Comparative Certainty of Evidence for Diabetic Foot Ulcer Therapies: A Narrative Synthesis

Background: Diabetic foot ulcers (DFUs) are a major cause of morbidity and lower extremity amputation. Numerous advanced wound therapies with various mechanisms of action have been developed to improve healing outcomes; however, the comparative certainty of evidence supporting these interventions remains unclear. This study evaluates randomized controlled trials (RCTs) of DFU therapies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Methods: A narrative synthesis of RCTs published between January 2016-January 2026 evaluating therapies for DFUs was performed. For studies that reported 12–week healing outcomes, risk of bias was assessed using the Cochrane Risk of Bias 2 tool and certainty of evidence for each therapy subgroup was evaluated using the GRADE framework. Results: A total of 143 RCTs were included with 45 RCTs undergoing GRADE assessment. The proportion of studies demonstrating statistically significant improvements in 12-week healing rates relative to controls varied and was not reflected in the GRADE assessment. Moderate-certainty evidence was assigned to the hyperbaric oxygen therapy subgroup. Low-certainty evidence was assigned to silver dressings, biosynthetic scaffolds, stem cell therapy, and negative pressure wound therapy. Very low-certainty evidence was assigned to topical oxygen, synthetic structural scaffolds, moisture-retaining dressings, local antimicrobial delivery, placental-derived skin substitutes, platelet-rich plasma, acellular dermal matrices, allografts/xenografts, and off-loading devices. No therapy subgroup was assigned high-certainty evidence. Conclusions: The certainty of evidence supporting DFU therapies varies substantially across intervention categories. These findings highlight the need for larger, methodologically rigorous comparative trials to clarify the effectiveness of DFU therapies and guide evidence-based wound care.