{
  "abstract": "Objective Diabetic foot ulcer (DFU) is a life-threatening complication associated with high amputation and mortality rates. While numerous topical therapies exist, their comparative efficacy and safety remain unclear. We aimed to compare the efficacy and safety of topical therapies for DFUs to identify optimal treatment strategies.Research design and methods We searched PubMed, Embase, and CENTRAL from inception to February 1, 2025, for randomized clinical trials (RCTs) evaluating topical therapies for DFUs. We excluded non-topical interventions to ensure clinically relevant comparisons. A Bayesian network meta-analysis was performed. The primary outcome was wound healing rate.Results We included 51 RCTs involving 6161 patients and 23 interventions. 12 topical therapies, including placenta-derived products, platelet-related products, ON101, epidermal growth factor, and tissue-engineered skin substitutes, significantly improved wound healing rates vs standard of care (SOC). Placenta-derived products showed the greatest efficacy (OR 7.85 (95% credible interval (CrI) 4.62 to 14.15)) and were the only intervention to significantly reduce adverse events vs SOC (0.25 (95% CrI 0.10 to 0.60)). No interventions differed significantly from SOC in time to wound healing, serious adverse events, or infections.Conclusions Placenta-derived products and other biological or advanced topical therapies may demonstrate greater efficacy than the SOC in facilitating the healing of DFUs. Nevertheless, the certainty of evidence for most comparisons remains in the low-to-moderate range. These findings suggest potential benefits in integrating these therapies into the management of DFUs. However, high-quality RCTs are necessary to verify long-term outcomes.",
  "authors": [
    {
      "affiliations": [
        "Department of Endocrinology & Metabolism, West China Hospital, Chengdu, Sichuan, China",
        "Innovation Research Center for Diabetic Foot, West China Hospital, Chengdu, Sichuan, China"
      ],
      "name": "Lihong Chen"
    },
    {
      "affiliations": [
        "Department of Medical Science, Microbio (Shanghai) Co., Ltd, Shanghai, China"
      ],
      "name": "Jui-Ching Chen"
    },
    {
      "affiliations": [
        "Department of Endocrinology & Metabolism, West China Hospital, Chengdu, Sichuan, China",
        "Innovation Research Center for Diabetic Foot, West China Hospital, Chengdu, Sichuan, China"
      ],
      "name": "Ting Lin"
    },
    {
      "affiliations": [
        "Department of Endocrinology & Metabolism, West China Hospital, Chengdu, Sichuan, China",
        "Innovation Research Center for Diabetic Foot, West China Hospital, Chengdu, Sichuan, China"
      ],
      "name": "Feiyan Shi"
    },
    {
      "affiliations": [
        "Department of Endocrinology & Metabolism, West China Hospital, Chengdu, Sichuan, China"
      ],
      "name": "Dawei Chen"
    },
    {
      "affiliations": [
        "Department of Endocrinology & Metabolism, West China Hospital, Chengdu, Sichuan, China"
      ],
      "name": "Chun Wang"
    },
    {
      "affiliations": [
        "Department of Endocrinology & Metabolism, West China Hospital, Chengdu, Sichuan, China"
      ],
      "name": "Yun Gao"
    },
    {
      "affiliations": [
        "Wound Care Unit, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia"
      ],
      "name": "Harikrishna K Ragavan Nair"
    },
    {
      "affiliations": [
        "Department of Endocrinology & Metabolism, West China Hospital, Chengdu, Sichuan, China",
        "Innovation Research Center for Diabetic Foot, West China Hospital, Chengdu, Sichuan, China"
      ],
      "name": "Xingwu Ran"
    }
  ],
  "full_text": "WHAT IS ALREADY KNOWN ON THIS TOPIC Diabetic foot ulcer (DFU) is a major cause of amputation and mortality worldwide.Numerous topical therapies exist, but evidence regarding their comparative efficacy is fragmented.Previous meta-analyses often compared non-mutually exclusive treatments, limiting their clinical guidance value.WHAT THIS STUDY ADDS In this Bayesian network meta-analysis of 51 randomized controlled clinical trials involving 6161 patients, 12 topical interventions significantly improved healing rates compared with the standard of care.Placenta-derived products demonstrated the highest probability of being the most effective treatment and were the only intervention to significantly reduce adverse events.Advanced therapies generally outperformed standard dressings in promoting wound closure.HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY Clinicians may consider prioritizing placenta-derived products and other biological agents over basic dressings for hard-to-heal DFUs.Future guidelines should distinguish between adjunctive therapies (like offloading) and topical wound treatments to provide clearer recommendations.Introduction Diabetic foot ulcer (DFU) is one of the most devastating chronic complications of diabetes, affecting ~6.3% of patients globally. 