The efficacy of DPP IV inhibitors as adjunct therapy for patients with auto-immune Diabetes: A systematic review and meta-analysis

Laurette Nakhoul; Tracy Nakhoul; Maria Abi Azar; Frederic Harb; Nancy Fawzi Nakhoul

doi:10.1371/journal.pone.0332191

Peer Review History

Original SubmissionMay 7, 2025
12 Jun 2025 Decision Letter - Toshiki Maeda, Editor PONE-D-25-24150The efficacy of DPP IV inhibitors as adjunct therapy for patients with auto-immune Diabetes: A Systematic review and Meta-analysisPLOS ONE Dear Dr. Nakhoul, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Jul 27 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Dear Authors, I am pleased to have the opportunity to review your manuscript. Your systematic review and meta-analysis address an interesting and highly debated clinical question regarding the efficacy and safety of DPP-4 inhibitors as an adjunct therapy for patients with type 1 diabetes mellitus (T1DM). Your methodology largely follows standard practices, and your comprehensive search strategy and quality assessment using the Cochrane Risk of Bias Tool 2.0 are commendable. However, there seem to be several significant problems with your study. 1. In many countries, DPP-4 inhibitors are not approved for use in patients with T1DM. In this context, studies involving the administration of these drugs to patients with T1DM may represent a specialized target population, and their validity should be substantiated. It is also important to acknowledge that the use of DPP-4 inhibitors in T1DM patients is often off-label and not covered by current guidelines or reimbursement policies in many countries. The included RCTs may have been conducted in specific research settings or may have involved a limited patient population (e.g., patients with early T1DM and preserved beta-cell function or purely exploratory studies conducted before regulatory approvals). More detailed information and discussion are needed regarding the background of these RCTs. This would clarify the extent to which your findings apply to routine clinical practice and highlight the limitations of generalizability. 2. Although the limitations section mentions the study duration, it is unclear how long-term administration would affect pancreatic beta-cell survival. Therefore, stating that this therapy is "to preserve residual beta-cell function" may not be entirely accurate. Either provide justification to explain this clearly to the reader, or consider modifying the wording in your response. Several times in your discussion and conclusion, you state that an increase in C-peptide levels suggests "the possibility of preserving or improving residual β-cell function." Ultimately, you conclude that DPP-4 inhibitors are "a safe and effective adjunct therapy to preserve residual β-cell function." While an increase in C-peptide may indicate an improvement in beta-cell insulin secretory response, it cannot be confirmed whether this directly translates to "survival" or "preservation" without much longer-term follow-up studies. This wording might mislead readers. I recommend using more cautious language. Alternatively, if you believe "preservation" is justified, please provide a more detailed discussion of the underlying physiological mechanisms or existing evidence from longer-term studies that support this claim.³ 3. Although a significant reduction in the total daily insulin dose (MD = -2.5 units/day) is reported, the clinical significance of this reduction in the daily lives of patients with type 1 diabetes mellitus (T1DM) should be discussed more specifically. For example, does this translate to fewer injections, reduced risk of weight gain, or reduced risk of hypoglycemia? Discussing the implications for patients' quality of life or management burden would enhance the clinical relevance of this finding. Reviewer #2: Definition and Justification of Risk and Treatment Burden Please provide a clearer explanation of how the “10-year cardiovascular risk” is calculated, including whether any model calibration was performed for individual countries. Define how "treatment burden" is operationalized—does it include polypharmacy, cost, frequency of monitoring, etc.? Statistical Transparency Clarify if complex survey designs (e.g., stratification, clustering) were adjusted for in the confidence intervals. Provide more details on how survey weights were applied. If multivariable modeling was considered and ruled out, please explain why. Overgeneralization of Conclusions The current wording implies causal conclusions in some sections. Please revise to maintain descriptive tone. Statements such as “policy should prioritize targeting high-risk individuals” are reasonable but should be supported with more robust discussion of feasibility, health system capacity, and heterogeneity between LMICs. Country Comparisons Consider stratifying countries by World Bank income classification or region for comparative clarity. Adding a figure to visualize between-country differences in risk or burden would improve accessibility. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0332191.r001
Revision 1
