Adjunctive therapies added to standard of care for diabetic foot ulcers: a systematic review and network meta-analysis with pairwise comparisons.

BACKGROUND

Diabetic foot ulcers (DFUs) remain one of the most disabling and costly complications of diabetes. Although standard of care (SOC) is the foundation of DFU management, many ulcers fail to heal adequately, prompting increasing use of adjunctive therapies. However, the comparative effectiveness of different adjunctive strategies remains uncertain.

OBJECTIVE

To evaluate and compare the efficacy and safety of adjunctive therapies added to SOC for patients with DFUs using systematic review, pairwise meta-analysis, and network meta-analysis.

METHODS

PubMed, Embase, CENTRAL, Web of Science, ClinicalTrials.gov, WHO ICTRP, and ChiCTR were searched from inception to February 18, 2026. Randomized controlled trials evaluating adjunctive therapies plus SOC for DFUs were included. Interventions were classified into eight clinically interpretable categories: oxygen-based therapies, device-based and physical wound therapies, growth factor and blood-derived therapies, placental and perinatal tissue-derived products, acellular matrix/skin substitute/scaffold products, cell-based and adipose-derived therapies, topical pharmacologic and bioactive agents, and nanotechnology-based, natural product, and bioactive dressing therapies. Outcomes included ulcer area reduction, complete healing, time to healing, adverse events, and amputation.

RESULTS

Eighty-four randomized controlled trials involving 7,232 participants were included. Compared with SOC alone, several adjunctive therapies improved healing-related outcomes. Device-based therapies, placental products, growth factor/blood-derived therapies, matrix/skin substitute products, and oxygen-based therapies were associated with greater ulcer area reduction. Oxygen-based therapies, matrix/skin substitute products, device-based therapies, placental products, topical pharmacologic/bioactive agents, and growth factor/blood-derived therapies increased the likelihood of complete healing. Cell-based/adipose-derived therapies, growth factor/blood-derived therapies, and matrix/skin substitute products shortened time to healing. Most adjunctive therapies did not increase adverse events, while placental products were associated with a lower risk of adverse events. Oxygen-based and growth factor/blood-derived therapies showed potential reductions in amputation risk, although the evidence was limited.

CONCLUSIONS

Adjunctive therapies added to SOC may improve healing outcomes in patients with DFUs, but their benefits vary across clinical endpoints. Oxygen-based therapies, device-based therapies, placental products, growth factor/blood-derived therapies, and matrix/skin substitute products showed the most consistent potential benefits. Nevertheless, heterogeneity, sparse networks, variable certainty of evidence, and limited direct comparisons preclude a definitive treatment hierarchy. High-quality randomized trials with standardized outcome definitions and adequate follow-up are needed to clarify the optimal use of adjunctive therapies in DFU management.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261385489.