1 If improperly managed, DFUs can progress to infection, osteomyelitis, and amputation—with one amputation occurring every 20 s worldwide. Even after treatment, amputated patients face a 22% annual mortality rate and 50%–70% 5-year mortality rate, exceeding that of many common malignancies.2 3Standard of care (SOC) for DFU typically involves multidisciplinary management: systemic medical management (such as glycemic control), restoration of tissue flow, infection treatment, pressure offloading of the affected foot, and local wound care such as debridement and utility of wound dressings.4 The management of DFU remains a challenge for clinicians. Over the past two decades, many adjunctive therapies, such as negative pressure wound therapy, topical oxygen therapy, various gels, natural products, various growth factors, and energy therapies, have emerged to address the dysregulated healing cascade in DFUs.5 In recent years, newer technologies and medications involving alteration of wound physiology to facilitate healing are being developed.5 ON101 targeting regulation of macrophage balance of DFU demonstrated its superior efficacy, along with favorable cost-effectiveness.6 7 Processed microvascular tissue (PMVT) has been developed as a platform technology to modify the local microenvironment and improve wound healing.8 9However, the optimal approach for DFU is controversial. Given the increasing global burden of diabetes-related complications, establishing high-quality comparative evidence is essential for strategic clinical planning and improving patient outcomes.10 Furthermore, existing evidence is fragmented: prior meta-analyses either focus on single interventions or inappropriately compare non-mutually exclusive therapies. For example, off-loading is foundational to local wound care and should be used in conjunction with other interventions, not as a standalone comparator. Similar situations can be applied to therapies, such as oxygen therapy, that can be used in combination with other topical therapies. To include these treatments, such as offloading and hyperbaric oxygen therapy, in a network meta-analysis (NMA) is inappropriate and clinically inexplicable.11 12 It is essential to consider the ‘position’ of every intervention—that is, its role in the overall care pathway and its potential synergistic or substitutive relationship with other treatments. Only in this way can a high-quality meta-analysis be designed. Otherwise, a simplistic head-to-head comparison of ‘treatment A versus treatment B’ risks overlooking the complex, real-world decision-making scenarios that clinicians face.To address this gap, we conducted a Bayesian NMA to compare the efficacy and safety of topical therapies for DFUs. We excluded non-topical interventions and non-mutually exclusive therapies to ensure clinically relevant comparisons, with the goal of identifying optimal topical strategies and guiding future research.Methods Study design This systematic review and NMA followed the Cochrane Handbook for Systematic Reviews of Interventions (V.6.5, 2024) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for NMA. 13 14 The study protocol was registered in PROSPERO (CRD420250653780) on February 28, 2025.Literature search and study selection We systematically searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) to identify eligible RCTs related to the research question from inception to February 1, 2025. The search strategy is provided in online supplemental file 1. Reference lists of included studies and relevant reviews were handsearched to identify additional eligible articles. Inclusion criteria were RCTs that evaluated a topical intervention (eg, growth factors, biological grafts) and reported wound healing rate of DFU. Only studies that enrolled ulcers with Wagner grades 1–3 without involvement of bone and joints, or Texas University Diabetic Wound Classification System (TEXAS) grades 1A, 1C, 2A, 2C were eligible. Studies that did not report wound grading but excluded active infection, osteomyelitis, bone/joint involvement were also eligible. But studies that included lower leg ulcers, active infection, osteomyelitis were excluded. In addition, studies that used non-topical interventions such as negative pressure wound therapy, oxygen therapy, electrical, ultrasound, shock wave, light, and other physical therapies were also excluded. Animal studies, reviews, editorials, letters, and comments were also not considered. Language and publication date were not restricted. Three investigators (LC, TL, and FS) independently selected studies. Discrepancies in the selection of studies and data extraction were resolved by consensus or consultation with a fourth investigator (XR).SP110.1136/bmjdrc-2026-006026.supp1Supplementary dataData extraction Three researchers (LC, TL, and FS) independently