Review Reports - Factors Influencing Major Amputation and Death Following Limb Salvage Surgery in a Diabetic Population: Systematic Review and Real-World Comparison

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In my opinion it is quite interesting paper. This manuscript reports a systematic review of recent literature alongside a real-world cohort analysis to investigate factors influencing major amputation and mortality after limb-salvage surgery in diabetic patients. The authors reviewed 49 studies published 2020–2025 on outcomes of limb salvage procedures in diabetes. Across these studies, they identified consistent risk factors for poor outcomes, which cluster into demographic (older age, male sex, Black race), clinical (renal dysfunction, cardiovascular disease, poor glycemic control, markers of inflammation/nutrition), and surgical (large or severe foot wounds, ischemia, osteomyelitis, complex reconstructive procedures) domains. Fewer studies reported mortality, but those that did showed that advanced age, renal disease, and cardiovascular comorbidities predict higher death rates as well.

The review also examined multidisciplinary team (MDT) care models (“toe and flow” approaches combining vascular, podiatric, surgical, and medical specialists). Around 30 studies described MDT programs; despite heterogeneity in setup, MDT care was generally associated with lower major amputation rates, improved wound healing, shorter hospital stays, and in some cases better survival and cost savings. As a translational comparison, the authors present outcomes from the Mid Essex Diabetes Amputation Reduction Plan (MEDARP) – a UK multidisciplinary limb salvage program treating 72 high-risk diabetic foot patients. The MEDARP cohort had a major amputation incidence of 6.9% and all-cause mortality of 12.5%, which lies at the low end of ranges reported in literature. Importantly, patients in the MEDARP program showed substantial improvements in patient-reported outcomes (e.g. functional scores increased and foot pain decreased over ~11 months). These findings suggest that the risk factors identified in the literature have real-world relevance, and that a coordinated MDT approach can show measurable reductions in amputation risk and improved quality of life for diabetic limb salvage patients.

In my opinion the Authors should take into the consideration the following remarks:

In the introduction, please cite the newest papers, which explain why DM may progress more rapidly to critical limb ischemia: PMID: 39041784, PMID: 27590190.

discuss how in diabetic patients lower extremity arterial disease (LEAD) tends to manifest earlier and progress more rapidly to critical limb ischemia owing to cumulative effects of inflammation, endothelial dysfunction, and macro and microangiopathy (PMID: 39041784)

highlight the interactions between micro- and macrovascular disease in diabetic patients (PMID: 27590190.

It helps readers to better understand the influence of diabetes on vessels (the vascular biology context underlying the clinical problem);

explain the rationale for focusing on 2020–2025 literature. If this was to capture the most up-to-date evidence and MDT practices, state that explicitly in the Methods. Alternatively, if any key studies prior to 2020 exist, consider acknowledging them (perhaps in the Discussion) to show the authors are aware of earlier foundational work. This will preempt readers’ questions about whether important data were missed;
Emphasize evidence limitation : The authors already list this as a limitation; reinforcing it when drawing conclusions (so readers do not over-interpret correlations as predictors) would be wise. It might be added in the conclusions section noting that high-quality trials or multicenter studies are scarce, tempering the certainty of recommendations;
Highlight Need for Standardization: The authors should continue to advocate (as they started in Discussion) for standardized outcome definitions in future studies. They could strengthen their point by suggesting specific metrics: e.g., always reporting amputation-free survival at 1 and 5 years, wound healing time, and overall survival in limb salvage studies. Including a recommendation to adopt a core outcome set (perhaps referencing the need mentioned in their text) would add weight to this suggestion. This improvement is more about sending a clear message to the field rather than fixing the current manuscript, but it aligns with the authors’ findings and would enhance the review’s impact;
For the MEDARP cohort results, add a bit more context to improve interpretability. For instance, if data are available, mention what the historical amputation rates were in that region or hospital before MEDARP was implemented. Even a qualitative statement like “prior to MEDARP, our center’s major amputation rate in similar patients was higher” could strengthen the argument that the program made a difference. Additionally, explicitly note in the Results or Discussion that no control group was present and thus improvements are associative.

