Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia

Yu-Chien Cheng; Yannis Guerra; Michael Morkos; Bettina Tahsin; Chioma Onyenwenyi; Louis Fogg; Leon Fogelfeld

doi:10.1371/journal.pone.0256682

Peer Review History

Original SubmissionMarch 5, 2021
7 Apr 2021 Decision Letter - Sun Young Lee, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-21-07298 Insulin Management in Hospitalized Patients with Diabetes Mellitus on High-Dose Glucocorticoids: Management of Steroid-Exacerbated Hyperglycemia PLOS ONE Dear Dr. Guerra, 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 May 22 2021 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: http://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, Sun Young Lee, MD 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. 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 [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: Partly 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: In this paper, the authors performed a retrospective cohort study of hospitalized patients with diabetes to examine the effects of glucocorticoid use on blood glucose readings and insulin doses. Strengths of this study include the standardized protocol where all patients are placed on a balanced basal bolus regimen and use of matching to control for age, gender, race, and hemogloblin A1c. Limitations include its retrospective nature and reporting of data across all hospitalization days. Specific comments: How are insulin doses adjusted per protocol based on the blood sugar readings? I understand from the discussion that “the current protocol is 0.5 units/kg with 50% of total dose being basal (glargine) and 50% being prandial (lispro).” Is this applied to every patient on admission who has a GFR > 30, regardless of other factors (such as hemoglobin A1c, liver disease, glucocorticoid use, etc)? From my understanding of this protocol, the starting dose of lispro would be 0.083 units/kg TID and 0.25 units/kg of glargine. The doses on hospital day 1 would be identical between the glucocorticoid exposed and unexposed groups and I suspect that differences in dosing between the groups would only start to emerge over time as the glucocorticoid exposed group’s insulin doses were increased in response to the blood sugars. On page 7 it is reported “supplemental insulin is added to bolus based on pre-meal glucose algorithm.” Please include this algorithm in a supplemental figure. Furthermore, in the discussion there is mention that “our protocol does not recommend supplemental insulin at bedtime.” How is the glargine dose titrated per protocol? It is surprising that there was no association between the glucocorticoid dose and the glargine dose. In the results, the median total daily glargine and lispro doses are compared between the exposed and unexposed groups. Does this include all of doses across every day of hospitalization? I would expect that the differences in the insulin doses to be larger after a few days of hospitalization where there has been titration since it sounds like both groups are started on the same weight-based dose on admission. The authors report the median total daily lispro dose was 20% higher in the glucocorticoid exposed group compared with the unexposed group, which I suspect represents a comparison of the doses including all hospital days. It would be more meaningful to compare insulin doses after a few days of insulin titration, or on the last day of glucocorticoid use, or on the day of discharge, as the differences in insulin doses between the exposed and unexposed groups would likely be larger than on admission. The changes in insulin doses and blood sugars over time could be shown with a table of the median doses of glargine and lispro per day and median blood sugars vs. day of hospitalization stratified by exposure. Was there any use of NPH or insulins other than lispro and glargine in this population? Were patients receiving continuous tube feeds excluded? Reviewer #2: Comments to the editor: Thank you for asking me to review this retrospective cohort study by Cheng and colleagues evaluating insulin doses and blood glucose values in non-critically ill, hospitalized patients with diabetes treated with glucocorticoids as compared to those not treated with glucocorticoids. This study adds to the literature regarding management strategies for steroid induced hyperglycemia in the inpatient setting, an area that has been relatively understudied and for which there is not yet an established best practice with respect to insulin dosing, particularly for rapid acting insulin. Prior to publication of their manuscript, several questions should be addressed. 1) Within the introduction, I would update the ADA Standards of Care reference to the 2021 version (of note there are no substantive changes in the recommendations but it is the most recent). 2) Within the methods section it is stated that the insulin protocol at the authors’ institution is dosed at 0.5u/kg/day and divided 50/50 basal and bolus for patients with GFR >30 ml/min and that those patients not dosed per protocol were excluded. The consort diagram suggests it is only patients who did not receive both basal and bolus insulin who were excluded and does not mention weight-based dosing. Can the authors please clarify if patients who received more or less than 0.5u/kg/day were excluded? I would assume given the insulin dosing results that there are patients included in the cohort who receive more or less insulin per this prescribed protocol. 