screened and extracted data. The extracted study characteristics include: authors’ names, publication year, study setting (country), number of participants, participant age, gender, ulcer grading system and grade, and ulcer area. Intervention measures, intervention dosage, follow-up time points, and blinding methods were also extracted. We also extracted the outcome indicators: Proportion of completely healed patients (n, %), time to wound healing (HR), adverse events (n, %), serious adverse events (n, %), and wound infection rates (n, %).Definition of interventions Many studies used the name ‘standard of care’ in the control group. However, the definition of SOC varies significantly across different research institutions and time periods. In addition to systemic medical management, local wound debridement, and offloading treatments, some studies also used dressings for wound treatment as part of standard care. For the convenience of the study, the following definitions were applied: If a study clearly describes the use of normal saline, normal saline gauze, povidone-iodine gauze, or Vaseline gauze as control, it is defined as the SOC. For interventions that adopt the current best treatment, including various wound-healing dressings (eg, in the study by Cazzell et al,15 which used alginate, foam, hydrogel, and other dressing options), it is defined as advanced SOC (aSOC). In addition, although various names were used, such as normal saline gel, placebo gel, or control gel, they were all categorized as hydrogels in this study. For three-arm studies, if two interventions differ only in drug dosage, the dosage with better outcomes is selected for inclusion16 17; if the interventions are similar, they are combined and included18; if the three interventions are different, they are included separately.Definition of outcomes For the primary outcome (wound healing rate), complete wound closure was defined as 100% re-epithelialization, as reported by the original trial investigators. Considering the variability in follow-up durations across trials, which ranged from 4 to 24 weeks, we extracted data from the primary time point specified by the authors. In cases where multiple time points were reported, the 12-week data were given priority; otherwise, the time point closest to 12 weeks was selected.With respect to secondary outcomes, wound-related infection, adverse events, and serious adverse events were extracted as defined and reported by the primary investigators. Due to the historical and regional diversity of the included trials, these definitions were not further harmonized.Risk of bias assessment Two investigators independently assessed risk of bias using the Cochrane Risk of Bias Tool (ROB 1.0). The assessment included the following aspects: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and researchers (performance bias), blinding of data collectors and analysts (detection bias), completeness of study data (attrition bias), selective reporting of study results (reporting bias), and other sources of bias (other bias). Each domain was rated ‘low risk’, ‘moderate’, or ‘high risk’. Overall risk of studies with more than one item rated as high risk were considered high risk. Studies with no high-risk items and no more than three unclear risk items were considered low risk; all others were considered moderate risk. 19 Overall risk of bias was used in the CINeMA assessment to assess the quality of evidence.Statistical analysis Bayesian NMA was carried out using the R package gemtc (V.1.0.2). The primary outcome was defined as the wound healing rate. In terms of the secondary outcomes, an analysis was conducted on the time to wound healing, adverse events, serious adverse events, and wound-related infections. ORs were used as the effect measure for categorical endpoints, while HR was applied for survival data. The results were presented with 95% credible intervals (CrIs).For categorical outcomes, a binomial likelihood model with a logit link function was utilized. The Markov Chain Monte Carlo simulation was established with 4 independent chains, 20 000 iterations subsequent to an initial 5000 iterations, and a thinning interval of 1. For the survival outcome, the HRs were estimated by means of a binomial likelihood model with a complementary log-log (cloglog) link function. The model was configured with 4 chains, 100 000 iterations (following 10 000 burn-in iterations), and a thinning interval of 10 to ensure model convergence. Multi-arm trials were handled by taking into account the inherent correlation between treatment arms. For zero-event arms, the binomial likelihood approach allowed for their inclusion without arbitrary continuity corrections; trials with zero events in all arms were excluded.Model fit was assessed by means of the Deviance Information Criterion (DIC). Although the difference in DIC between the fixed and random-effects models for the primary