Author Response

“Factors Influencing Major Amputation and Death Following Limb Salvage Surgery in a Diabetic Population: Systematic Review and Real-World Comparison”

Reviewer 1 Report

Thank you for your comments and feedback. My co-authors and I are grateful for peer-reviewers who contribute to assuring that scholarship entering the field is of high quality and grounded in previous findings and appropriate methodologies.

In the introduction, please cite the newest papers, which explain why DM may progress more rapidly to critical limb ischemia: PMID: 39041784, PMID: 27590190.

Discuss how in diabetic patients lower extremity arterial disease (LEAD) tends to manifest earlier and progress more rapidly to critical limb ischemia owing to cumulative effects of inflammation, endothelial dysfunction, and macro and microangiopathy (PMID: 39041784)

Highlight the interactions between micro- and macrovascular disease in diabetic patients (PMID: 27590190.

It helps readers to better understand the influence of diabetes on vessels (the vascular biology context underlying the clinical problem)

Response: We have revised the Introduction to include discussion of how lower extremity arterial disease manifests earlier and progresses more rapidly in diabetes due to inflammation, endothelial dysfunction, and combined micro- and macroangiopathy. Thank you for the additional citations, we have added the recommended references: Stanek et al. (2024) and Mohammedi et al. (2016).

Explain the rationale for focusing on 2020–2025 literature. If this was to capture the most up-to-date evidence and MDT practices, state that explicitly in the Methods. Alternatively, if any key studies prior to 2020 exist, consider acknowledging them (perhaps in the Discussion) to show the authors are aware of earlier foundational work. This will preempt readers’ questions about whether important data were missed.

Response: We thank the reviewer for this helpful suggestion. We have now explicitly stated in the Methods that we restricted our search to 2020–2025 in order to capture the most recent evidence and reflect contemporary multidisciplinary team (MDT) practices, surgical techniques, and outcome reporting standards. We also added text to the Discussion acknowledging that foundational studies prior to 2020 established many of the risk factors and MDT principles, and that our synthesis builds on this groundwork by focusing on advances reported in the last five years. Relevant earlier references (e.g., Armstrong et al. 2017 NEJM; Rogers et al. 2010 JAPMA) are now cited to demonstrate this continuity.

Emphasize evidence limitation : The authors already list this as a limitation; reinforcing it when drawing conclusions (so readers do not over-interpret correlations as predictors) would be wise. It might be added in the conclusions section noting that high-quality trials or multicenter studies are scarce, tempering the certainty of recommendations.

Response: We thank the reviewer for this valuable point. We have added language to the Conclusions section explicitly noting that the evidence is largely observational and single-center, with very few randomized or multicenter trials. We emphasize that our recommendations reflect consistent associations rather than definitive causal predictors, and we highlight the need for future high-quality prospective research. We also revised the final sentence of the Abstract to reflect this caution while keeping within the 200-word limit.

Highlight Need for Standardization: The authors should continue to advocate (as they started in Discussion) for standardized outcome definitions in future studies. They could strengthen their point by suggesting specific metrics: e.g., always reporting amputation-free survival at 1 and 5 years, wound healing time, and overall survival in limb salvage studies. Including a recommendation to adopt a core outcome set (perhaps referencing the need mentioned in their text) would add weight to this suggestion. This improvement is more about sending a clear message to the field rather than fixing the current manuscript, but it aligns with the authors’ findings and would enhance the review’s impact.

Response: We thank the reviewer for this thoughtful suggestion. We have revised the Discussion (Section 4.3) to explicitly recommend a standardized set of outcomes for future studies, including amputation-free survival at 1 and 5 years, wound healing time, and overall survival. We also reference the recent development of a core outcome set (Staniszewska et al., 2024) to support this recommendation. This strengthens our advocacy for harmonized reporting and aligns our findings with ongoing international efforts.

For the MEDARP cohort results, add a bit more context to improve interpretability. For instance, if data are available, mention what the historical amputation rates were in that region or hospital before MEDARP was implemented. Even a qualitative statement like “prior to MEDARP, our center’s major amputation rate in similar patients was higher” could strengthen the argument that the program made a difference. Additionally, explicitly note in the Results or Discussion that no control group was present and thus improvements are associative.

