The effect of SGLT2 inhibitor in patients with type 2 diabetes and atrial fibrillation

Yongin Cho; Sung-Hee Shin; Min-Ae Park; Young Ju Suh; Sojeong Park; Ji-Hun Jang; Dae-Young Kim; So Hun Kim

doi:10.1371/journal.pone.0314454

Peer Review History

Original SubmissionMarch 14, 2024
24 Jul 2024 Decision Letter - Xinlin Zhang, Editor PONE-D-24-09659The effect of SGLT2 inhibitor in patients with type 2 diabetes and atrial fibrillationPLOS ONE Dear Dr. Shin, 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 Sep 07 2024 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, Xinlin Zhang 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 2. Thank you for stating the following financial disclosure: “This work was supported by a research grant from the Inha University.(Grant Number: Inha 70431) to S-H Shin.” Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 3. We note that your Data Availability Statement is currently as follows: [All relevant data are within the manuscript and its Supporting Information files.] Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition). For example, authors should submit the following data: - The values behind the means, standard deviations and other measures reported; - The values used to build graphs; - The points extracted from images for analysis. Authors do not need to submit their entire data set if only a portion of the data was used in the reported study. If your submission does not contain these data, please either upload them as Supporting Information files or deposit them to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. If data are owned by a third party, please indicate how others may request data access. 4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: 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: 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: 1. In the results section, the authors stated “The effect of the SGLT2 inhibitor on the primary outcome was consistent across all subgroups (Figure 3)”. This sentence does not reflect whether the results in each subgroup were significant or not. I recommend adding a much clearer statement about this result. 2. In the discussion section, the authors stated “we selected DPP4 inhibitors as an active comparator like other prior studies because it is a relatively new and widely used oral antihyperglycemic agent”. Authors should improve justification on why DPP4 inhibitors are an adequate comparator to evaluate effect differences from SGLT-2 inhibitors. Also, authors should give reasons on why they do not make comparisons with other pleiotropic drugs such as Metformin or GLP-1 analogs. I suggest, if there is available data from the cohort, add analyses including all other anti-diabetic medications as a “usual therapy” control group in the supplement. 3. In the discussion section, you stated “DPP4 inhibitors are the most commonly used drug in Korea as a second-line therapy after metformin”. If DPP4 inhibitors are considered a second line medication in your study population, diabetic patients prescribed with this medication may be less controlled overall, which may be a source of confound if you are evaluating the effect in CV outcomes. 4. In the discussion section, the authors used the following statement “Several studies have shown that the use of SGLT2 inhibitors was associated with a reduced risk of incident AF”. I recommend rewriting the sentence avoiding the word “several” as you only cite 2 studies. Reference 24 is a review of individual studies, I suggest citing all of them instead of just citing the review. 5. Finally, in the discussion section you make an interesting acknowledgement about the limitation of your study to assess the effect in SGLT-2 inhibitors in non-diabetic patients with AF. I recommend adding a suggestion to further research in this population. Reviewer #2: This research presents a retrospective cohort study investigating the efficacy of SGLT2i in patients with type 2 diabetes (T2D) complicated by atrial fibrillation (AF). Leveraging the Korean National Health Insurance Service database, the study assesses the impact of SGLT2i on the composite endpoint of hospitalization for heart failure (HF) or death. The merits of this research lie in: 1) Demonstrating that SGLT2i significantly reduce the risk of HF hospitalization or death among T2D patients with AF, providing novel evidence for the application of SGLT2i in this patient population. 2) Conducting a large-scale retrospective study utilizing the national health insurance database, enhancing the reliability and representativeness of the findings. 3) Implementing propensity score matching for 37 confounding variables, effectively mitigating their influence and ensuring the rigor of the study design. However, I have the following questions regarding this research: 1. The lack of detailed subgroup analyses by different types of AF (e.g., paroxysmal, persistent, or permanent) or by specific SGLT2i limits the generalizability of the results. 2. Given that SGLT2i can improve blood pressure, lipid profiles, and exhibit diuretic effects, all of which may contribute to better AF outcomes, could mediation analysis be employed to explore the role of these improvements in mediating the observed effects? 3. Subgroup analyses based on patient baseline characteristics are crucial to gain a fuller understanding of the efficacy variations of SGLT2i across different patient groups. 4. The situation of combination therapy should be carefully elucidated. GLP-1RA use could impact cardiac outcomes. While SGLT2i patients likely have GLP-1RA co-treatment, DPP4i patients should not. Yet, Table 1 shows 8% GLP-1RA co-use in both, raising doubts about a statistical error. ****** 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: Marcelo Reategui-Diaz Reviewer #2: Yes: Xiaowen Zhang ******** [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.0314454.r001