outcome was negligible (195.89 vs 195.56), the random-effects model was preselected to conservatively address clinical heterogeneity. Convergence was verified via both trace plots and the Gelman-Rubin diagnostic (potential scale reduction factor<1.05). Network relationship diagrams were constructed to visualize the direct comparisons between interventions for the respective outcomes. Forest plots and league tables were utilized to present the estimates. Surface Under the Cumulative Ranking Curve (SUCRA) values were calculated to rank interventions.Global inconsistency was evaluated through a comparison of the DIC between the consistency and inconsistency models. Local inconsistency was investigated using the node-splitting method, with a p value threshold of less than 0.05 indicating significant inconsistency. The DIC values were determined to be comparable, indicating the lack of significant global inconsistency. Node-splitting analysis identified local inconsistencies in several specific comparisons. To address this issue, sensitivity analyses were performed. Transitivity was assumed to be valid due to the standardized DFU grading and intervention definitions, although potential confounders such as age, gender ratio, and wound size were recognized. A p<0.05 was considered statistically significant. Given the inherent variability in standard care protocols, two sensitivity analyses were carried out to test the robustness of the primary outcome (wound healing rate). The NMA model was re-run by collapsing the control nodes (SOC and aSOC) and then by restricting the network to trials using only basic SOC to determine whether the granularity of the control definition influenced the relative ranking.Certainty of evidence The CINeMA method was used to grade the certainty of evidence for wound healing rate (primary outcome), considering six aspects: within-study bias (risk of bias), between-study bias (publication bias or reporting bias), indirectness, imprecision, heterogeneity, and inconsistency. Like Grading of Recommendations Assessment, Development and Evaluation, 20 the CINeMA method classifies evidence quality into high, moderate, low, and very low.21Patient and public involvement Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of our research.Results A total of 2970 articles were initially identified through database searches and supplemented by reference lists. After removing duplicates, irrelevant studies, reviews, study protocols, phase I/II studies, and studies not meeting the inclusion/exclusion criteria, 51 articles were included in the meta-analysis ( figure 1). The 51 included studies involved 6161 patients and 23 different interventions. The baseline characteristics of the 51 studies are shown in online supplemental file 2. The 23 interventions are listed in online supplemental file 3.Figure 1Flow chart for study selection.The 51 included RCTs (1994–2024) spanned North America, Europe, and Asia, with sample sizes ranging from 30 to 348. The participants were predominantly male (more than 60%) and aged between 55 and 65. The majority of ulcers were of Wagner grades 1–2 (or equivalent Texas grades). At the baseline, the wound areas exhibited significant variability, predominantly clustered between 2 and 10 cm2. The duration of ulcers, as reported in 30 trials, ranged from 4 weeks to 1 year. The majority of studies (43 out of 51, 84.3%) excluded patients with significant ischemic ulcers, although the exclusion criteria varied (eg, ABI cutoffs ranging from less than 0.7 to less than 0.9, or the absence of palpable pulses). Two trials involved postrevascularized or mild ischemic ulcers that did not necessitate further surgical intervention. While most studies mentioned debridement and offloading in line with guidelines or investigator’s discretion, specific details regarding the intensity of debridement and adherence were generally lacking.Risk of bias assessment The risk of bias for the included studies is summarized in online supplemental file 4 and online supplemental file 5. 75% of studies did not clearly report the implementation of blinding or the method used. Blinding of outcome assessment was not used in fifty percent of studies. The outcome indicators such as wound healing rate and time to wound healing are objective measurements and are less likely to be affected by blinding. The overall risk of bias was: low (n=21, 41.2%), moderate (n=16, 31.4%), high (n=14, 27.5%).Wound healing rate Wound healing rate, defined as the proportion of patients with complete wound healing during follow-up, is one of the primary outcome indicators in DFU intervention studies. The network relationship diagram is shown in figure 2. The results of pairwise comparisons among various interventions are shown in online supplemental file 6A.Figure 2Network plot of wound healing rate. Treatments with direct comparisons are linked with a line; its thickness corresponds