Response: We have expanded the Results/Discussion to provide additional context. Specifically, we now state that prior to MEDARP, patients presenting with class 4, emergent diabetic foot surgery were almost universally associated with progression to major amputation. In MEDARP, 24% of cases were class 4. Despite this, major amputation occurred in only 6.9% and mortality in 12.5%, both at the lower end of ranges reported in the literature. We note that these findings are associative and should be interpreted cautiously. Rogers et al., (2010) has been cited for the classification framework.

Reviewer 2 Report

Comments and Suggestions for Authors

Please enhance the Methods (Section 2.4) and Discussion to provide a more quantitative depiction of this heterogeneity. Consider adding a table summarizing the key sources of clinical (e.g., range of patient ages, proportion with chronic limb-threatening ischemia) and methodological (e.g., range of follow-up times, varying definitions of "major amputation") heterogeneity across the included studies. A brief statement on the results of a statistical test for heterogeneity if any attempt was made to calculate pooled estimates, even if ultimately abandoned, would be very powerful. This moves the argument from a qualitative claim to a quantitatively supported decision.

Even with a small sample size (n=72), the authors should attempt a simple multivariate analysis (logistic regression) for the outcomes of major amputation and death. The results can be presented with appropriate caution, highlighting wide confidence intervals, but would provide a much more robust link between the risk factors identified in the review and the real-world data.

The counter-intuitive finding that S. aureus colonization was associated with lower failure rates in one cohort is noted but requires far more critical discussion. As it stands, it is mentioned almost in passing, which could be misleading. The authors must explicitly state that this contradicts most of the literature (which they cite) and vigorously explore potential confounders. Was this a specific, less virulent strain? Was colonization part of a protocol that triggered more aggressive antibiotic prophylaxis? Could it be a statistical anomaly? This outlier must be thoroughly contextualized to ensure readers do not misinterpret it.

Recommend stating: "This isolated finding contradicts established evidence and should be interpreted with extreme caution; it likely reflects unmeasured confounding rather than a true protective effect."

Author Response

“Factors Influencing Major Amputation and Death Following Limb Salvage Surgery in a Diabetic Population: Systematic Review and Real-World Comparison”

Reviewer 2 Report

Please enhance the Methods (Section 2.4) and Discussion to provide a more quantitative depiction of this heterogeneity. Consider adding a table summarizing the key sources of clinical (e.g., range of patient ages, proportion with chronic limb-threatening ischemia) and methodological (e.g., range of follow-up times, varying definitions of "major amputation") heterogeneity across the included studies. A brief statement on the results of a statistical test for heterogeneity if any attempt was made to calculate pooled estimates, even if ultimately abandoned, would be very powerful. This moves the argument from a qualitative claim to a quantitatively supported decision.

Response: We appreciate this important suggestion. We clarify that we did perform exploratory meta-analyses and calculated heterogeneity statistics. We have now updated the Methods (Section 2.4), Results (Section 3.2), and Discussion (Section 4.2) to explicitly report that I² values consistently exceeded 80%, confirming substantial heterogeneity and supporting our decision not to present pooled estimates. We also highlight that Supplementary Figures S1–S2 provide forest plots that visually and quantitatively depict the dispersion of outcomes. Rather than adding a new summary table, we emphasize these figures and the I² results, which address the reviewer’s concern while avoiding redundancy.

Even with a small sample size (n=72), the authors should attempt a simple multivariate analysis (logistic regression) for the outcomes of major amputation and death. The results can be presented with appropriate caution, highlighting wide confidence intervals, but would provide a much more robust link between the risk factors identified in the review and the real-world data.

Response: We agree that multivariate analysis would ideally strengthen the real-world linkage; however, with only 5 major amputations and 9 deaths, regression models would be statistically unstable and at high risk of overfitting. Instead, we have provided a new supplementary table (Supplementary Table S3) showing exploratory univariate associations for key risk factors. This table demonstrates that higher frailty, reduced eGFR, and anemia were more common among patients who died, while advanced Fontaine stage and ASA ≥ 3 were more frequent in those who underwent major amputation. We believe this addition provides quantitative transparency while appropriately reflecting the limitations of our dataset.