Revision 1
2 Sep 2024 Author Response Reviewer #1: 1. In the results section, the authors stated “The effect of the SGLT2 inhibitor on the primary outcome was consistent across all subgroups (Figure 3)”. This sentence does not reflect whether the results in each subgroup were significant or not. I recommend adding a much clearer statement about this result. First, we sincerely appreciate all your constructive and valuable comments. In our subgroup analysis, SGLT2 inhibitors showed a lower risk in the composite of HF hospitalization or death than DPP2 inhibitors regardless of age, gender, comorbidities, prior history of ASCVD or heart failure, and use of beta blocker or RAS blocker. The p value for interaction for all these subgroups were greater than 0.05. We included this in the revised manuscript for clearer understanding as the reviewer suggested. Revision in the manuscript on page 8: The effect of the SGLT2 inhibitor on the primary outcome was consistent across all subgroups, indicating that SGLT2 inhibitors were associated with a lower risk of the composite of HF hospitalization or death compared to DPP2 inhibitors, regardless of age, gender, comorbidities, prior history of atherosclerotic CV disease or HF, and the use of beta blocker or renin-angeiotensin system blocker (all p for interaction>0.05, Figure 3). 2. In the discussion section, the authors stated “we selected DPP4 inhibitors as an active comparator like other prior studies because it is a relatively new and widely used oral antihyperglycemic agent”. Authors should improve justification on why DPP4 inhibitors are an adequate comparator to evaluate effect differences from SGLT-2 inhibitors. Also, authors should give reasons on why they do not make comparisons with other pleiotropic drugs such as Metformin or GLP-1 analogs. I suggest, if there is available data from the cohort, add analyses including all other anti-diabetic medications as a “usual therapy” control group in the supplement. We thank to the reviewer for the insightful comments. Unfortunately, since we received data exclusively on users of SGLT2 inhibitors and DPP4 inhibitors from the National Health Insurance Service, it is difficult to perform a comparative analysis between SGLT2 inhibitors and all other anti-diabetic medications with the current data, as the reviewer suggested. We chose DPP4 inhibitors as an active comparator in our study, similar to other prior studies, because it is a relatively new and widely used oral antihyperglycemic agent. Indeed, DPP4 inhibitors are the most commonly used second line drug after metformin in Korea. In addition, they have shown a neutral effect in most CV outcome trials and have a moderate effect in reducing HbA1c with a low risk of hypoglycemia, similar to SGLT2 inhibitors. While most medical costs are covered by the National Health Insurance Service in South Korea, the National Health Insurance system in Korea generally recommends metformin as the first-line treatment for diabetes. Other antidiabetic medications, including SGLT2 inhibitors, are typically used as second-line treatments after metformin. Therefore, we considered that comparing SGLT2 inhibitors with metformin may be inappropriate due to significant differences in their recommended indications and usage patterns, which would not allow for proper patient matching. Moreover, other medications such as insulin, thiazolidinediones, GLP-1 receptor agonists, and alpha-glucosidase inhibitors are used less frequently in patients with diabetes and atrial fibrillation (less than 10% usage) in Korea. This limited use poses challenges for robust statistical analysis. Although Sulfonylureas are used more frequently, they have a different hypoglycemia risk profile compared to SGLT2 inhibitors and are subject to different insurance reimbursement criteria, complicating direct comparisons. We added this in the revised manuscript as the following. Revision in the manuscript on page 9-10: In our study, we selected DPP4 inhibitors as an active comparator like other prior studies, because they are relatively new and widely used oral antihyperglycemic agents.9 10 Like SGLT2 inhibitors, DPP4 inhibitors are commonly used as second-line therapies after metformin in Korea. 11 Both DPP-4 inhibitors and SGLT2 inhibitors are prescribed under similar clinical circumstances, specifically for patients who do not achieve sufficient glycemic control with metformin alone. This similarity would help reduce the potential for confounding in our evaluation of CV outcomes. In addition, DPP4 inhibitors have shown a neutral effect in most CV outcome trials,12 13 and they have a moderate effect in reducing HbA1c with a low risk of hypoglycemia, similar to SGLT2 inhibitors.14 By choosing DPP-4 inhibitors, we aimed to compare the efficacy and safety of SGLT2 inhibitors against a drug with a similar clinical profile, thereby providing meaningful insights into their relative effects. 