to the number of trials evaluating the comparison. aSOC, advanced standard of care; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; PDRN, polydeoxyribonucleotide; PMVT, processed microvascular tissue; TESS, tissue-engineered skin substitutes.12 (55%) of 22 interventions were associated with significant improvement in wound healing compared with SOC (figure 3, online supplemental file 6A). The 12 effective treatments included placenta-derived products, platelet-related products, whole blood clot, PMVT, ON101, epidermal growth factor (EGF), tissue-engineered skin substitutes (TESS), fish skin graft, honey products, polydeoxyribonucleotide (PDRN), platelet-derived growth factor (PDGF), and alginate. The ORs for interventions associated with significant improvement ranged between 7.85 (95% CrI 4.62 to 14.15) for placenta-derived products to 2.35 (95% CrI 1.28 to 4.35) for alginate dressing (figure 3).Figure 3Network meta-analysis results for the comparisons of treatments versus standard of care for wound healing. Effect sizes are listed on the basis of SUCRA (Surface Under the Cumulative Ranking curve) rankings. The evidence is graded using the CINeMA system (Confidence in Network Meta-Analysis). Colors indicate the confidence in the evidence: red=moderate, gray=low, blue=very low. aSOC, advanced standard of care; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; PDRN, polydeoxyribonucleotide; PMVT, processed microvascular tissue; TESS, tissue-engineered skin substitutes.Pairwise comparisons among the 12 effective interventions (figure 4, online supplemental file 6A) showed that placenta-derived products were found to be superior to tissue-engineered skin, honey products, PDRN, PDGF, and alginate, with statistically significant differences. No other pairwise comparisons were statistically significant.Figure 4League table for the 12 effective interventions for wound healing. Light blue indicates that the intervention in the column is superior to the intervention in the row. Effects are presented as OR (95% CrI). Blood clot, whole blood clot; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; PDRN, polydeoxyribonucleotide; Placental, placental-derived products; Platelet, platelet-related products; PMVT, processed microvascular tissue; TESS, tissue-engineered skin substitutes.Time to wound healing Nine studies reported time to wound healing (HR with 95% CIs). After excluding one study by Huang et al that could not be integrated into the network,7 eight studies were used to compare the time to wound healing among interventions. The network relationship diagram was shown in online supplemental file 7A. A total of seven treatments, including placenta-derived products, collagen, PDRN, aSOC, TESS, alginate dressing, and hydrogel, were compared with SOC. None of the treatments showed significant difference with SOC (online supplemental file 6B and online supplemental file 8A).Safety outcomes Adverse event Among the 51 included studies, 22 reported adverse events. We include studies that reported the number of participants who had adverse events, while the studies that only report the number of adverse events but rather the number of participants were excluded. The reported incidence of adverse events varied significantly across these studies, ranging from 5.7% to 64.8%. The network diagram for adverse events is shown in online supplemental file 7B. Placenta-derived products seemed to have fewer adverse events than SOC (OR 0.25, 95% CrI 0.1 to 0.6). Most ORs between the remaining treatments were small or very uncertain (online supplemental file 6C and online supplemental file 8B).Serious adverse event Among the 51 included studies, 16 reported serious adverse events. As in the analysis of adverse events, we calculated the number of participants who had serious adverse events. After excluding the studies that could not be integrated into the network, 22 23 14 studies were used to compare the serious adverse events among interventions. The incidence of serious adverse events also varied significantly, ranging from 2.1% to 39.3%. The network plot for serious adverse events was shown in online supplemental file 7C. None of the treatments showed significant difference for serious adverse events with SOC (online supplemental file 6D and online supplemental file 8C).Wound-related infection Wound-related infections are a significant concern in the treatment of DFU. Among the 51 included studies, 16 reported wound-related infections. The network plot for wound-related infections is shown in online supplemental file 7D. The results indicated no statistically significant difference in the risk of wound-related infections between the interventions and SOC (online supplemental file 6E and online supplemental file 8D).Certainty of evidence The CINeMA method was used to assess the quality of evidence for the primary outcome, namely wound healing. In this NMA, there were 