Efficacy and safety of external phytotherapy in diabetic foot ulcers: a GRADE-assessed systematic review and meta-analysis of randomized controlled trials

Abstract Background Diabetic Foot Ulcers (DFUs) represent a global healthcare challenge, imposing substantial socioeconomic burdens due to their increasing incidence and associated mortality. This study evaluates the efficacy and safety of external phytotherapy (utilizing various plant-derived compounds, including Chinese herbal medicines and plant-derived liposomes, administered topically) for the treatment of DFUs. Methods Relevant studies were identified from major electronic databases (PUBMED, EMBASE, WOS, and the Cochrane Library) that were searched up to April 30, 2024. Randomized controlled trials (RCTs) that evaluated the effects of external phytotherapy for DFUs. The treatment group was treated with external phytotherapy plus conventional treatment, while the control group received conventional treatment alone. Two evaluators independently screened and selected literature, extracted data, and assessed the risk of bias. The outcome measures included complete ulcer healing, ulcer improvement, ulcer area reduction, and healing time. Weighted mean difference (WMD), standardized mean difference (SMD), and relative risk (RR) with 95% confidence intervals (CI) were used for data analysis. Heterogeneity was quantified using I² statistics, with appropriate application of fixed-effects or random-effects models. Methodological quality was ensured through Review Manager and Stata software, complemented by GRADE evidence assessment. Results Twenty studies with a total of 1,854 participants were identified. Our analysis suggested that compared with conventional treatment, external phytotherapy significantly enhances complete ulcer healing (RR: 1.84; 95% CI: 1.55 to 2.19), promotes ulcer improvement (RR: 1.32; 95% CI: 1.11 to 1.57), reduces ulcer area (WMD: -1.14; 95% CI: -1.45 to -0.83), and accelerates healing time (WMD: -3.93; 95% CI: -7.48 to -0.39). Safety profiles and ulcer depth measurements showed no significant intergroup differences. GRADE assessments indicated high-certainty evidence for most primary outcomes, whereas the evidence for percentage ulcer reduction was of low certainty due to serious inconsistency and imprecision. Conclusion External phytotherapy demonstrates potential as an adjunctive treatment for diabetic foot ulcers, improving primary outcomes like complete healing with moderate to high certainty of evidence. Nevertheless, regional bias—with most evidence derived from East Asia—warrants caution in generalizing these results. Further rigorous, multi-regional trials are needed to solidify the evidence base and refine clinical application.