3) The authors’ decided to convert glucocorticoids to prednisone equivalent doses and evaluate the impact on CBG and insulin dosing overall. Can they provide their rationale for this decision? It may be interesting to evaluate insulin dosing needs by type of glucocorticoid (specifically for prednisone and dexamethasone as these were the 2 most commonly used GC) as it has previously been demonstrated that prednisone and dexamethasone result in varying degrees of insulin resistance (Yasuda K et al, doi:10.1210/jcem-55-5-910). 4) Within the results section on insulin dosing, while glargine dosing was similar between groups it would be helpful for the authors to clarify which group corresponded to which doses. 5) Would specify that changes in insulin dosing and hypoglycemia were not statistically significant. I would argue that nearly 20% increase in insulin dose and nearly a doubling of hypoglycemia at breakfast are clinically significant findings. Would likely see statistical significance with a slightly larger sample size. 6) The last line of the limitations paragraph regarding requirement of further increase in bolus insulin feels out of place, would suggest that this be moved to earlier in the discussion (for example the first paragraph of discussion). 7) While the authors demonstrate higher rapid acting insulin doses at dinner and increased CBG at lunch and dinner in patients on GC, I do not believe their findings support the conclusion that a 30% increase in rapid acting insulin at lunch and 20% increase in rapid acting insulin at dinner may be recommended as this was not specifically evaluated in this study. Instead, I would argue that their data do suggest higher doses of bolus insulin are required in the mid-day and evening but that specific recommendations regarding percentage increase should be evaluated in a future prospective study. While they include a statement regarding this need for further evaluation of the proposed strategy, it should also be mentioned in the abstract conclusions and first paragraph of the discussion. ****** 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:** Dylan Thomas 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.0256682.r001
Revision 1
26 May 2021 Author Response 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: Partly 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: In this paper, the authors performed a retrospective cohort study of hospitalized patients with diabetes to examine the effects of glucocorticoid use on blood glucose readings and insulin doses. Strengths of this study include the standardized protocol where all patients are placed on a balanced basal bolus regimen and use of matching to control for age, gender, race, and hemogloblin A1c. Limitations include its retrospective nature and reporting of data across all hospitalization days. Specific comments: How are insulin doses adjusted per protocol based on the blood sugar readings? I understand from the discussion that “the current protocol is 0.5 units/kg with 50% of total dose being basal (glargine) and 50% being prandial (lispro).” Is this applied to every patient on admission who has a GFR > 30, regardless of other factors (such as hemoglobin A1c, liver disease, glucocorticoid use, etc)?From my understanding of this protocol, the starting dose of lispro would be 0.083 units/kg TID and 0.25 units/kg of glargine. The doses on hospital day 1 would be identical between the glucocorticoid exposed and unexposed groups and I suspect that differences in dosing between the groups would only start to emerge over time as the glucocorticoid exposed group’s insulin doses were increased in response to the blood sugars. On page 7 it is reported “supplemental insulin is added to bolus based on pre-meal glucose algorithm.” Please include this algorithm in a supplemental figure. Furthermore, in the discussion there is mention that “our protocol does not recommend supplemental insulin at bedtime.” How is the glargine dose titrated per protocol? It is surprising that there was no association between the glucocorticoid dose and the glargine dose. We do follow the in-patient protocol which has been added as supplemental material. Our protocol does use the liver disease status to adjust the insulin dose but not the A1c or the glucocorticoid. As mentioned in the Methods, those with GFR <30 were excluded with no change in protocol for those with GFR >30. For the supplemental insulin and the glargine dose adjustment, please see supplemental material. The finding that the glargine was not associated with glucocorticoid dose seemed to be in line with previous evidence that steroids affect mostly post-prandial glucose (Eur J Endocrinol 2010;162:729-735) In the results, the median total daily glargine and lispro doses are compared between the exposed and unexposed groups. Does this include all of doses across every day of hospitalization? I would expect that the differences in the insulin doses to be larger after a few days of hospitalization where there has been titration since it sounds like both groups are started on the same weight-based dose on admission. As per our inpatient protocol, there were no initial differences