23 interventions, including SOC, for wound healing and 253 pairwise comparisons. Among the 253 pairwise comparisons, 25 were rated as moderate (9.9%), 224 as low (88.5%), and 4 as very low (1.6%) ( online supplemental file 9). Notably, placenta-derived products showed superior efficacy compared with SOC with moderate certainty, while the evidence for most other advanced dressings was of low certainty due to imprecision and within-study bias.Sensitivity analysis Sensitivity analyses for the primary outcome were conducted to evaluate the potential impact of control group definitions on the robustness of our results. Among the included studies, 25 trials used the basic SOC and 6 trials used the aSOC. When these two categories were merged into a single SOC node, the superior efficacy and ranking of the 12 identified interventions remained unchanged ( online supplemental file 10A). Furthermore, we restricted the network by excluding the 6 aSOC trials. In this subnetwork analysis, whole blood clot and LeucoPatch were disconnected from the main network and the results for the remaining interventions remained stable (online supplemental file 10B). These findings indicate that the classification of control group did not introduce bias into the relative efficacy estimates of the topical therapies.The global inconsistency assessment showed a comparable DIC between the consistency (195.56) model and inconsistency (194.21) model, which suggests the absence of significant global inconsistency. However, node-splitting analysis identified local inconsistencies in specific comparisons, including those between Collagen and SOC, Collagen and TESS, and Placental-derived products and TESS (online supplemental file 11). After a comprehensive clinical review, these disparities may potentially be attributed to the extensive time frame of the included studies, during which the quality of standard care evolved, and the substantial clinical heterogeneity within the collagen-based intervention category. To address this issue, a sensitivity analysis was carried out by excluding studies involving collagen-related products. In this modified network, the primary ranking of treatments remained unchanged (online supplemental file 12).Discussion Principal findings This NMA of 51 RCTs ( online supplemental file 13) systematically compared topical therapies for DFUs while excluding non-mutually exclusive interventions. The central finding is that a diverse range of 12 interventions, including advanced wound care products and novel biological agents, are associated with a significant improvement in wound healing rates compared with SOC. The study also suggests a general similarity in safety profiles among the various topical therapies. These findings are crucial for a clinical field that has long grappled with the optimal therapeutic approach for DFU.Analysis of efficacy The NMA study identified 12 topical interventions (biological products, growth factors, advanced dressings) that offered a significant benefit over SOC for DFU wound healing. Placenta-derived products showed the greatest efficacy (OR, 7.85; CrI 4.62 to 14.15), followed by platelet-related products, whole blood clot, PMVT, ON101, EGF, and TESS. Placenta-derived products demonstrated statistically significant superiority in the pairwise comparisons. However, the vast majority of pairwise comparisons among the 12 effective treatments were not statistically significant. This finding is likely a direct consequence of the small number of available studies for many of the interventions, which results in wide CrIs and an inability to detect meaningful differences between therapies that are all demonstrably effective. Therefore, while the SUCRA ranking provides a probabilistic order of effectiveness, it is not an absolute measure of one therapy’s superiority over another. The clinical implication is that many of the top-performing interventions may offer a similar therapeutic benefit, and the final choice of treatment may depend on other factors such as cost, local availability, and the specific patient profile.The analysis of time to wound healing highlights the limitations of the current evidence base. Despite being clinically crucial outcomes, only a small number of studies reported time to wound healing, and no intervention demonstrated a significant difference from SOC. This lack of findings does not necessarily imply that the therapies are ineffective in these areas; rather, it underscores the need for standardized, comprehensive outcome reporting in future clinical trials. For patients and clinicians, a reduction in time to healing is often as important as the eventual wound closure, and the current evidence is insufficient to guide decision-making on these key metrics.Placenta-derived products emerged as the most effective intervention identified in this study. These products present a bioactive extracellular matrix scaffold abundant in growth factors and immunomodulatory cells, which synergistically promote neovascularization and epithelialization while alleviating inflammation. Such comprehensive regenerative properties enable optimal cell proliferation and tissue repair, thereby contributing to their remarkable clinical efficacy in wound healing.24 A previous meta-analysis of RCTs has likewise confirmed that human amniotic membranes offer a robust therapeutic approach for both DFUs and venous leg ulcers.25 Platelet-related products, especially platelet-rich plasma, have also demonstrated significant potential, consistent with their four-decade history of clinical use. By delivering a high concentration of growth factors, cytokines, and platelets, they stimulate angiogenesis and accelerate tissue regeneration.26 Recent evidence further validates their effectiveness in enhancing wound healing, reducing healing time, infection, and amputation risks.27 Closely following these biological grafts, ON101 represents a significant pharmacological advance by specifically targeting macrophage dysregulation-a hallmark of impaired DFU healing.7 28 Evidence from a multicenter phase III clinical trial7 and real-world study29 has demonstrated the superior efficacy of the macrophage regulator. Collectively, the high ranking of these targeted therapies suggests that future research should prioritize interventions that address the underlying pathophysiology of chronic wounds rather than solely focusing on traditional wound coverage.Analysis of safety The safety analysis in the NMA is a critical component of the overall assessment, yet it is significantly constrained by the limited and highly variable data reported in the included studies. Only 22 of the 51 studies reported adverse events, and a mere 16 reported serious adverse events and wound-related infections, with incidence rates varying widely across the literature. This scarcity of data makes it challenging to draw definitive conclusions about the safety profiles of most interventions.Against this backdrop of limited information, the finding that placenta-derived products are associated with a statistically significant reduction in adverse events compared with SOC is particularly noteworthy. This finding, when considered alongside its superior efficacy ranking, positions placenta-derived products as a potentially ideal therapeutic option. The combination of high efficacy and a demonstrable safety benefit, while based on a small number of studies, represents a compelling data point that warrants prioritization in future, well-powered clinical trials.Strengths and limitations The present NMA demonstrates several important methodological strengths. The study used rigorous inclusion/exclusion criteria, which explicitly defined DFU grades and filtered out non-comparable interventions, contributing to the high clinical relevance of the final network. Second, in this study, we addressed a fundamental flaw identified in previous meta-analyses of DFU treatments that included mutually exclusive interventions. By stringently excluding such adjunctive therapies as offloading, oxygen therapy, and physical therapies, this study establishes a more valid and clinically relevant network of comparisons. This deliberate methodological choice enhances the interpretability and applicability of the results for clinicians making real-world treatment decisions.Despite these strengths, several fundamental limitations temper the confidence in the overall findings. First, the included studies had a high risk of bias. Although objective measures like wound healing rate are less susceptible to this bias, the measurement of wound size reduction over time and the final determination of complete epithelialization can be subjective. Another significant limitation is the scarcity of data for many of the interventions, which directly contributes to the imprecision of the effect estimates. The fact that only a small number of studies were available for most interventions led to the wide CrIs and the lack of statistical significance in most pairwise comparisons. This data scarcity makes it impossible to definitively declare one therapy superior to another, despite the general ranking provided by the SUCRA analysis. Third, the inherent heterogeneity in the definition of ‘standard of care’ is a potential threat to the transitivity assumption, a core requirement of NMA. The SOC varies significantly across different research institutions and time periods. Although we have made definitions for SOC, the SOC comparator node in the network is not truly homogeneous. This may invalidate the indirect comparisons between interventions and introduce confounding factors that are not fully accounted for. Nevertheless, our sensitivity analyses aim to alleviate these concerns by demonstrating that the superiority of the identified interventions remained robust, regardless of whether they were