3. In the discussion section, you stated “DPP4 inhibitors are the most commonly used drug in Korea as a second-line therapy after metformin”. If DPP4 inhibitors are considered a second line medication in your study population, diabetic patients prescribed with this medication may be less controlled overall, which may be a source of confound if you are evaluating the effect in CV outcomes. We apologize for any confusion caused by our previous explanation. As noted, in Korea, DPP-4 inhibitors are used as a second-line therapy following metformin, and SGLT2 inhibitors are similarly used as second-line treatments when metformin alone does not achieve adequate glycemic control. In clinical practice, both medications are considered for patients whose glycemic levels remain inadequately controlled with metformin alone. Therefore, within the context of our study, the clinical scenarios in which DPP-4 inhibitors and SGLT2 inhibitors are prescribed are comparable. It is indeed true that patients using DPP-4 inhibitors may exhibit less glycemic control overall compared to those on first-line treatment with metformin. However, this reflects a common scenario where both DPP-4 inhibitors and SGLT2 inhibitors are considered for similar patient populations who have not achieved satisfactory glycemic control with metformin alone. This similarity in clinical context helps mitigate the risk of confounding due to differential treatment practices, making DPP-4 inhibitors a relevant comparator for evaluating the effects of SGLT2 inhibitors on cardiovascular outcomes. We have revised our discussion section to provide a clearer understanding and to more accurately reflect this rationale. <Revision in the manuscript on page 9-10> In our study, we selected DPP4 inhibitors as an active comparator like other prior studies, because they are relatively new and widely used oral antihyperglycemic agents.9 10 Like SGLT2 inhibitors, DPP4 inhibitors are commonly used as second-line therapies after metformin in Korea. 11 Both DPP-4 inhibitors and SGLT2 inhibitors are prescribed under similar clinical circumstances, specifically for patients who do not achieve sufficient glycemic control with metformin alone. This similarity would help reduce the potential for confounding in our evaluation of CV outcomes. In addition, DPP4 inhibitors have shown a neutral effect in most CV outcome trials,12 13 and they have a moderate effect in reducing HbA1c with a low risk of hypoglycemia, similar to SGLT2 inhibitors.14 By choosing DPP-4 inhibitors, we aimed to compare the efficacy and safety of SGLT2 inhibitors against a drug with a similar clinical profile, thereby providing meaningful insights into their relative effects. 4. In the discussion section, the authors used the following statement “Several studies have shown that the use of SGLT2 inhibitors was associated with a reduced risk of incident AF”. I recommend rewriting the sentence avoiding the word “several” as you only cite 2 studies. Reference 24 is a review of individual studies, I suggest citing all of them instead of just citing the review We appreciate your comments. Reference 24 provides a pooled analysis of CV and renal outcome trials. As suggested by the reviewer, we have replaced the word “several” with “previous” and added more references to support this point. Revision in the manuscript on page 11: Previous studies have shown that the use of SGLT2 inhibitors was associated with a reduced risk of incident AF. 7,8,24-27 5. Finally, in the discussion section you make an interesting acknowledgement about the limitation of your study to assess the effect in SGLT-2 inhibitors in non-diabetic patients with AF. I recommend adding a suggestion to further research in this population. We thank for your invaluable suggestion. We added this in the discussion section as the reviewer suggested. Revision in the manuscript on page 12: Fourth, we assessed the effects of SGLT inhibitors in diabetic patients with AF. Thus, whether SGLT2 inhibitors improve clinical outcomes in non-diabetic patients with AF is uncertain. Further research is warranted to explore the effects of SGLT2 inhibitors in patients with AF, irrespective of their diabetes status. Reviewer #2: This research presents a retrospective cohort study investigating the efficacy of SGLT2i in patients with type 2 diabetes (T2D) complicated by atrial fibrillation (AF). Leveraging the Korean National Health Insurance Service database, the study assesses the impact of SGLT2i on the composite endpoint of hospitalization for heart failure (HF) or death. The merits of this research lie in: 1) Demonstrating that SGLT2i significantly reduce the risk of HF hospitalization or death among T2D patients with AF, providing novel evidence for the application of SGLT2i in this patient population. 2) Conducting a large-scale retrospective study utilizing the national health insurance database, enhancing the reliability and representativeness of the findings. 