in dosing between the groups. Analysis was done by dose per day with every day a unit of analysis as we expected the dosing to progressively increase daily as mentioned by the reviewer. The authors report the median total daily lispro dose was 20% higher in the glucocorticoid exposed group compared with the unexposed group, which I suspect represents a comparison of the doses including all hospital days. It would be more meaningful to compare insulin doses after a few days of insulin titration, or on the last day of glucocorticoid use, or on the day of discharge, as the differences in insulin doses between the exposed and unexposed groups would likely be larger than on admission. The changes in insulin doses and blood sugars over time could be shown with a table of the median doses of glargine and lispro per day and median blood sugars vs. day of hospitalization stratified by exposure. We did not analyze glucose median during the entire hospitalization as we expected that those on steroids may have a longer length of stay resulting in a skewed analysis if compared day-by-day. Was there any use of NPH or insulins other than lispro and glargine in this population? Were patients receiving continuous tube feeds excluded? Per our inpatient protocol, NPH is primarily used on OB/GYN patients who were excluded from our study population. Insulin Regular is only used on IV drips in MICU. Continuous tube feeds in our hospital are primarily used in MICU patients who were excluded from the study. Reviewer #2: Comments to the editor: Thank you for asking me to review this retrospective cohort study by Cheng and colleagues evaluating insulin doses and blood glucose values in non-critically ill, hospitalized patients with diabetes treated with glucocorticoids as compared to those not treated with glucocorticoids. This study adds to the literature regarding management strategies for steroid induced hyperglycemia in the inpatient setting, an area that has been relatively understudied and for which there is not yet an established best practice with respect to insulin dosing, particularly for rapid acting insulin. Prior to publication of their manuscript, several questions should be addressed. 1) Within the introduction, I would update the ADA Standards of Care reference to the 2021 version (of note there are no substantive changes in the recommendations but it is the most recent). The text and reference were updated. 2) Within the methods section it is stated that the insulin protocol at the authors’ institution is dosed at 0.5u/kg/day and divided 50/50 basal and bolus for patients with GFR >30 ml/min and that those patients not dosed per protocol were excluded. The consort diagram suggests it is only patients who did not receive both basal and bolus insulin who were excluded and does not mention weight-based dosing. Can the authors please clarify if patients who received more or less than 0.5u/kg/day were excluded? I would assume given the insulin dosing results that there are patients included in the cohort who receive more or less insulin per this prescribed protocol. The assumption of the reviewer was correct. Our inpatient protocol allows to use a converted home dose of insulin. See supplemental material. 3) The authors’ decided to convert glucocorticoids to prednisone equivalent doses and evaluate the impact on CBG and insulin dosing overall. Can they provide their rationale for this decision? It may be interesting to evaluate insulin dosing needs by type of glucocorticoid (specifically for prednisone and dexamethasone as these were the 2 most commonly used GC) as it has previously been demonstrated that prednisone and dexamethasone result in varying degrees of insulin resistance (Yasuda K et al, doi:10.1210/jcem-55-5-910). The rationale for converting steroids to prednisone equivalents was two-fold. First, it would permit us to compare patients across different therapies. Second, there are multiple patients who during the same hospitalization may have received different types of steroids. Due to our unit of analysis being day of hospitalization, the conversion allowed us to compare the different doses of different steroids on various days. 4) Within the results section on insulin dosing, while glargine dosing was similar between groups it would be helpful for the authors to clarify which group corresponded to which doses. We clarified the groups in the beginning of Insulin Dosing in the Results section. 5) Would specify that changes in insulin dosing and hypoglycemia were not statistically significant. I would argue that nearly 20% increase in insulin dose and nearly a doubling of hypoglycemia at breakfast are clinically significant findings. Would likely see statistical significance with a slightly larger sample size. We agree that the difference found is likely clinically significant yet within our available sample size, the current findings are as reported. 6) The last line of the limitations paragraph regarding requirement of further increase in bolus insulin feels out of place, would suggest that this be moved to earlier in the discussion (for example the first paragraph of discussion). As suggested, the sentence has been moved to the first paragraph of Discussion. 