Data-driven long-term glycaemic control trajectories and their associated health and economic outcomes in Finnish patients with incident type 2 diabetes

Piia Lavikainen; Emma Aarnio; Miika Linna; Kari Jalkanen; Hilkka Tirkkonen; Päivi Rautiainen; Tiina Laatikainen; Janne Martikainen

doi:10.1371/journal.pone.0269245

Peer Review History

Original SubmissionFebruary 24, 2022
1 Apr 2022 Decision Letter - Dylan A Mordaunt, Editor PONE-D-22-05229Data-driven long-term glycemic control clusters and their associated health and economic outcomes in patients with incident type 2 diabetesPLOS ONE Dear Dr. Lavikainen, 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 16 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. 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We will update your Data Availability statement on your behalf to reflect the information you provide. 4. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data. 5. 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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. Additional Editor Comments: Thank you for your submission. One of our reviewers has recommended rejection, however the rational is due to a perceived lack of novelty. PLoS One criteria for publication does not include novelty, but rather originality of work. The work does appear to be original. With regards to novelty, the reviewer makes suggestions for improvement that I think the authors should consider. It's also worth considering whether this is novel in the context of the Finish health system and society, since economic outcomes in particular would be health system and society specific. This is the reason I have not receommended rejecting the manuscript. My major area of comment is that any perceived novelty can and should be made clearer, though I've opted to call this a minor rather than major revision. With specific regards to the criteria for publication: 1. The study appears to present the results of original research. 2. Results do not appear to have been reported elsewhere. 3. Experiments, statistics, and other analyses are performed to a high technical standard and are described in sufficient detail. One reviewer has suggested the authors consider further stratification. I also suggest considering making it clear (e.g. in the title) that this is within the context of Finland, though there may well be generalisable elements or insights. 4. Conclusions are presented in an appropriate fashion and are supported by the data. 5. The article is presented in an intelligible fashion and is written in standard English. Some minor suggestions are made by one of the reviewers, though to a technical English reader, this could affect the perceived credibility of the work since the English is otherwise of a good standard. 6. The research meets all applicable standards for the ethics of experimentation and research integrity. 7. The article could be refined against an appropriate observational study checklist from the Equator Network, such as one of the STROBE checklists. This adds rigour to the reporting. The checklist should be attached to the resubmission as it also adds value to the submission in terms of later meta-research on the resulting publication. [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: I Don't Know ****** 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: a useful work which confirms already accepted knowledge regarding the nature and natural history of diabetes, would have been add on to currently known data if there was any stratifications of the drug used and if there was any impact of the class of drugs especially new classes with presumed additive benefits on cardiovascular outcomes rather than just focusing on the progression of the disease Reviewer #2: Piia Lavikainen et al have applied a clustering strategy to study patients with newly diagnosed type 2 diabetes and examined the association of these groups with heath outcomes including all-cause death and incident micro- and macrovascular complications. 4 groups were identified using this latent-class growth analysis clustering approach : “Stable, adequate” (large majority, 2/3 of the study population), “Slowly deteriorating” (second largest, one fourth of the population) and 2 smal lgroups “Rapidly deteriorating” glycaemic control (6.2%) and “Late diagnosed” patients (3.4%). Most of the interest is focused on these 2 last groups. The paper is interesting but an effort should be made to facilitate direct access to salient clinical results General comment I see A1c not only as a biomarker of treatment efficacy but also as a possible biomarker indicative of severity of the disease as used in Ahlquist intial clustering work (Lancet DE). In addition the response of A1c cannot be seen as a universal response to drugs since diabetes drugs are limited to 8 large classes in patients with T2D (SU/glinides ; TZDs; Metformin; DPP4-Is ; SGLT2-Is; AG-Is; GLP1RA; insulin) although AG-Is do not appear in the current paper. Table 1 The authors should present data on eGFR and not only serum creatinine values. Do the authors have access to Fasting plasma glucose at diagnosis ? it would help to confront FPG and A1c. Table 3 needs to be more directly self-comprehensive as the amount should correspond to yearly expenses (please clarify this) I am wondering how to adjust on baseline characteristics which are different between the 4 selected groups, particularly age and sex, regarding the effect of each group on complications. This would be appreciated. The discussion is interesting and could however be shortened. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0269245.r001
Revision 1