3) Implementing propensity score matching for 37 confounding variables, effectively mitigating their influence and ensuring the rigor of the study design. However, I have the following questions regarding this research: 1. The lack of detailed subgroup analyses by different types of AF (e.g., paroxysmal, persistent, or permanent) or by specific SGLT2i limits the generalizability of the results. We sincerely appreciate all your constructive and detailed comments. Due to the nature of the national insurance claims data we analyzed, most cases did not clearly specify the subtype of AF (e.g., paroxysmal, persistent, or permanent). This limitation precluded us from conducting detailed subgroup analyses based on different types of AF. Furthermore, we could not obtain specific data on individual SGLT2 inhibitors; the dataset provided drug information only at the class level to protect personal information. This restriction is in accordance with the national health insurance service's policy, which aims to limit the release of data that could potentially identify individuals and be misused for pharmaceutical marketing purposes. We have included these points in our limitations section of the revised manuscript to enhance clarity. Revision in the manuscript on page 11: First, the national cohort database used in our analysis provides drug information only by class to protect personal information. Consequently, we were unable to assess the effects according to the specific types of each drug used. Also, detailed patient information, AF subtype, and laboratory results were not available, which did not allow us to conduct analyses related to these aspects. Therefore, we could not perform detailed analysis to explore the mechanisms by which SGLT2 inhibitors exert their effects, such as potential associations with blood pressure, lipid profiles, or diuretic effects. 2. Given that SGLT2i can improve blood pressure, lipid profiles, and exhibit diuretic effects, all of which may contribute to better AF outcomes, could mediation analysis be employed to explore the role of these improvements in mediating the observed effects? We appreciate your insightful comments regarding the potential influence of SGLT2 inhibitors on blood pressure, lipid metabolism, and diuretic effects contributing to AF outcomes. It is indeed a fascinating area to explore which factors predominantly contribute to better outcome in this population. However, the dataset does not provide detailed information on individual patients' altered indicators, making such mediation analysis challenging. We acknowledged this limitation more specifically in the revised manuscript. Revision in the manuscript on page 11: First, the national cohort database used in our analysis provides drug information only by the class to protect personal information. Therefore, we were unable to assess the effects according to the specific types of each drug used. Also, detailed patient information, AF subtype, and laboratory results were not available, which did not allow us to conduct analyses related to these aspects. Thus, we could not perform detailed analysis to explore the mechanisms by which SGLT2 inhibitors exert their effects, such as potential associations with blood pressure, lipid profiles, or diuretic effects. 3. Subgroup analyses based on patient baseline characteristics are crucial to gain a fuller understanding of the efficacy variations of SGLT2i across different patient groups. We thank for your suggestion. We have added a subgroup analysis based on patient baseline characteristics in Fig 3 of the revised manuscript, as suggested by the reviewer. Revision in the manuscript: Figure 3 4. The situation of combination therapy should be carefully elucidated. GLP-1RA use could impact cardiac outcomes. While SGLT2i patients likely have GLP-1RA co-treatment, DPP4i patients should not. Yet, Table 1 shows 8% GLP-1RA co-use in both, raising doubts about a statistical error. We appreciate your critical comments. Upon re-checking our dataset, we identified a critical error in Table 1, where the orders of medications was incorrectly arranged. Specifically, the prescription rate of GLP-1RA was 0.3% in both the SGLT2 inhibitors and DPP4 inhibitors group. Thes low co-use rate of SGLT2i and GLP1RA can be attributed to specific insurance guidelines in Korea. In our country, most medical costs are covered by the national health insurance system, which sets the reimbursement criteria for medication prescriptions. Currently, the combination use of SGLT2i and GLP-1RA is not reimbursed in Korea, resulting in a financial burden for patients who would need to pay out-of-pocket for these medications. This financial constraint likely contributes to the low rate of combination therapy. Similarly, the combination of DPP4 inhibitors and GLP-1RA is not reimbursed and is actually contraindicated. However, in some cases, both medications might be prescribed together. For instance, a patient already on DPP4 inhibitor for diabetes management may be prescribed a GLP-1RA either for weight loss or to achieve better glycemic control, possibly by a different healthcare provider or due to an oversight in clinical judgment. We have corrected Table 1 accordingly in the revised manuscript. Once again, we deeply appreciate the reviewer’s all the detailed and constructive comments and suggestions. Revision in Table 1 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0314454.r002
