DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A meta-analysis

Yan Yang; Zixin Cai; Jingjing Zhang

doi:10.1371/journal.pone.0251916

Peer Review History

Original SubmissionNovember 9, 2020
17 Feb 2021 Decision Letter - Ghulam Md Ashraf, Editor PONE-D-20-34362 DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis PLOS ONE Dear Dr. Zhang, 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 15th March 2021. 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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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: Partly Reviewer #2: Yes ******** 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: No Reviewer #2: No ****** 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: DPP-4 Ace receptor are part of the receptor for viral entry. Studies from various European contries especially study from French Cohort has shown that the effect ACE inhibitor is neither harmful nor beneficial. Do they think same type of response from DPP-4 Inhibitor? Page-3 paragraph 2= DPP-4 are neutral agents but not hypoglycemic agents. Sentence need to be modified. Page-4, para 2.1= We started article started from...…..= sentence needs to be modified. Page-6, search results.. what was the probable cause of duplication? Page-9, paragraph 2 line3= DPP-4 should be replaced from DPP-4 inhibitor Page-9 Para3= Is this phenomena agent specific or non-specific? Outcome of results should be mentioned properly not in a sketchy manner. The stratification of Covid-19 positive patients should have been done by using various tools like modified APACHE-2 and SOFA,MIMS etc. In Discussion- Inconclusive. Number of subjects very less. It should have been compared with SGLT-2 inhibitors with or without ACE inhibitors. Reviewer #2: The authors have conducted a meta-analysis of the existing studies on the effect of DPP4i use on COVID-19 mortality in T2DM patients. The findings are of great interest. However, the rationale of the study (SARS-CoV and SARS-CoV2 do not use DPP4 as the receptor, see Cell Study Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, Volume 181, Issue 2, 2020, Pages 271-280.e8,ISSN 0092-8674, https://doi.org/10.1016/j.cell.2020.02.052., Jean K Millet, Javier A Jaimes, Gary R Whittaker, Molecular diversity of coronavirus host cell entry receptors, FEMS Microbiology Reviews, 2020;, fuaa057, https://doi.org/10.1093/femsre/fuaa057), the presentation of the data (writing of the results section) and therefore the discussion is not adequate The grammar and syntax are not up to Standard for smooth reading experience. In addition, there are spelling mistakes ****** 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.0251916.r001
Revision 1
21 Mar 2021 Author Response Dear Reviewers, We were pleased that the reviewers agreed that “the findings are of great interest”. Thank you for the constructive comments and suggestions; we found them helpful for improving our manuscript. We have modified the manuscript according to these suggestions. Our responses to the comments on the manuscript are provided below. Reviewer #1: DPP-4 Ace receptor are part of the receptor for viral entry. Studies from various European contries especially study from French Cohort has shown that the effect ACE inhibitor is neither harmful nor beneficial. Do they think same type of response from DPP-4 Inhibitor? Thank you for the constructive comments. We presume that you would like us to include the results of the study by the Carious team [1]. The authors mentioned in their article that a significant difference in the effect of ACE inhibitors on COVID-19 was not observed (OR=1.43 95% CI, 0.99-2.08), and the effects of DPP-4 inhibitors were not significantly different, but they tended to exert a protective effect (OR=0.85 95% CI, 0.55-1.32). Interestingly, when we combined their results with the results of the other included studies [2-4], we ultimately observed a significantly different protective effect (Figure 2). Page-3 paragraph 2= DPP-4 are neutral agents but not hypoglycemic agents. Sentence need to be modified. Thank you for the constructive suggestion. We have modified this sentence to “DPP-4 inhibitors (DPP-4is), one of the new oral therapies for diabetes characterized by neutral weight and few adverse effects, is now used to improve insulin secretion as a treatment for T2DM” in the manuscript (lines 8 to 10 on page 3 ). Page-4, para 2.1= We started article started from...…..