compared with the basic or advanced SOC. This consistency provides additional assurance regarding the stability of our primary findings. Fourth, although our eligibility criteria (Wagner 1–3) guaranteed a certain degree of population homogeneity, potential bias could still arise from several factors. Specifically, the presence of ischemia in some of the included ulcers, the lack of standardized ischemia definitions across trials, and variations in both offloading adherence and baseline ulcer durations could result in residual confounding in our efficacy estimates. Fifth, the timing and definitions of outcomes were not comprehensively standardized across all the included trials. Although 12 weeks was the most frequently reported follow-up duration, our analysis pooled results ranging from 4 to 24 weeks, which were based on the primary endpoints reported by the original authors. Definitions of wound healing varied across studies. While some trials defined healing based on a single observation of complete closure, others followed the US Food and Drug Administration guidance for chronic wounds, which requires confirmation at two consecutive visits over 2 weeks. Similarly, definitions for secondary outcomes, such as ‘wound infection,’ ‘adverse events,’ and ‘serious adverse events’ were contingent on the clinical judgment and reporting standards of individual trial investigators. The inherent variability in these definitions and timing may give rise to clinical heterogeneity and affect the precision of our effect estimates.Beyond short-term healing outcomes discussed above, the clinical value of DFU therapies lies in their ability to prevent recurrence and amputation—outcomes recently emphasized in the Core Outcome Set for diabetes-related foot ulceration.30 The case of ON101 is illustrative in this context; besides achieving wound closure, it demonstrated a marked reduction in amputation rates (1.96% vs 10% in RCT data), a trend mirrored in real-world studies even for infected DFUs (3.2% vs 19.2%) or complex cases with both infection and ischemia (3.5% vs 22.7%).31 These converging lines of evidence illustrate how integrating RCT follow-up and real-world outcomes may enhance the translational interpretation of wound-healing studies. Conceptually, this approach aligns with the evolving evidence-continuum framework that bridges efficacy observed in controlled settings with effectiveness and prognostic impact in clinical practice.Clinical implications The findings from this NMA have direct and important clinical implications. The results provide high-level evidence that a select group of topical therapies are significantly more effective than SOC for achieving DFU wound closure. In the absence of a clear statistical winner among the top-performing interventions, the choice of therapy may be guided by a combination of factors, including the therapy’s specific OR, its cost-effectiveness, and its safety profile. The compelling data for placenta-derived products, demonstrating both high efficacy and a potential safety advantage, suggests it should be considered a front-line advanced therapy where available.The limitations of the current evidence base necessitate a detailed and actionable roadmap for future research. First, further large-scale, well-designed RCTs that directly compare the most promising interventions identified in this NMA are warranted. Second, future studies must implement and report standardized outcome measures for both efficacy and safety. This includes meticulously defining and reporting the incidence of complete wound closure, time to healing, recurrent ulceration, infection, amputation, health-related quality of life, and mortality.30 Standardized reporting will enable future meta-analyses to provide more robust and clinically relevant conclusions. Finally, the success of therapies that target biological mechanisms suggests interventions that address the underlying pathophysiology of chronic wounds may be a promising direction for the field.Conclusions This systematic review and NMA provides a comprehensive overview of the efficacy and safety of topical therapies for DFUs. The results suggest that several advanced therapies, such as placenta-derived products, platelet-related products, whole blood clot, PMVT, and ON101, might offer superior healing benefits in comparison to the SOC. However, it is critical to note that the certainty of evidence for the majority of comparisons is rated as low to moderate, primarily due to high risk of bias and data scarcity. The findings underscore a pressing need for a new generation of high-quality, well-powered, and meticulously designed clinical trials to definitively establish the optimal and most cost-effective treatment strategies for the management of DFUs.",
  "title": "Topical therapies for diabetic foot ulcers: a systematic review and network meta-analysis",
  "uid": "7f21c514-cbf8-5a8c-8b09-7e39fe26bd61"
}