Is metformin use associated with low mortality in patients with type 2 diabetes mellitus hospitalized for COVID-19? a multivariable and propensity score-adjusted meta-analysis

Zhiyuan Ma; Mahesh Krishnamurthy

doi:10.1371/journal.pone.0282210

Peer Review History

Original SubmissionNovember 29, 2021
11 Nov 2022 Decision Letter - Jennifer A. Hirst, Editor PONE-D-21-37827Does Metformin Decrease Mortality in Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19? A Multivariable and Propensity Score-adjusted Meta-analysisPLOS ONE Dear Dr. Krishnamurthy, 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 take particular consideration to overinterpretation of findings and use of language that suggests causation. Please submit your revised manuscript by Nov 28 2022 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. 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. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Jennifer A. Hirst, DPhil Academic Editor PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Additional Editor Comments (if provided): General comments – please add line numbers to help reviewers The main finding of this paper is that although unadjusted analysis suggests a significant benefit of metformin, there is no effect of metformin on mortality after adjustment for confounders. This should be highlighted in the discussion, rather than the significant finding of the unadjusted analysis. Amend this in the abstract and main body of paper. Methods. The Prospero page needs updating as it indicates that the authors are still at the search stage. Searches: These only identified a very small number of studies. Was a medical librarian consulted to assist with searches? Please provide full details of the search strategy, as the described searches would have missed articles. Consider including terms such as covid, death, biguanide, and metformin brand names. Were terms for diabetes included in the search? In the meta-analysis of adjusted data, please give details of methods used to allow odds ratio and hazard ratios to be combined. Were they assumed to be the same? If this is the case, then I would expect sensitivity analyses to be carried out to assess the impact of these approximations. Results: Outpatient metformin use and in-hospital mortality Page 6 – the following sentence needs some clarification: “There were 15 studies with or without attempt to adjust for confounding examining the association between outpatient metformin use and in-hospital mortality” What is meant by with or without adjusting? Is this a repeat of the numbers in the previous paragraph? The results section contains methods and interpretation – please ensure that methods are in the methods section and interpretation is moved to the discussion leaving results only to be reported in the results Include details of quality assessment scores for each of the included studies and risk of bias. Discussion This needs to be structured, starting with the key findings. Discuss risk of bias. [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: No Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: No 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: No Reviewer #2: No ****** 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: What would be of particular interest is to be the first to draw some lessons from rather robust studies. This consists in fact of – to my knowledge – seventh meta-analysis. Moreover, there are major drawbacks. There are several errors: - We are speaking about observational studies, not about interventional studies. Therefore the words “decrease” (mortality), as early as in the title, and “reduction”, appearing numerous times in the text, are not appropriate. - The terms “outpatients” and “inpatients” are also inappropriate. The question should rather be phrased as whether or not the putative beneficial association between metformin treatment and COVID outcomes is due to metformin treatment prior to hospital admission, its continuation during the hospital stay, or both. Therefore the wording would be: “metformin discontinued”, “metformin continued”, “maintenance of metformin”, etc. (during a hospital stay). - Title: what means “A Multivariable and Propensity Score-adjusted Meta-analysis?” - The wording is often weak (one example, in the abstract: “Random effect models were applied for meta-analysis due to variation among studies”. In fact, the issue is not that of “variations” (between studies). Rather it is as following: the inclusion of a large number of covariates does not compensate for a lack of key variables (such as BMI, the estimated glomerular filtration rate, duration of diabetes, etc.). Given that, the studies with a low sample size, with a low number of covariates, and with a lack of the major covariates should not even be considered. It is already impossible to compare studies with either 172 or more than 2 million people with diabetes! - There are just a few words about the putative protective effects for metformin; this is clearly not enough (what about effects on microvascular blood flow and pericytes, microvascular permeability, hemostasis, glycocalyx, hydrogen sulfide, ER stress, etc.?). - The first lines of the Discussion do not deal with the main results. - To put it simply, the compilation of short and/or weak studies cannot lead to a firm conclusion. And, as it happens, the by far largest study (more than 2 million people: Ojeda-Fernandez, Diabetes Obesity Metab 2022) is lacking. - Given all these difficulties, the limitations subsection is far too weak. Reviewer #2: Thank you for pursuing this question of metformin's role. - You state that you assessed bias and refer to internal to analysis confounding issues as well as publication bias, but you do not characterize the latter. What were your systematic bias assessment results across the studies? - Heterogeneity is quite high across pooled analyses. This should be discussed. For instance, (1) how was A1C and complicated diabetes accounted across studies; and, (2) in which studies was metformin already part of the patients' regimen versus added while in house or once diagnosis with SARS-CoV-2 was accomplished. - The discussion and conclusion language should acknowledge more directly (depending upon your response to the previous questions) that metformin may indicate lower risk because being managed for diabetes... currently, your presented data and analyses does not support a direct effect and yet you close the article expressing only a caveat of pooled analyses statistical significance. ****** 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: Yes: Jean-Daniel Lalau 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.0282210.r001
Revision 1
27 Nov 2022 Author Response 1. “Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.” “please add line numbers to help reviewers” Response: We have revised our manuscript according to PLOS ONE’s style requirements and added the line numbers. 2. “The main finding of this paper is that although unadjusted analysis suggests a significant benefit of metformin, there is no effect of metformin on mortality after adjustment for confounders. This should be highlighted in the discussion, rather than the significant finding of the unadjusted analysis. Amend this in the abstract and main body of paper.” Response: We updated search and have performed new analysis. The results have been included in the section of Results and discussion. 3. “The Prospero page needs updating as it indicates that the authors are still at the search stage.” Response: We have updated the status in the PROSPERO. 4. “Searches: These only identified a very small number of studies. Was a medical librarian consulted to assist with searches? Please provide full details of the search strategy, as the described searches would have missed articles. Consider including terms such as covid, death, biguanide, and metformin brand names. Were terms for diabetes included in the search?” Response: We did not consult librarian for assisting with the search. We did not include the keyword diabetes in the search. We manually screened diabetic patients in the studies after identification. Since our search was more than 1 year ago, we performed updated search using the expression “((SARS-CoV-2) OR (Covid-19)) AND ((Metformin) OR (Biguanides) OR (Fortamet) OR (Glumetza) OR (Glucophage) OR (Biomet)) AND ((Mortality) OR (Death))” as suggested. Three new studies have been included for analyses. 5. “In the meta-analysis of adjusted data, please give details of methods used to allow odds ratio and hazard ratios to be combined. Were they assumed to be the same? If this is the case, then I would expect sensitivity analyses to be carried out to assess the impact of these approximations.” Response: Raw event data extracted from individual study were pooled using the Mantel-Haenszel approach and effect size (OR, HR) was pooled using the inverse-variance method. This has been described in the methods. We also included sensitivity analyses in Figure 2 and 3. 6. “Outpatient metformin use and in-hospital mortality Page 6 – the following sentence needs some clarification: “There were 15 studies with or without attempt to adjust for confounding examining the association between outpatient metformin use and in-hospital mortality” What is meant by with or without adjusting? Is this a repeat of the numbers in the previous paragraph?” Response: We have revised the text. 7. “The results section contains methods and interpretation – please ensure that methods are in the methods section and interpretation is moved to the discussion leaving results only to be reported in the results” Response: We have revised the results. 8. “Include details of quality assessment scores for each of the included studies and risk of bias.” Response: the Newcastle-Ottawa Scale scores have been included in Table 1. 9. “This needs to be structured, starting with the key findings. Discuss risk of bias.” Response: We have revised the section of discussion and discussed more on bias. Reviewer #1: 1. “What would be of particular interest is to be the first to draw some lessons from rather robust studies. This consists in fact of – to my knowledge – seventh meta-analysis.” Response: Thank you for your comments. Of note, we performed this study and submitted it more than a year ago. In this study, we aimed to address whether outpatient (prior to admission) or inpatient metformin (during hospitalization) therapy offers low in-hospital mortality in patients with type 2 diabetes mellitus hospitalized for COVID-19 especially by multivariable and propensity score-adjusted effect sizes (OR and HR). We discussed the issues in the previously published meta-analysis in the second paragraph of the section of the discussion. We think our study is interesting. 