Comparison of the efficacy and safety of different growth factors in the treatment of diabetic foot ulcers: an updated network meta-analysis

Abstract

Objective: This study aimed to evaluate the efficacy and safety of different growth factors (GFs) in the treatment of diabetic foot ulcers (DFUs) through a network meta-analysis.

Methods: A systematic search was conducted in PubMed, Embase, The Cochrane Library, and Web of Science to identify randomized controlled trials (RCTs) comparing GFs with standard of care (SOC) or comparing different GFs for the treatment of DFU. Two independent reviewers screened the studies, extracted data, and assessed the quality of the included literature according to predefined inclusion and exclusion criteria. A network meta-analysis was performed using R software. Relative risk (RR) was used as the effect measure for dichotomous outcomes, and mean difference (MD) was used for continuous outcomes.

Results: A total of 51 RCTs, involving 3,401 patients with DFUs and six different types of GFs, were included. The network meta-analysis revealed that, compared with SOC, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and platelet-rich plasma (PRP) significantly improved the healing rate. EGF and PRP also significantly reduced healing time, while PDGF significantly reduced ulcer area. Moreover, PRP was associated with a significant reduction in the incidence of adverse events (AEs) and amputation rates. In terms of ranking: For healing rate, the top three GFs were EGF, vascular endothelial growth factor (VEGF), and granulocyte colony-stimulating factor (G-CSF). For healing time, EGF, PRP, and fibroblast growth factor (FGF) ranked the highest. For ulcer area reduction, PDGF, EGF, and PRP were the top-ranking interventions. Regarding AEs, PRP, PDGF, and FGF showed the most favorable safety profiles. For amputation rate, PRP, G-CSF, and PDGF were ranked the highest.

Conclusion: Almost all GFs outperformed SOC in terms of healing rate, healing time, and ulcer area reduction. Compared to SOC, EGF, PDGF, and PRP significantly improved healing rates; EGF and PRP significantly reduced healing time; and PDGF significantly decreased ulcer area. Among them, EGF may be the most effective GF. Except for VEGF, which significantly increased AEs, other GFs did not show a significant increase in AEs compared to SOC. PRP had the lowest amputation rate and incidence of AEs.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420251035765.

Keywords: diabetic foot ulcer; growth factors; network meta-analysis; randomized controlled trial; standard of care.

Figure 1

Literature screening process and results.

Figure 2

Network evidence plots for (A) healing rate, (B) healing time, (C) ulcer area reduction, (D) incidence of adverse events, and (E) amputation rate. PRP, platelet-rich plasma; SOC, standard of care; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; G-CSF, granulocyte colony-stimulating factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor.

Figure 3

League table of pairwise comparisons for healing rates among different treatment interventions. Each cell presents the relative risk (RR) and 95% confidence interval (CI) for the treatment listed in the column compared with the treatment listed in the row. If the RR is greater than 1 and the difference is statistically significant, the treatment in the column is superior to the treatment in the row. Statistically significant results (p < 0.05) are highlighted in bold red font. PRP, platelet-rich plasma; SOC, standard of care; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; G-CSF, granulocyte colony-stimulating factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor.

Figure 4

Cumulative ranking curves (SUCRA plots) for (A) healing rate, (B) healing time, (C) ulcer area reduction, (D) incidence of adverse events, and (E) amputation rate. The surface under the cumulative ranking curve (SUCRA) indicates the relative ranking probability of each treatment, with higher SUCRA values representing better performance for positive outcomes and lower risk for negative outcomes. PRP, platelet-rich plasma; SOC, standard of care; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; G-CSF, granulocyte colony-stimulating factor; EGF, epidermal growth factor; VEGF, vascular endothelial growth factor.