25 Apr 2022 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: Yes Reviewer #2: Yes ________________________________________ 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: I Don't Know ________________________________________ 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: a useful work which confirms already accepted knowledge regarding the nature and natural history of diabetes, would have been add on to currently known data if there was any stratifications of the drug used and if there was any impact of the class of drugs especially new classes with presumed additive benefits on cardiovascular outcomes rather than just focusing on the progression of the disease Our response: We thank the Reviewer for the comments. However, we would prefer not to conduct additional stratified analyses. First, diabetes medication use changes over time as is seen from figure 2 and table S4, which also show how medication use modifies HbA1c trajectories. Modeling such a time-varying factor that is also associated with HbA1c would be challenging in this study and we feel that stratified analyses would require different study design. Second, we have submitted another study where we have examined changes in diabetes medication use and its association with treatment outcomes. Reviewer #2: Piia Lavikainen et al have applied a clustering strategy to study patients with newly diagnosed type 2 diabetes and examined the association of these groups with heath outcomes including all-cause death and incident micro- and macrovascular complications. 4 groups were identified using this latent-class growth analysis clustering approach : “Stable, adequate” (large majority, 2/3 of the study population), “Slowly deteriorating” (second largest, one fourth of the population) and 2 smal lgroups “Rapidly deteriorating” glycaemic control (6.2%) and “Late diagnosed” patients (3.4%). Most of the interest is focused on these 2 last groups. The paper is interesting but an effort should be made to facilitate direct access to salient clinical results General comment I see A1c not only as a biomarker of treatment efficacy but also as a possible biomarker indicative of severity of the disease as used in Ahlquist intial clustering work (Lancet DE). In addition the response of A1c cannot be seen as a universal response to drugs since diabetes drugs are limited to 8 large classes in patients with T2D (SU/glinides ; TZDs; Metformin; DPP4-Is ; SGLT2-Is; AG-Is; GLP1RA; insulin) although AG-Is do not appear in the current paper. Our response: We have added to the Discussion section on baseline clustering conducted by Ahlqvist et al. as follows: “To note, also clustering based on patient characteristics (age, HbA1c, BMI, homeostasis model assessment (HOMA2) estimates of β-cell function and insulin resistance) at the time of diagnosis in general diabetic population has been conducted[28] instead of longitudinal clustering based on HbA1c solely.” We have also discussed about the HbA1c being possible indicator of disease severity as follows: “HbA1c may not reflect only treatment response but also the underlying severity of the disease[28]. Late diagnosed patients used most often insulin reflecting more severe disease, seen also as higher incidence of complications during the 7-year follow-up despite of reaching good glycaemic control 2–3 years after the diagnosis.” AG-Is are not included in the paper as they are not used in Finland. AG-Is are not mentioned in the treatment guidelines of type 2 diabetes in Finland, and there seems to be no AG-I products on the market at the moment. Table 1 The authors should present data on eGFR and not only serum creatinine values. Do the authors have access to Fasting plasma glucose at diagnosis ? it would help to confront FPG and A1c. Our response: We thank the Reviewer for the suggestion and have added eGFR and FPG to the table 1. FPG confronts the observed HbA1c values at baseline. Serum creatinine values were converted to eGFR utilizing the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation (Levey et al. Ann Intern Med 2009;150:604-612) that accounts for age and gender. Table 3 needs to be more directly self-comprehensive as the amount should correspond to yearly expenses (please clarify this) Our response: We thank the Reviewer for commenting on this. We have clarified that the table presents average accumulated 4-year per-person costs over 2014-2017 for the stable cluster and additional costs in other clusters compared with the stable one. We would prefer presenting the accumulated costs along the HbA1c trajectories rather than presenting average yearly costs although they are often reported in cost-effectiveness analyses. I am wondering how to adjust on baseline characteristics which are different between the 4 selected groups, particularly age and sex, regarding the effect of each group on complications. This would be appreciated. Our response: We thank the Reviewer for noticing this. Individual level Cox regression models were used to examine adjusted associations of the 4 groups with complications. The models were adjusted for age, sex, concordant and discordant diseases, and microvascular and macrovascular comorbidities of a patient at baseline. Unfortunately, we had not mentioned this in the paragraph of Statistical analyses. Therefore, we have refined the text as follows: “Models were adjusted for age, sex, concordant and discordant diseases, and microvascular and macrovascular comorbidities at baseline.” The discussion is interesting and could however be shortened. Our response: We have shortened the discussion by removing, for example, detailed description of HbA1c clusters identified in previous studies. ________________________________________ 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0269245.r002
18 May 2022 Decision Letter - Dylan A Mordaunt, Editor Data-driven long-term glycaemic control trajectories and their associated health and economic outcomes in Finnish patients with incident type 2 diabetes PONE-D-22-05229R1 Dear Dr. Lavikainen, 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, Dylan A Mordaunt, MD, MPH, FRACP Academic Editor PLOS ONE Additional Editor Comments (optional): Thank you for your resubmission. This now meets the criteria for publication. Reviewers' comments: https://doi.org/10.1371/journal.pone.0269245.r003
Formally Accepted
23 May 2022 Acceptance Letter - Dylan A Mordaunt, Editor PONE-D-22-05229R1 Data-driven long-term glycaemic control trajectories and their associated health and economic outcomes in Finnish patients with incident type 2 diabetes Dear Dr. Lavikainen: 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 Associate Professor Dylan A Mordaunt Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0269245.r004

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