15 Oct 2024 Decision Letter - Xinlin Zhang, Editor PONE-D-24-09659R1The effect of SGLT2 inhibitor in patients with type 2 diabetes and atrial fibrillationPLOS ONE Dear Dr. Shin, 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 Nov 29 2024 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, Xinlin Zhang 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: (No Response) 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: 1. The authors have made significant improvements to the presentation of subgroup results. However, the revised statement indicates that the subgroup analysis demonstrates a causal interaction. This finding should also be addressed in the methods section, particularly regarding the interpretation of the p-value for interaction. To further elucidate this observation, I recommend the following article: Brankovic M, Kardys I, Steyerberg EW, et al. "Understanding Interaction (Subgroup) Analysis in Clinical Trials." European Journal of Clinical Investigation. 2019; 49:e13145. https://doi.org/10.1111/eci.13145. Reviewer #2: The authors have thoroughly addressed my previous comments and suggestions. The changes made have significantly improved the clarity, rigor, and overall quality of the manuscript. I have no further concerns and believe that the manuscript is now suitable for publication in this journal. ****** 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: Marcelo Reategui-Diaz Reviewer #2: Yes: Xiaowen Zhang ******** [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.0314454.r003
Revision 2
3 Nov 2024 Author Response Reviewer #1: 1. The authors have made significant improvements to the presentation of subgroup results. However, the revised statement indicates that the subgroup analysis demonstrates a causal interaction. This finding should also be addressed in the methods section, particularly regarding the interpretation of the p-value for interaction. To further elucidate this observation, I recommend the following article: Brankovic M, Kardys I, Steyerberg EW, et al. "Understanding Interaction (Subgroup) Analysis in Clinical Trials." European Journal of Clinical Investigation. 2019; 49:e13145. https://doi.org/10.1111/eci.13145. We would like to thank you for your valuable comments and suggestions, which have greatly contributed to the improvement of this manuscript. We added/modified the text in the method section and result section as per your suggestion. Method - Statistical analysis After propensity score matching, we performed survival analyses to estimate the effect of SGLT2 inhibitors on clinical outcomes. The Kaplan–Meier estimates were performed. The difference between the survival curves was assessed by the log-rank test. A marginal Cox proportional hazards regression models for a cluster in a matched pair were performed. We assessed the consistency of the drug effect on the primary outcome in subgroups. Subgroup analyses were performed to assess whether the effect of SGLT2 inhibitor on clinical outcomes varied across different baseline characteristics. We computed interaction p-values to detect effect modification. An interaction p-value < 0.05 would indicate a statistically significant interaction effect between the treatment and the subgroup variable, suggesting the presence of effect modification, but it is important to note that non-significant interaction p-values do not rule out the possibility of clinically relevant differences in subgroups.1 In addition, to evaluate whether the benefit of the SGLT2 inhibitor varied with the follow-up period after the time of initiation, analyses were performed according to the time after initiation of the drug (30, 90, 180 days, 1, and 3 years after the index date). Two-sided p values < 0.05 were considered statistically significant. All analyses were performed with SAS (ver. 9.4; SAS Institute, Cary, NC, USA) and R software (ver. 4.0.3; R Development Core Team, Vienna, Austria). Result The effect of the SGLT2 inhibitor on the primary outcome was consistent across all subgroups, indicating that SGLT2 inhibitors were associated with a lower risk of the composite of HF hospitalization or death compared to DPP4 inhibitors, regardless of age, gender, comorbidities, prior history of atherosclerotic CV disease or HF, and the use of beta blocker or renin-angiotension system blocker (all p for interaction>0.05, Fig 3). This suggests that the impact of SGLT2 inhibitor relative to the DPP-4 inhibitor was consistent across the baseline characteristics evaluated. However, this should not be interpreted as definitive evidence of uniform effects across all subgroups. Further studies with more power or focusing on specific subgroups may provide additional insights. Patients with SGLT2 inhibitor demonstrated a significantly lower risk of primary outcome from 90 days after initiating the drug to the third year, as compared with those with DPP4 inhibitor (P<0.05, Table 3). Reference 1 Brankovic M, Kardys I, Steyerberg EW, et al. Understanding of interaction (subgroup) analysis in clinical trials. European journal of clinical investigation 2019;49:e13145. Attachments Attachment Submitted filename: 2nd revision response letter.docx https://doi.org/10.1371/journal.pone.0314454.r004
12 Nov 2024 Decision Letter - Xinlin Zhang, Editor The effect of SGLT2 inhibitor in patients with type 2 diabetes and atrial fibrillation PONE-D-24-09659R2 Dear Dr. Shin, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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, Xinlin Zhang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0314454.r005
Formally Accepted
15 Nov 2024 Acceptance Letter - Xinlin Zhang, Editor PONE-D-24-09659R2 PLOS ONE Dear Dr. Shin, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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 Professor Xinlin Zhang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0314454.r006

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .