PONE-D-24-30732Cost Effectiveness of Empagliflozin in Adult Patients with Chronic Kidney Disease in the NetherlandsPLOS ONE

Dear Dr. Slob,

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 Oct 03 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,

Larry Allan Weinrauch, MD

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 study was funded by Boehringer Ingelheim Netherlands."

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. Thank you for stating the following in the Competing Interests section: 

"CB and MP receive grants and honoraria from various pharmaceutical companies, including Boehringer Ingelheim. They are both shareholders of Health-Ecore, the Netherlands. TF, BS and LJ are employed as consultants at Health-Ecore, which received a consultancy fee for the conduct of this study. MW is an employee at Boehringer Ingelheim Netherlands, the funder of this study. The EMPA-KIDNEY trial was initiated, designed, and conducted by the University of Oxford in collaboration with a Steering Committee of experts and Boehringer Ingelheim. The presented analyses were initiated and conducted by Boehringer Ingelheim independently from the EMPA-KIDNEY Collaborative Group. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment related to the development of this manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations."

We note that one or more of the authors are employed by a commercial company: Health-Ecore, Boehringer Ingelheim Netherlands

1) Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement. 

“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement. 

2) Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc.  

Within your Competing Interests Statement, please confirm that this commercial affiliation does not alter your adherence to all PLOS ONE policies on sharing data and materials by including the following statement: ""This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests) . If this adherence statement is not accurate and  there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf.

4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

Additional Editor Comments:

The analysis of the Cost Effectiveness of Empagliflozin in Adult Patients with Chronic Kidney Disease in the Netherlands purports to suggest that the addition of empagliflozin to standard of care medications might be cost saving. Several points have been brought up by the reviewers that do need to be addressed. One, of course is the influence of industry upon the presentation. Another is on the price of empagliflozin and whether it is similar in other countries (particularly with respect to those outside of the EU). Yet another, and perhaps even more important is that not all CKD is the same. A large proportion of CKD involves patients with diabetes. It would be helpful to break down the differences in the value of adding empagliflozin to standard of care with respect to nondiabetic vs diabetic patients, or perhaps those who are underweight vs. those who are overweight. This would give us additional information (e.g J Diabetes Complications 2021 Feb;35(2):107761)

Please respond to the requests made by the reviewers as well.

[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: No

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: This study provides valuable insights into the cost-effectiveness of empagliflozin for patients with chronic kidney disease (CKD) in the Netherlands. It is commendable that the researchers adhered to the KDIGO guidelines for CKD definition, which include both GFR levels and for eGFR >60 mll/min also the evidence of kidney damage, such as albuminuria or structural abnormalities.

The Empa Kidney study inclusion criteria, focusing on patients with eGFR less than 45 ml/min/1.73 m2 or those with eGFR between 45 and 90 ml/min/1.73 m2 and albuminuria, ensured that all participants met the KDIGO criteria. The current study presentation, particularly Figure 1, does not adequately address this aspect.

Additionally, it would be insightful to know if patients with eGFR greater than 60 ml/min without albuminuria or other signs of kidney damage, who would not meet the KDIGO criteria for CKD, were included. Furthermore, data on patients with eGFR between 45 and 60 ml/min, who meet KDIGO criteria but were excluded from the Empa kidney study, would provide valuable context and contribute to a more comprehensive understanding of empagliflozin's cost-effectiveness across different stages of CKD.

Reviewer #2: Slob et al present a detailed cost effectiveness analysis of empagliflozin in the Netherlands comparing standard of care for chronic kidney disease plus empagliflozin (empa) and standard of care alone (SoC0. Using a Markov model they show that the cost effectiveness of SoC+empag versus SoC alone is a savings of 34,381 Euros. They show that SoC+empa adds an additional 1.22 life years compared to SoC alone. The authors present data on CKD in the Netherlands that shows prevalence around 12% but only 5.1% of the Dutch population is diagnosed. I have the following questions.

1. Why was only empagliflozin studied and not the other major SGLT2 inhibitors (dapagliflozin and canagliflozin)? Are there cost analyses for them and how does the cost effectiveness of empagliflozin compare to the cost effectiveness of the others?

2. What is the standard of care for CKD in the Netherland and does it vary from co-morbidity to co-morbidity (diabetes, heart failure, coronary artery disease. How does the analysis take account of the fact that standard cof care might differ with underlying co-morbidities. The authors provide the details from KDIGO (lines 82-93, but should include regimens specific to the Netherlands.

3. How does Cost-effectiveness of empagliflozin and SoC differ across the European Union? What was the need to calculate cost effectiveness for empagliflozin specifically for the Netherlands?

**********

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: Bijan Roshan

Reviewer #2: Yes: George Bayliss, MD

**********

[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.

Cost effectiveness of empagliflozin in adult patients with chronic kidney disease in the Netherlands

PONE-D-24-30732R1

Dear Dr. Slob

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,

Larry Allan Weinrauch, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

My apologies for the long delay in accepting this work. The concerns of the reviewers and the editor have been satisfied in the revision

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: (No Response)

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: The authors have addressed my concerns. I think they addressed the commercial interest of the pharmaceutical company, provided information about other SGLT2 inhibitors in the context of the Dutch healthcare system and noted the need for individual drug analysis

**********

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: Bijan Roshan

Reviewer #2: Yes: George Bayliss, MD, FACP, FASN

**********