2. “We are speaking about observational studies, not about interventional studies. Therefore the words “decrease” (mortality), as early as in the title, and “reduction”, appearing numerous times in the text, are not appropriate.” Response: Thank you for your comments. We agree that we did a meta-analysis of observational studies. We have revised our title. But we believe metformin therapy is interventional and treatment, so “decrease” and “reduction is related to metformin therapy not to study types. 3. “The terms “outpatients” and “inpatients” are also inappropriate. The question should rather be phrased as whether or not the putative beneficial association between metformin treatment and COVID outcomes is due to metformin treatment prior to hospital admission, its continuation during the hospital stay, or both. Therefore the wording would be: “metformin discontinued”, “metformin continued”, “maintenance of metformin”, etc. (during a hospital stay).” Response: Thank you for your suggestion. We have specifically clarified “outpatient” and “inpatient” metformin use in the introduction. 4. “what means “A Multivariable and Propensity Score-adjusted Meta-analysis?”” Response: Meta-analysis of studies with adjusted effect size derived from multivariable regression or propensity score matching. 5. “The wording is often weak (one example, in the abstract: “Random effect models were applied for meta-analysis due to variation among studies”. In fact, the issue is not that of “variations” (between studies). Rather it is as following: the inclusion of a large number of covariates does not compensate for a lack of key variables (such as BMI, the estimated glomerular filtration rate, duration of diabetes, etc.). Given that, the studies with a low sample size, with a low number of covariates, and with a lack of the major covariates should not even be considered. It is already impossible to compare studies with either 172 or more than 2 million people with diabetes!” Response: Thank you for your comments. We have revised the text. The random-effects model is conventionally used to address between-study heterogeneity. We did unadjusted and adjusted analyses to address other bias. we excluded studies with the number of subjects less than 50. 6. “There are just a few words about the putative protective effects for metformin; this is clearly not enough (what about effects on microvascular blood flow and pericytes, microvascular permeability, hemostasis, glycocalyx, hydrogen sulfide, ER stress, etc.?).” Response: We have revised the text and added the protected effects on microvessels. 7. “The first lines of the Discussion do not deal with the main results.” Response: We have revised the section of discussion. 8. “To put it simply, the compilation of short and/or weak studies cannot lead to a firm conclusion. And, as it happens, the by far largest study (more than 2 million people: Ojeda-Fernandez, Diabetes Obesity Metab 2022) is lacking.” Response: We completed our search before Oct 1st, 2021 and submitted our paper on Nov. 29th, 2021. Now We completed new search and have included the above study along with 2 more studies. 9. “Given all these difficulties, the limitations subsection is far too weak.” Response: We have revised the limitation subsection. Reviewer #2: 1. “You state that you assessed bias and refer to internal to analysis confounding issues as well as publication bias, but you do not characterize the latter. What were your systematic bias assessment results across the studies?” Response: We have performed the analyses of publication bias using funnel plots and Egger’s tests. We also included the Newcastle-Ottawa Scale scores in Table 1. 2. “Heterogeneity is quite high across pooled analyses. This should be discussed. For instance, (1) how was A1C and complicated diabetes accounted across studies; and, (2) in which studies was metformin already part of the patients' regimen versus added while in house or once diagnosis with SARS-CoV-2 was accomplished.” Response: We have revised the limitation subsection. 3. “The discussion and conclusion language should acknowledge more directly (depending upon your response to the previous questions) that metformin may indicate lower risk because being managed for diabetes... currently, your presented data and analyses does not support a direct effect and yet you close the article expressing only a caveat of pooled analyses statistical significance.” Response: We have performed new analyses with more studies. We have revised the results and conclusions. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0282210.r002
30 Jan 2023 Decision Letter - Jennifer A. Hirst, Editor PONE-D-21-37827R1Is Metformin Use Associated with Low Mortality in Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19? A Multivariable and Propensity Score-adjusted Meta-analysisPLOS ONE Dear Dr. Krishnamurthy, 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 Mar 16 2023 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. 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. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Jennifer A. Hirst, DPhil Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. 