Antidiabetic drug utilization pattern, affordability and cost analysis in Iran from 2009 to 2021: A need to revise guideline

Saman Zartab; Hadi Abbasian

doi:10.1371/journal.pone.0333186

Peer Review History

Original SubmissionDecember 5, 2024
24 Apr 2025 Decision Letter - Steve Zimmerman, Editor Dear Dr. Abbasian, 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. The manuscript has been evaluated by two reviewers, and their comments are available below. -->?> Please submit your revised manuscript by Jun 08 2025 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. 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, Steve Zimmerman, PhD Senior 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 [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? Reviewer #1: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? -->?> Reviewer #1: N/A 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 Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ******** Reviewer #1: This study presents valuable insights into the utilization and cost trends of antidiabetic medications in Iran over a 13-year period. The manuscript addresses important topics such as affordability and market dynamics; however, there are several areas that require improvement, as outlined below: 1. Use of Abbreviations: The manuscript does not consistently introduce abbreviations before their first use. Several abbreviations, such as DDD, ATC, DID, DU, GDP, ADA, and ESAD, … are used without prior definition, which may hinder comprehension—particularly in the abstract. It is strongly recommended that the authors carefully review the whole manuscript and ensure that all abbreviations are properly defined upon first mention. 2. Comparison with Existing Literature: The study utilizes public data from Amarnameh; however, data from Amarnameh on trends in blood glucose-lowering medications have been previously analyzed and reported in other published works and the manuscript does not acknowledge these prior studies, nor does it compare its findings to them. For instance, the following study provides relevant insights: Kheirandish M, Varahrami V, Kebriaeezade A, Cheraghali AM. Impact of economic sanctions on access to noncommunicable diseases medicines in the Islamic Republic of Iran. East Mediterr Health J. 2018 Apr 5;24(1):42-51. PMID: 29658620. I recommend the authors to clarify how their study differs from previous works, whether it provides additional insights, updates the findings, or introduces a new analytical approach. 3. Consideration of Bias and Confounding Factors: Given the retrospective nature of the study, it is important to address potential sources of bias and confounding factors. For example, the assumption that minimum wage accurately reflects purchasing power may not be entirely valid, as income disparities exist within the population. Additionally, changes in healthcare policies, pricing regulations, or diagnostic practices may have influenced the observed trends. While some policy changes are briefly mentioned (e.g., line 196: Liraglutide was unaffordable in all the years studied, despite the price reduction following the policy of using biosimilar drugs), a more detailed discussion of their details and impact on the observed trends would enhance the manuscript. 4. Title and Recommendations: The title includes the phrase "a need to revise guidelines”, yet the manuscript does not provide clear, actionable recommendations based on the findings. While the study highlights the economic burden of antidiabetic drugs, it would benefit from a discussion on potential policy adjustments or strategies to address the observed trends. 5. Speculative Statements: Some sections of the discussion contain statements that appear speculative or opinion-based rather than being fully supported by data or citations of the previous literature. Specifically, lines 247–248 and 294–322 should be revised to either include supporting evidence from the literature or be explicitly framed as author’s hypotheses to avoid misinterpretation. 6. Lack of Statistical Analysis: A key limitation of the study is the absence of statistical analysis. While the manuscript presents descriptive statistics (e.g., trends over time, market share changes), it does not employ inferential statistical methods to assess the significance of these trends. For instance, regression analysis could be used to evaluate the relationship between drug costs and utilization over time or to compare the affordability of different drug classes. Incorporating statistical analysis would strengthen the validity of the conclusions drawn. Reviewer #2: Overall, this is a well-structured and well-written manuscript. I have a few comments for some revision. The introduction section is relevant; however, it does not provide a clear overview of the background and rationale for the study. The study's objectives and procedures must be added and presented logically, making it easy for the reader to follow. You need to include global, regional, and then Iranian diabetes prevalence. In the abstract, lines 31-32, first write the full meaning of DID abbreviation. Line 95 (please use × sing instead of ) DDD1000/, please use DDD×1000 Line 144, for Table heading years, is broken down; you need to adjust the table size or change it to a smaller font size. Line 170, the full meaning of DU abbreviation. Figure 2, for the vertical axis heading, please add "US dollar in million" Figure 4, in the horizontal axis, years are not readable; please adjust the figure size or make the year's font smaller to make it readable. The same also applies to figure 5 You may add the generalizability of this study's findings before the conclusion. For the method section, you may add a few more statistics such as 95% confidence intervals for Insusin and analogues and blood glucose lowering drugs. For Figures 2 and 3, you should check to use the Chi-square test or any other type of test. If you want to compare the mean outcome (antidiabetic medicine expenditure) across the three medicines, you can use statistical test and suggested test5 is one-way ANOVA. Please also check the English and spelling throughout the paper. Please add Iran in the conclusion. ******** 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: Yes: Montasir Ahmed ******** [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.0333186.r001
Revision 1