= sentence needs to be modified. Thank you for the kind reminder. We have modified this sentence in the revised manuscript (line 13 to 14 on page 4). Page-6, search results.. what was the probable cause of duplication? Thank you for the useful suggestion. When we searched different databases with the same keywords, the same documents or results are often retrieved. Here, we used Endnote to find duplicate results and avoid wasting effort in screening documents. Page-9, paragraph 2 line3= DPP-4 should be replaced from DPP-4 inhibitor Thank you for the constructive suggestion. We have replaced DPP-4 with DPP-4 inhibitor in our revised manuscript (line 18 on page 8). Page-9 Para3= Is this phenomena agent specific or non-specific? Outcome of results should be mentioned properly not in a sketchy manner. We thank the reviewer for this constructive suggestion. DPP-4 degrades GLP-1, and GLP-1 exerts an anti-inflammatory effect, but researchers have not determined whether DPP-4is also inhibit the degradation of GLP-1 in patients with COVID-19. The anti-inflammatory effect is only our conjecture at present, and further proof is needed. We have added this explanation to the manuscript (lines 13-16 on page 9). The stratification of Covid-19 positive patients should have been done by using various tools like modified APACHE-2 and SOFA,MIMS etc. Thank you for the kind reminder. Unfortunately, since the available literature does not provide sufficient grouping information, we are unable to conduct this experiment based on this constructive suggestion. In Discussion- Inconclusive. Number of subjects very less. It should have been compared with SGLT-2 inhibitors with or without ACE inhibitors. Thank you for this constructive suggestion. We have added the control groups of our included researches in the Table 1. Unfortunately, due to the incomplete raw data of the included articles, it is unclear whether SGLT-2 inhibitors or ACE inhibitors is involved. Reviewer #2: The authors have conducted a meta-analysis of the existing studies on the effect of DPP4i use on COVID-19 mortality in T2DM patients. The findings are of great interest. However, the rationale of the study (SARS-CoV and SARS-CoV2 do not use DPP4 as the receptor, see Cell Study Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Krüger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Müller, Christian Drosten, Stefan Pöhlmann, SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell, Volume 181, Issue 2, 2020, Pages 271-280.e8,ISSN 0092-8674, https://doi.org/10.1016/j.cell.2020.02.052., Jean K Millet, Javier A Jaimes, Gary R Whittaker, Molecular diversity of coronavirus host cell entry receptors, FEMS Microbiology Reviews, 2020;, fuaa057, https://doi.org/10.1093/femsre/fuaa057), We sincerely appreciate this constructive suggestion. Taking into account the latest developments on the role of DPP-4is in the entry of COVID-19 into cells, as you suggested, we have corrected and updated our manuscript (lines 3-4 on page 2 and lines 6-13 on page 3). the presentation of the data (writing of the results section) and therefore the discussion is not adequate Thank you for this constructive suggestion. We have modified the descriptions of the presentation of the data in the discussion section (line 5 on page 8). The grammar and syntax are not up to Standard for smooth reading experience. In addition, there are spelling mistakes Thank you for this valuable advice; we have modified the whole manuscript carefully. Moreover, we have submitted our manuscript to American Journal Experts for language editing, and the entire manuscript has been revised. References 1. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia 2020;63(8):1500-1515.doi:10.1007/s00125-020-05180-x 2. Fadini GP, Morieri ML, Longato E, Bonora BM, Pinelli S, Selmin E, et al. Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes: A case-control study. Diabetes, obesity & metabolism 2020;22(10):1946-1950.doi:10.1111/dom.14097 3. Solerte SB, D'Addio F, Trevisan R, Lovati E, Rossi A, Pastore I, et al. Sitagliptin Treatment at the Time of Hospitalization Was Associated With Reduced Mortality in Patients With Type 2 Diabetes and COVID-19: A Multicenter, Case-Control, Retrospective, Observational Study. Diabetes care 2020;43(12):2999-3006.doi:10.2337/dc20-1521 4. Strollo R, Maddaloni E, Dauriz M, Pedone C, Buzzetti R, Pozzilli P. Use of DPP4 inhibitors in Italy does not correlate with diabetes prevalence among COVID-19 deaths. Diabetes research and clinical practice 2021;171:108444.doi:10.1016/j.diabres.2020.108444 Attachments Attachment Submitted filename: Response letter.docx https://doi.org/10.1371/journal.pone.0251916.r002