27 Jul 2025 Author Response Reviewer #1: Dear Authors, I am pleased to have the opportunity to review your manuscript. Your systematic review and meta-analysis address an interesting and highly debated clinical question regarding the efficacy and safety of DPP-4 inhibitors as an adjunct therapy for patients with type 1 diabetes mellitus (T1DM). Your methodology largely follows standard practices, and your comprehensive search strategy and quality assessment using the Cochrane Risk of Bias Tool 2.0 are commendable. However, there seem to be several significant problems with your study. 1. In many countries, DPP-4 inhibitors are not approved for use in patients with T1DM. In this context, studies involving the administration of these drugs to patients with T1DM may represent a specialized target population, and their validity should be substantiated. It is also important to acknowledge that the use of DPP-4 inhibitors in T1DM patients is often off-label and not covered by current guidelines or reimbursement policies in many countries. The included RCTs may have been conducted in specific research settings or may have involved a limited patient population (e.g., patients with early T1DM and preserved beta-cell function or purely exploratory studies conducted before regulatory approvals). More detailed information and discussion are needed regarding the background of these RCTs. This would clarify the extent to which your findings apply to routine clinical practice and highlight the limitations of generalizability. Thank you for your comments, we have updated the manuscript to clarify the off label use of DPP-4 in T!DM. we have updated the discussion to include the background of these studies when mentioned, and added the limitation o generalizability in the discussion . 2. Although the limitations section mentions the study duration, it is unclear how long-term administration would affect pancreatic beta-cell survival. Therefore, stating that this therapy is "to preserve residual beta-cell function" may not be entirely accurate. Either provide justification to explain this clearly to the reader, or consider modifying the wording in your response. Several times in your discussion and conclusion, you state that an increase in C-peptide levels suggests "the possibility of preserving or improving residual β-cell function." Ultimately, you conclude that DPP-4 inhibitors are "a safe and effective adjunct therapy to preserve residual β-cell function." While an increase in C-peptide may indicate an improvement in beta-cell insulin secretory response, it cannot be confirmed whether this directly translates to "survival" or "preservation" without much longer-term follow-up studies. This wording might mislead readers. I recommend using more cautious language. Alternatively, if you believe "preservation" is justified, please provide a more detailed discussion of the underlying physiological mechanisms or existing evidence from longer-term studies that support this claim. We Thank the reviewer for this comment and we have revised the manuscript to use more cautious language.Specifically we have replaced the word preserve/preservation by to potential improvement. 3. Although a significant reduction in the total daily insulin dose (MD = -2.5 units/day) is reported, the clinical significance of this reduction in the daily lives of patients with type 1 diabetes mellitus (T1DM) should be discussed more specifically. For example, does this translate to fewer injections, reduced risk of weight gain, or reduced risk of hypoglycemia? Discussing the implications for patients' quality of life or management burden would enhance the clinical relevance of this finding. We thank the reviewer for his valuable comment. Clinically, a reduction of approximately 3-4 insulin units per day can be meaningful for several reasons: - Reduced injection burden: While the absolute reduction of ~3 units per day may not necessarily lead to fewer injections in patients using multiple daily injection regimens, it may lead to a lower requirement for bolus insulin. Indeed, the meta-analysis found that the most pronounced insulin-sparing effect was specifically on bolus insulin units (-2.61 units/day). This decrease could facilitate simplified carbohydrate counting and more flexible meal planning. - Hypoglycemia risk reduction: Although the study did not directly show significant changes in hypoglycemia events, reduced insulin doses, particularly bolus insulin, theoretically lower hypoglycemia risk by minimizing insulin excess during periods of unpredictable carbohydrate intake or physical activity. This is particularly relevant for patients with variable daily routines or dietary habits. - Weight management: Despite the lack of direct impact on weight and BMI observed in this analysis, insulin reduction, particularly bolus insulin, may indirectly prevent insulin-associated weight gain. Lower insulin doses could mitigate insulin-driven lipogenesis, contributing positively to weight management strategies in the longer term. - Quality of life and patient satisfaction: Even modest insulin reductions can positively influence patient perceptions regarding the complexity of diabetes management. Reduced insulin dosing can ease mental burdens related to meticulous dosage calculations, thereby improving adherence and overall satisfaction with diabetes care. Thus, although the numerical change might appear modest, the broader implications regarding patient management, potential hypoglycemia prevention, and quality of life enhancements underscore the clinical relevance of these findings. Reviewer #2: Definition