29 Jun 2025 Author Response Reviewer #1: This study presents valuable insights into the utilization and cost trends of antidiabetic medications in Iran over a 13-year period. The manuscript addresses important topics such as affordability and market dynamics; however, there are several areas that require improvement, as outlined below: 1. Use of Abbreviations: The manuscript does not consistently introduce abbreviations before their first use. Several abbreviations, such as DDD, ATC, DID, DU, GDP, ADA, and ESAD, … are used without prior definition, which may hinder comprehension—particularly in the abstract. It is strongly recommended that the authors carefully review the whole manuscript and ensure that all abbreviations are properly defined upon first mention. Response to reviewer1 #1: Thanks to the careful attention of the esteemed reviewer, the abbreviations in the text have been corrected. 2. Comparison with Existing Literature: The study utilizes public data from Amarnameh; however, data from Amarnameh on trends in blood glucose-lowering medications have been previously analyzed and reported in other published works and the manuscript does not acknowledge these prior studies, nor does it compare its findings to them. For instance, the following study provides relevant insights: Kheirandish M, Varahrami V, Kebriaeezade A, Cheraghali AM. Impact of economic sanctions on access to noncommunicable diseases medicines in the Islamic Republic of Iran. East Mediterr Health J. 2018 Apr 5;24(1):42-51. PMID: 29658620. I recommend the authors to clarify how their study differs from previous works, whether it provides additional insights, updates the findings, or introduces a new analytical approach. Response to reviewer1 #2: Thanks to the reviewer’s valuable comments, the requested material was added and referenced. 3. Consideration of Bias and Confounding Factors: Given the retrospective nature of the study, it is important to address potential sources of bias and confounding factors. For example, the assumption that minimum wage accurately reflects purchasing power may not be entirely valid, as income disparities exist within the population. Additionally, changes in healthcare policies, pricing regulations, or diagnostic practices may have influenced the observed trends. While some policy changes are briefly mentioned (e.g., line 196: Liraglutide was unaffordable in all the years studied, despite the price reduction following the policy of using biosimilar drugs), a more detailed discussion of their details and impact on the observed trends would enhance the manuscript. Response to reviewer1 #3: Thanks for your suggestions. According to the World Health Organization, “affordability” depends on the purchasing power and price of the product, and many people in Iranian society work below the declared minimum wage, which has been added to the text. Unfortunately, there has been no change in the diagnostic methods during the studied period in Iran, and the Cost Plus method has been used for drug pricing in Iran for a long time. The only significant policy change in this matter is the growth of the private sector and their market share, which was mentioned in the text. 4. Title and Recommendations: The title includes the phrase "a need to revise guidelines”, yet the manuscript does not provide clear, actionable recommendations based on the findings. While the study highlights the economic burden of antidiabetic drugs, it would benefit from a discussion on potential policy adjustments or strategies to address the observed trends. Response to reviewer1 #4: Added with thanks. 5. Speculative Statements: Some sections of the discussion contain statements that appear speculative or opinion-based rather than being fully supported by data or citations of the previous literature. Specifically, lines 247–248 and 294–322 should be revised to either include supporting evidence from the literature or be explicitly framed as author’s hypotheses to avoid misinterpretation. Response to reviewer1 #5: Thanks, corrected in the text. 6. Lack of Statistical Analysis: A key limitation of the study is the absence of statistical analysis. While the manuscript presents descriptive statistics (e.g., trends over time, market share changes), it does not employ inferential statistical methods to assess the significance of these trends. For instance, regression analysis could be used to evaluate the relationship between drug costs and utilization over time or to compare the affordability of different drug classes. Incorporating statistical analysis would strengthen the validity of the conclusions drawn. Response to reviewer1 #6: Time series regression equations were added to examine the trend of increasing consumption, and Figure 1 was modified. Reviewer #2: Overall, this is a well-structured and well-written manuscript. I have a few comments for some revision. The introduction section is relevant; however, it does not provide a clear overview of the background and rationale for the study. The study's objectives and procedures must be added and presented logically, making it easy for the reader to follow. You need to include global, regional, and then Iranian diabetes prevalence. Thanks for your attention, it has been corrected in the text. In the abstract, lines 31-32, first write the full meaning of DID abbreviation. Thanks for your attention, it has been corrected in the text. Line 95 (please use × sing instead of ) DDD1000/, please use DDD×1000 Thanks for your attention, it has been corrected in the text. Line 144, for Table heading years, is broken down; you need to adjust the table size or change it to a smaller font size. The table has been adjusted. Line 170, the full meaning of DU abbreviation. The abbreviation was changed to the whole word, and the whole word was added to the abstract. Figure 2, for the vertical axis heading, please add "US dollar in million" Thanks for your attention, it has been corrected in the text. Figure 4, in the horizontal axis, years are not readable; please adjust the figure size or make the year's font smaller to make it readable. The same also applies to figure 5 You may add the generalizability of this study's findings before the conclusion. Thanks for your attention, it has been corrected in the text. For the method section, you may add a few more statistics such as 95% confidence intervals for Insusin and analogues and blood glucose lowering drugs. For Figures 2 and 3, you should check to use the Chi-square test or any other type of test. If you want to compare the mean outcome (antidiabetic medicine expenditure) across the three medicines, you can use statistical test and suggested test5 is one-way ANOVA. Given that this study uses a national database and is not a hospital-level study, the data is for the total population and generalization from the sample to the population has not occurred. Therefore, statistical tests that analyze sample data to express the probability of accuracy of the results in the statistical population are not applicable to it. So time series regression equations were added to examine the trend of increasing consumption, and Figure 1 was modified. Please also check the English and spelling throughout the paper. Thanks, the corrections have been made. Please add Iran in the conclusion. Thanks, your point has been added and highlighted. Attachments Attachment Submitted filename: response to reviewers.docx https://doi.org/10.1371/journal.pone.0333186.r002
13 Aug 2025 Decision Letter - Eyob Alemayehu Gebreyohannes, Editor Dear Dr. Abbasian, 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. ============================== ACADEMIC EDITOR: ============================== Please submit your revised manuscript by Sep 27 2025 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. 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 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, Eyob Alemayehu Gebreyohannes, PhD Academic Editor PLOS ONE Journal Requirements: If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 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 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??> 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 Reviewer #1: Yes Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English??> Reviewer #1: Yes Reviewer #2: Yes ****** Reviewer #1: I would like to thank the authors for their thoughtful revision and comprehensive responses to the comments. Reviewer #2: Thank you for the revised version. It appears that the authors have addressed all of my comments, and the manuscript reads well. I am pleased to recommend acceptance. However, I would like to note a few additional points for improvement before final submission: Language and Style While the study contains valuable data, the manuscript still suffers from grammatical errors, which may hinder reader comprehension. A thorough professional English language edit is strongly recommended. Figures and Tables Readability: The current use of light ash colour in Figures 1–6 makes key elements difficult to read. Please use black for improved visibility. For example, in Figure 5, the "Minimum daily wage" lines and the horizontal axis years would be more legible if displayed in black. Figure Titles: Please remove titles from inside the figures. For instance, Figure 2 is titled “Antidiabetic drugs expenditure” in the caption but also contains the title “Antidiabetic medicine expenditure” within the figure itself. This duplication detracts from the professional appearance. The same applies to other figures—retain the title only in the caption, not within the figure. Addressing these issues will significantly improve the presentation and clarity of your work. ****** 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: Yes: Montasir Ahmed ******** [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 https://doi.org/10.1371/journal.pone.0333186.r003
Revision 2
3 Sep 2025 Author Response Reviewer 2: Language and Style While the study contains valuable data, the manuscript still suffers from grammatical errors, which may hinder reader comprehension. A thorough professional English language edit is strongly recommended. Thank you for your suggestion, the article was edited and improved in terms of English. Figures and Tables Readability: The current use of light ash colour in Figures 1–6 makes key elements difficult to read. Please use black for improved visibility. For example, in Figure 5, the "Minimum daily wage" lines and the horizontal axis years would be more legible if displayed in black. According the suggestion of reviewer 2 and editor the ash color changed to black in all part of the figures so visibility od them enhanced. Figure Titles: Please remove titles from inside the figures. For instance, Figure 2 is titled “Antidiabetic drugs expenditure” in the caption but also contains the title “Antidiabetic medicine expenditure” within the figure itself. This duplication detracts from the professional appearance. The same applies to other figures—retain the title only in the caption, not within the figure. Titles removed from inside the figures. ACADEMIC EDITOR: While the manuscript has merit, the language must undergo a thorough professional edit to address grammatical errors, awkward phrasing, and inconsistent tense usage, ensuring clarity and fluency throughout. In addition, the presentation of figures must be improved by enhancing visibility and removing embedded titles to avoid duplication with captions. Any changes made must be indicated as tracked changes. These refinements are essential to enhance readability and professional presentation. Please note that failure to fully address these concerns in the revised submission may result in rejection of the manuscript. All corrections and improvements to the article's text have been made based on your suggestions. Attachments Attachment Submitted filename: second rebuttal letter.docx https://doi.org/10.1371/journal.pone.0333186.r004
10 Sep 2025 Decision Letter - Eyob Alemayehu Gebreyohannes, Editor Anti-diabetic drug utilization pattern, affordability and cost analysis in Iran from 2009 to 2021; a need to revise guideline PONE-D-24-56063R2 Dear Dr. Abbasian, 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. For questions related to billing, please contact billing support . 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, Eyob Alemayehu Gebreyohannes, PhD Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0333186.r005
Formally Accepted
Acceptance Letter - Eyob Alemayehu Gebreyohannes, Editor PONE-D-24-56063R2 PLOS ONE Dear Dr. Abbasian, 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 You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days 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. You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing. 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 Dr. Eyob Alemayehu Gebreyohannes Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0333186.r006

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