7) While the authors demonstrate higher rapid acting insulin doses at dinner and increased CBG at lunch and dinner in patients on GC, I do not believe their findings support the conclusion that a 30% increase in rapid acting insulin at lunch and 20% increase in rapid acting insulin at dinner may be recommended as this was not specifically evaluated in this study. Instead, I would argue that their data do suggest higher doses of bolus insulin are required in the mid-day and evening but that specific recommendations regarding percentage increase should be evaluated in a future prospective study. While they include a statement regarding this need for further evaluation of the proposed strategy, it should also be mentioned in the abstract conclusions and first paragraph of the discussion. We agree with the reviewers that the specific recommendations need to be studied and this was not the purpose of the study. We revised the manuscript accordingly in abstract conclusion and in the Discussion. ________________________________________ 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: Dylan Thomas 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 Response to Reviewers 5-20-21.docx https://doi.org/10.1371/journal.pone.0256682.r002
18 Jun 2021 Decision Letter - Sun Young Lee, Editor PONE-D-21-07298R1 Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia PLOS ONE Dear Dr. Guerra, 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 review the comments by both reviewers regarding the revision and include additional discussions as suggested by the reviewers. Please submit your revised manuscript by Aug 02 2021 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: http://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, Sun Young Lee, MD 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: I Don't Know 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: The authors have addressed my comments. I would consider adding a reference to an ongoing randomized clinical trial to address The Management of Glucocorticoid-Induced Hyperglycemia in Hospitalized Patients: https://clinicaltrials.gov/ct2/show/NCT01810952 I would also add that there is some data to suggest that the insulin dosing pattern should be tailored to match the glucocortoid dosing and type (e.g. optimal dosing for prednisone may be different than for dexamethasone). Hence, a single protocol for all inpatients on steroids may not be optimal. https://eje.bioscientifica.com/view/journals/eje/179/4/EJE-18-0315.xml Reviewer #2: The authors have not yet sufficiently addressed the comment regarding the decision to convert glucocorticoid doses to prednisone equivalent within the text of the manuscript. The rationale provided in the response to reviewers should be included within the methods section. ****** 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:** Dylan Thomas 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.0256682.r003
Revision 2
28 Jul 2021 Author Response Reviewer #1: The authors have addressed my comments. I would consider adding a reference to an ongoing randomized clinical trial to address The Management of Glucocorticoid-Induced Hyperglycemia in Hospitalized Patients: https://clinicaltrials.gov/ct2/show/NCT01810952 This ongoing trial is now referenced in the Discussion section. I would also add that there is some data to suggest that the insulin dosing pattern should be tailored to match the glucocortoid dosing and type (e.g. optimal dosing for prednisone may be different than for dexamethasone). Hence, a single protocol for all inpatients on steroids may not be optimal. https://eje.bioscientifica.com/view/journals/eje/179/4/EJE-18-0315.xml We’ve added reference to this approach in our Introduction. Reviewer #2: The authors have not yet sufficiently addressed the comment regarding the decision to convert glucocorticoid doses to prednisone equivalent within the text of the manuscript. The rationale provided in the response to reviewers should be included within the methods section. The rationale provided in our prior response is now included in the Methods section. Attachments Attachment Submitted filename: Response to Reviewers 7-28-21.docx https://doi.org/10.1371/journal.pone.0256682.r004
13 Aug 2021 Decision Letter - Sun Young Lee, Editor Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia PONE-D-21-07298R2 Dear Dr. Guerra, 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, Sun Young Lee, MD 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 #1: All comments have been addressed Reviewer #2: 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 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: All of my comments have been addressed. All of my comments have been addressed. All of my comments have been addressed. Reviewer #2: The authors have addressed my comments in a satisfactory fashion. My recommendation is to accept the manuscript. ****** 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:** Dylan D. Thomas Reviewer #2: No https://doi.org/10.1371/journal.pone.0256682.r005
Formally Accepted
3 Sep 2021 Acceptance Letter - Sun Young Lee, Editor PONE-D-21-07298R2 Insulin management in hospitalized patients with diabetes mellitus on high-dose glucocorticoids: Management of steroid-exacerbated hyperglycemia Dear Dr. Guerra: 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. Sun Young Lee Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0256682.r006

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