15 Apr 2021 Decision Letter - Ghulam Md Ashraf, Editor PONE-D-20-34362R1 DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis PLOS ONE Dear Dr. Zhang, 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. The authors are advised to address the minor concerns raised by one of the reviewers. Please submit your revised manuscript by 30th April 2021. 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. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. 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Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] 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 Reviewer #2: (No Response) ******** 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 Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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 Reviewer #2: 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 Reviewer #2: 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: No Changes required. Manuscript accepted after revision. The revised paper has incorporated all the required changes. After correction the paper has achieved excellence. Hence accepted. Reviewer #2: The authors have addressed some of my comments. However, they need to address additional concerns that have arisen due to oversight and/or not adequately addressing them on the revision. 1. Last para on Pg8 of the manuscript, did the authors mean DPP4 or DPP4 inhibitors 2. Reference 27 is not directly related to ARDS although it could be extrapolated from an LPS-induced mouse model. The way it is written, it seems that Sitagliptin has proven efficacy against ARDS ****** 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: Yes:** Pinaki Dutta 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. Attachments Attachment Submitted filename: PLOS ONE REVIEW.docx https://doi.org/10.1371/journal.pone.0251916.r003
Revision 2
21 Apr 2021 Author Response Dear Reviewers, We were pleased that the reviewers agreed that “the findings are of great interest”. Thank you for the constructive comments and suggestions; we found them helpful for improving our manuscript. We have modified the manuscript according to these suggestions. Our responses to the comments on the manuscript are provided below. Reviewer #2: The authors have addressed some of my comments. However, they need to address additional concerns that have arisen due to oversight and/or not adequately addressing them on the revision. 1. Last para on Pg8 of the manuscript, did the authors mean DPP4 or DPP4 inhibitors Thank you for the constructive comments. We have replaced the “DPP4 inhibitors” with “DPP4” in the revised manuscript (lines 19 on page 8). 2. Reference 27 is not directly related to ARDS although it could be extrapolated from an LPS-induced mouse model. The way it is written, it seems that Sitagliptin has proven efficacy against ARDS Thank you for the useful suggestion. We have redescribed this sentence as you suggested in our revised manuscript (lines 2 to 3 on page 9). Attachments Attachment Submitted filename: Response letter.docx https://doi.org/10.1371/journal.pone.0251916.r004
6 May 2021 Decision Letter - Ghulam Md Ashraf, Editor DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis PONE-D-20-34362R2 Dear Dr. Zhang, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. 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, Ghulam Md Ashraf, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): 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 #2: (No Response) ******** 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 #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #2: 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 #2: 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 #2: 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 #2: My comment 2. Reference 27 is not directly related to ARDS although it could be extrapolated from an LPS-induced mouse model. The way it is written, it seems that Sitagliptin has proven efficacy against ARDS Author's response Thank you for the useful suggestion. We have redescribed this sentence as you suggested in our revised manuscript (lines 2 to 3 on page 9). What the authors wrote Moreover, it seems that Sitagliptin "has proven efficacy" against acute respiratory distress syndrome (ARDS), the common causes of COVID-19-related death, because this drug inhibits IL-6, IL-1, and TNF in individuals with lung injury [27]. My suggestion was that Reference 27 pertains to work with LPS in "mice" which is NOT ARDS in "humans" but may mimic some of the features. Therefore, the authors "CANNOT" make statements such as above. Please correct the statement to accurately reflect the utility of Sitagliptin ****** 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 #2: No https://doi.org/10.1371/journal.pone.0251916.r005
Formally Accepted
11 May 2021 Acceptance Letter - Ghulam Md Ashraf, Editor PONE-D-20-34362R2 DPP-4 inhibitors may improve the mortality of coronavirus disease 2019: A Meta-Analysis Dear Dr. Zhang: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Ghulam Md Ashraf Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0251916.r006

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