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: Partly ****** 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: I must admit that I am not very interested in meta-analyses but I would also highlight the great work done by the authors for improving their manuscript. I agree with all modifications but one: as long as studies are observational, it is never possible to speak about “reduction” (of mortality – because of metformin) (lines 21, 158, 211, 266, 269…), and even less about a “trend toward a reduction” (L. 158: non-scientific). Reviewer #2: Thank you for your work addressing editorial and reviewer comments. The manuscript is improved. - Consider doing a quick sensitivity analysis where you remove all studies that have a 6 or lower Newcastle-Ottowa score (indicating high risk). Those studies are substantially smaller than the studies that you scored more highly and so a single study removal method for sensitivity analysis would likely be insufficient to discern the effect by class. - The bigger issue for me is that the manuscript is written in a way that suggests that metformin was applied for the purpose of COVID-19 therapy. That seems unlikely, particularly in the one category where you observed a multi-variate statistically significant effect. This matters in how readers (even technically grounded ways) understand the role of metformin here. You also seem to avoid talking about DM management in your background as a reason for exploring the effect. This needs to be addressed through-out. The Limitations section additions relevant to my earlier comments are appropriate. What I am talking about now is how the question is framed and the discussion and conclusions are proffered. I suspect that you simply have taken for granted that readers will understand this difference, but you do not state it, and your language suggests direct therapeutic application for the purpose of COVID-19 in a milieu where it has been among several problematic narratives avoiding more rounded approaches to patient management. This can be stated succinctly in the intro, discussion, and conclusion sections and easily corrected. ****** 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: Jean-Daniel Lalau 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.0282210.r003
Revision 2
4 Feb 2023 Author Response Reviewer #1: 1. “I must admit that I am not very interested in meta-analyses but I would also highlight the great work done by the authors for improving their manuscript. I agree with all modifications but one: as long as studies are observational, it is never possible to speak about “reduction” (of mortality – because of metformin) (lines 21, 158, 211, 266, 269…), and even less about a “trend toward a reduction” (L. 158: non-scientific)” Response: Thank you for your comment. As you pointed out that this is a meta-analysis of observational studies, we have revised the text and made it clear throughout the study that there is an association between metformin use and hospital mortality, but not direct causation. The word “reduction” is used as a noun or adjective not as a verb which may imply direct causation. Reviewer #2: 1. “Consider doing a quick sensitivity analysis where you remove all studies that have a 6 or lower Newcastle-Ottowa score (indicating high risk). Those studies are substantially smaller than the studies that you scored more highly and so a single study removal method for sensitivity analysis would likely be insufficient to discern the effect by class” Response: We have added additional analysis regarding this (Supp fig. 1A). 2. “The bigger issue for me is that the manuscript is written in a way that suggests that metformin was applied for the purpose of COVID-19 therapy. That seems unlikely, particularly in the one category where you observed a multi-variate statistically significant effect. This matters in how readers (even technically grounded ways) understand the role of metformin here. You also seem to avoid talking about DM management in your background as a reason for exploring the effect. This needs to be addressed through-out. The Limitations section additions relevant to my earlier comments are appropriate. What I am talking about now is how the question is framed and the discussion and conclusions are proffered. I suspect that you simply have taken for granted that readers will understand this difference, but you do not state it, and your language suggests direct therapeutic application for the purpose of COVID-19 in a milieu where it has been among several problematic narratives avoiding more rounded approaches to patient management. This can be stated succinctly in the intro, discussion, and conclusion sections and easily corrected.” Response: Thank you for your comment. We have revised the text. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0282210.r004
10 Feb 2023 Decision Letter - Jennifer A. Hirst, Editor Is Metformin Use Associated with Low Mortality in Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19? A Multivariable and Propensity Score-adjusted Meta-analysis PONE-D-21-37827R2 Dear Dr. Krishnamurthy, 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, Jennifer A. Hirst, DPhil Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0282210.r005
Formally Accepted
14 Feb 2023 Acceptance Letter - Jennifer A. Hirst, Editor PONE-D-21-37827R2 Is Metformin Use Associated with Low Mortality in Patients with Type 2 Diabetes Mellitus Hospitalized for COVID-19? A Multivariable and Propensity Score-adjusted Meta-analysis Dear Dr. Krishnamurthy: 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. Jennifer A. Hirst Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0282210.r006

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