremity amputation. Five-year mortality following a DFU rivals that of many cancers. Despite advances in wound care, ulcer recurrence remains high and healing is often protracted. Chronic hyperglycaemia, peripheral neuropathy, impaired immune function, and vascular insufficiency converge to disrupt every phase of normal wound repair — creating the biological context in which the broader effects of GLP-1 RAs may be particularly relevant.
Clinical Evidence: Amputation Risk and Wound Healing
A 2025 retrospective cohort study published in Diabetes Research and Clinical Practice examined patients with type 2 diabetes and peripheral artery disease (PAD). It found that GLP-1 receptor agonist therapy was associated with approximately a 20% lower risk of lower-extremity amputation, gangrene, and limb-threatening events compared with SGLT2 inhibitors and DPP-4 inhibitors. Among individual agents, semaglutide was specifically linked to a 24% reduction in major amputation risk.
A complementary analysis using the TriNetX US Research Network, published in 2025, assessed outcomes in 6,329 semaglutide users with diabetes-related foot ulcers against 118,821 non-users across 64 healthcare organizations. Semaglutide users demonstrated significantly lower relative risks for wound complications, chronic pain, and amputation — effects that appeared to be partly independent of glycaemic control, suggesting additional mechanisms at work.
Earlier evidence comes from the LEADER cardiovascular outcomes trial, which enrolled over 9,000 patients with type 2 diabetes. Analysis published in Diabetes Care (2018) showed that liraglutide was not associated with increased DFU events and was linked to significantly fewer DFU-related amputations compared with placebo — one of the first signals from a randomised trial that GLP-1 RAs could protect the lower limb.
Survival After Diabetic Foot Ulcers
Among the most striking recent findings is a nationwide observational study published in Diabetes Care in April 2026, which analysed 133,791 patients in France with an incident diabetic foot ulcer. After adjusting for age, comorbidities, and other confounders, GLP-1 receptor agonist use was independently associated with significantly lower one-year mortality. A consistent survival benefit was also observed among patients who subsequently underwent major lower-limb amputation. The authors concluded that GLP-1 RAs, alongside structured multidisciplinary follow-up, should be prioritised in patients who develop a first diabetic foot ulcer.
Mechanisms: How GLP-1 Receptor Agonists May Support Wound Repair
The biological rationale for these clinical findings is becoming clearer. A 2025 review in the Journal of Investigative Dermatology described GLP-1 RAs as emerging modulators of inflammation and angiogenesis in chronic cutaneous wound healing. Key mechanisms include:
- Anti-inflammatory activity: GLP-1 RAs suppress TNF-α and NF-κB signalling, reducing the excessive inflammation that stalls chronic diabetic wounds. Animal models show accelerated wound closure associated with lower interleukin-6 levels.
- Improved perfusion and angiogenesis: GLP-1R activation promotes endothelial progenitor cell mobilisation, VEGF upregulation, and capillary formation. Clinical studies of liraglutide in patients with PAD demonstrated measurable improvements in peripheral perfusion sustained at 18-month follow-up.
- Re-epithelialisation: GLP-1R activation stimulates epidermal stem cell proliferation via β-catenin signalling, promoting keratinocyte migration and accelerating wound surface coverage.
A 2025 systematic review in Wound Repair and Regeneration concluded that GLP-1 RAs hold genuine promise as adjunctive agents in DFU management. A review in Frontiers in Endocrinology (2025) also explored dual- and triple-target GLP-1-based agents — such as tirzepatide — as potentially offering broader benefit in the diabetic foot setting, though dedicated DFU outcome trials are still early.
Conclusion
GLP-1 receptor agonists do not replace offloading, debridement, infection management, or revascularisation in diabetic foot care. However, the consistency of their protective signal — across mortality, amputation risk, and wound outcomes — raises an important clinical question for the multidisciplinary foot team: in a patient with a DFU who is not already on a GLP-1 receptor agonist, is there a compelling case to consider one? Ongoing randomised trials will provide more definitive answers, but the existing data suggest this drug class deserves a prominent place in the broader management plan for diabetic foot disease.
References
- Lewis JE et al. The impact of semaglutide on wound healing in diabetes related foot ulcer patients: A TriNetX database study. Diabetes & Vascular Disease Research. 2025. doi:10.1177/14791641251322909
- Gruzmark T et al. Exploring the role of GLP-1 agents in managing diabetic foot ulcers: A narrative and systematic review. Wound Repair and Regeneration. 2025. doi:10.1111/wrr.70085
- Andersen NB et al. GLP-1 Receptor Agonists Are Associated With Reduced Mortality Following Diabetic Foot Ulcers: A Nationwide Observational Study. Diabetes Care. 2026;49(5):730.
- Risk of lower extremity complications with GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors in peripheral artery disease. Diabetes Research and Clinical Practice. 2025.
- Gerber PA et al. The impact of liraglutide on diabetes-related foot ulceration and associated complications: Results from the LEADER trial. Diabetes Care. 2018;41(9):2014–2020.
- GLP-1 Receptor Agonists as Emerging Modulators of Inflammation and Angiogenesis in Chronic Cutaneous Wound Healing. Journal of Investigative Dermatology. 2025.
- Potential application of mono-, dual-, and triple-target GLP-1 receptor agonists in improving the prognosis of patients with diabetic foot ulcers. Frontiers in Endocrinology. 2025. doi:10.3389/fendo.2025.1754925
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