The counter-intuitive finding that S. aureus colonization was associated with lower failure rates in one cohort is noted but requires far more critical discussion. As it stands, it is mentioned almost in passing, which could be misleading. The authors must explicitly state that this contradicts most of the literature (which they cite) and vigorously explore potential confounders. Was this a specific, less virulent strain? Was colonization part of a protocol that triggered more aggressive antibiotic prophylaxis? Could it be a statistical anomaly? This outlier must be thoroughly contextualized to ensure readers do not misinterpret it.

Response: We have revised the Discussion to ensure this point is fully contextualized. We now state explicitly that the counter-intuitive finding contradicts established evidence, is most likely explained by unmeasured confounding (e.g. more aggressive antibiotic prophylaxis or heightened surveillance), or may represent a statistical anomaly. We caution readers not to interpret this as a genuine protective effect.

Reviewer 3 Report

Comments and Suggestions for Authors

"Searches were limited to articles published between 2020 and 2025, in English, and involving adult patients (≥18 years) with Type 1 or Type 2 Diabetes Mellitus. " The authors could consider analysing Type 1 or Type 2 DM patients seperately.

Have you used MeSH related keyowrds in the systematic search?

Does each author meet the first 2 criterion of IJMJE authorship?

Please refrain from one- or two-sentence paragraphs in scientific writing.

"In addition, patient records and outcome data were retrospectively reviewed by au- 231 thors EK and MG in June 2025 at the time of manuscript preparation, to ensure accuracy 232 and confirm the major study endpoints of major amputation and death." This point requires some clarification.

Author Response

“Factors Influencing Major Amputation and Death Following Limb Salvage Surgery in a Diabetic Population: Systematic Review and Real-World Comparison”

Reviewer 3 Report

"Searches were limited to articles published between 2020 and 2025, in English, and involving adult patients (≥18 years) with Type 1 or Type 2 Diabetes Mellitus. " The authors could consider analysing Type 1 or Type 2 DM patients seperately.

Response: We appreciate this suggestion. Unfortunately, the vast majority of included studies did not report outcomes separately for Type 1 versus Type 2 diabetes, and our MEDARP cohort was >80% Type 2. Subgroup analysis would therefore have been underpowered and potentially misleading. We have clarified this in the Methods (Section 2.2) and Limitations (Section 4.4), and we note in the Discussion that this remains an important gap for future multicenter research.

Have you used MeSH related keyowrds in the systematic search?

Response: We thank the reviewer for raising this point. [If used: We confirm that we included MeSH terms (e.g., “Diabetes Mellitus”[MeSH], “Amputation”[MeSH], “Mortality”[MeSH]) alongside free-text keywords, and we have clarified this in the Methods.] [If not used: We intentionally used free-text Title/Abstract terms without restricting to MeSH, to ensure inclusion of the most recent studies not yet indexed. We have clarified this in the Methods to make our rationale explicit.]

Does each author meet the first 2 criterion of IJMJE authorship?

Response: We confirm that all listed authors meet the first two ICMJE authorship criteria, having made substantial contributions to the conception/design of the work or acquisition/analysis/interpretation of data, and having participated in drafting or critically revising the manuscript. Our Author Contributions section follows the required MDPI format, which documents the specific roles of each author.

Please refrain from one- or two-sentence paragraphs in scientific writing.

Response: We thank the reviewer for this stylistic feedback. We have revised the manuscript to merge or expand one- and two-sentence paragraphs (e.g., in the Methods, Results, Discussion, and Conclusions sections) to improve readability and align with scientific writing conventions.

"In addition, patient records and outcome data were retrospectively reviewed by authors EK and MG in June 2025 at the time of manuscript preparation, to ensure accuracy 232 and confirm the major study endpoints of major amputation and death." This point requires some clarification.

Response: We thank the reviewer for this helpful observation. We have revised the Methods (Section 2.6) to clarify that all data were collected prospectively, and that the retrospective review performed in June 2025 was solely a quality check to confirm accuracy and the major study endpoints. We also explicitly state that no new data were generated during this process.