and Justification of Risk and Treatment Burden Please provide a clearer explanation of how the “10-year cardiovascular risk” is calculated, including whether any model calibration was performed for individual countries. Thank You for Your comment , we feel the comment does not belong to our manuscript since we did not include any the “10-year cardiovascular risk” calculation in our manuscript. Define how "treatment burden" is operationalized—does it include polypharmacy, cost, frequency of monitoring, etc.? Thank You for Your comment , we feel the comment does not belong to our manuscript since we did not include any the “ Treatment Biurden” calculation in our manuscript. Statistical Transparency Clarify if complex survey designs (e.g., stratification, clustering) were adjusted for in the confidence intervals. We thank the reviewer for his relevant question. The meta-analysis presented was based on randomized controlled trials (RCTs), and it explicitly used a random-effects model to pool results due to expected clinical and methodological heterogeneity. This statistical approach inherently considers between-study variance. However, the meta-analysis did not explicitly indicate the adjustment for complex survey designs such as stratification or clustering because the included studies were individual RCTs with standard randomization procedures rather than observational or epidemiological surveys. RCTs typically do not employ complex sampling designs that require adjustments (such as stratification or clustering) seen in population-based surveys. Therefore, adjustments specifically for complex survey designs were not applicable or reported in this meta-analysis. Provide more details on how survey weights were applied. We thank the reviewer for this constructive remark. The current meta-analysis included randomized controlled trials that inherently do not apply survey weights typically used in observational studies or population-based surveys. Survey weighting is relevant primarily when aiming to ensure the representativeness of results to broader populations or accounting for sampling methods in cross-sectional, observational studies. Since the meta-analysis combined data from RCTs with equal weighting through a random-effects approach, the typical survey weighting methods (such as those applied in observational epidemiology) were neither applicable nor required. If multivariable modeling was considered and ruled out, please explain why. We thank the reviewer for his valuable comment. Multivariable modeling is generally employed in observational studies or epidemiological analyses where adjustment for potential confounding variables is crucial. In contrast, meta-analyses of randomized controlled trials inherently aim to minimize confounding through randomization. Therefore, standard meta-analytic practice focuses on direct comparisons using aggregated unadjusted data, typically without multivariable modeling. Specifically, in this meta-analysis: Randomization: RCT designs included in this review provided inherent control for confounding variables, limiting the necessity for multivariable adjustments. Heterogeneity management: Instead of multivariable modeling, subgroup analyses (by treatment duration, diabetes duration, BMI) and sensitivity analyses were explicitly performed to explore heterogeneity and robustness of the results, adequately managing potential variability. Hence, multivariable modeling was appropriately not employed given the context of the study design (meta-analysis of randomized trials) and the statistical methodology chosen. Overgeneralization of Conclusions The current wording implies causal conclusions in some sections. Please revise to maintain descriptive tone. Statements such as “policy should prioritize targeting high-risk individuals” are reasonable but should be supported with more robust discussion of feasibility, health system capacity, and heterogeneity between LMICs. Country Comparisons Consider stratifying countries by World Bank income classification or region for comparative clarity. We thank the reviewer for this valuable suggestion. We agree that stratifying the included studies by World Bank income classification will enhance comparative clarity. Accordingly, we will include this stratification if this comment is related to our manuscript. Adding a figure to visualize between-country differences in risk or burden would improve accessibility. Attachments Attachment Submitted filename: Rebuttal_reviwerscomments.docx https://doi.org/10.1371/journal.pone.0332191.r002
28 Aug 2025 Decision Letter - Toshiki Maeda, Editor The efficacy of DPP IV inhibitors as adjunct therapy for patients with auto-immune Diabetes: A Systematic review and Meta-analysis PONE-D-25-24150R1 Dear Dr. Nakhoul, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support . If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Toshiki Maeda Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewer #1: Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Dear Authors, Thank you for your detailed and thoughtful response. Your answer completely clarifies my questions. I have no further comments and questions. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy . Reviewer #1: No ******** https://doi.org/10.1371/journal.pone.0332191.r003
Formally Accepted
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