Vitamin B12 deficiency in diabetic patients treated with metformin: A cross-sectional study

Dat Tan Huynh; Ngoc Thi Nguyen; Minh Duc Do

doi:10.1371/journal.pone.0302500

Peer Review History

Original SubmissionJanuary 10, 2024
18 Jan 2024 Decision Letter - Joseph Alan Bauer, Editor PONE-D-24-00863VITAMIN B12 DEFICIENCY IN DIABETIC PATIENTS TREATED WITH METFORMIN: A CROSS-SECTIONAL STUDYPLOS ONE Dear Dr. Do, 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 Mar 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. 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You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible. We will update your Data Availability statement on your behalf to reflect the information you provide. 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 delete it from any other section. 5. Please include a caption for figure 1. Additional Editor Comments (if provided): The manuscript titled "VITAMIN B12 DEFICIENCY IN DIABETIC PATIENTS TREATED WITH METFORMIN: A CROSS-SECTIONAL STUDY" addresses a significant issue in diabetic care. The relationship between long-term metformin use and vitamin B12 deficiency is well-documented in the literature, with several studies indicating a clear association. This is an area of concern given the widespread use of metformin in managing type 2 diabetes. Your manuscript should consider incorporating findings from various studies that have explored this relationship. For instance, the HOME trial, as published in the BMJ in 2010, provides valuable insights into the effects of metformin on vitamin B12 levels in diabetic patients. This randomized placebo-controlled trial observed changes in vitamin B12 levels over different phases of metformin treatment, offering a structured and comprehensive understanding of the issue. Further, a systematic review on PubMed highlights various articles that delve into the association between metformin use, vitamin B12 deficiency, and its clinical implications like peripheral neuropathy. These studies collectively underscore the importance of monitoring vitamin B12 levels in diabetic patients on long-term metformin therapy. Additionally, the association between metformin-induced vitamin B12 deficiency and peripheral neuropathy, as discussed in several articles on PubMed, is a critical aspect that should be addressed in your manuscript. The prevalence of vitamin B12 deficiency among diabetic patients on metformin and its potential impact on peripheral neuropathy is a significant area of concern, and your study could benefit from discussing these findings. Regarding the use of homocysteine (HCY) and methylmalonic acid (MMA) as indicators of vitamin B12 deficiency in tissues, these are reliable markers for diagnosing vitamin B12 deficiency at the tissue level. Their omission in the experimental design of your study is a point that should be addressed. The rationale for not including these markers should be clarified, considering their relevance in understanding the biochemical and clinical implications of vitamin B12 deficiency. It is also advisable to incorporate open-access references, as they would align with the broader accessibility goals of current scientific research. The inclusion of such references would not only enhance the credibility of your manuscript but also ensure its wider reach and impact. Finally, conducting a current literature search through databases like PubMed would provide the most recent and relevant studies, ensuring that your manuscript reflects the current understanding and research trends in this field. https://pubmed.ncbi.nlm.nih.gov/?term=metformin+b12+deficiency&sort=date [Note: HTML markup is below. Please do not edit.] [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.0302500.r001
Revision 1
22 Feb 2024 Author Response Response to Reviewers: The manuscript titled "VITAMIN B12 DEFICIENCY IN DIABETIC PATIENTS TREATED WITH METFORMIN: A CROSS-SECTIONAL STUDY" addresses a significant issue in diabetic care. The relationship between long-term metformin use and vitamin B12 deficiency is well-documented in the literature, with several studies indicating a clear association. This is an area of concern given the widespread use of metformin in managing type 2 diabetes. Your manuscript should consider incorporating findings from various studies that have explored this relationship. For instance, the HOME trial, as published in the BMJ in 2010, provides valuable insights into the effects of metformin on vitamin B12 levels in diabetic patients. This randomized placebo-controlled trial observed changes in vitamin B12 levels over different phases of metformin treatment, offering a structured and comprehensive understanding of the issue. Thank you so much for your suggestions, we’ve added this information to the Introduction part to emphasize the important role of the HOME trial as one of the randomized control trials confirming the causative role of metformin in vitamin B12 deficiency[1]. Further, a systematic review on PubMed highlights various articles that delve into the association between metformin use, vitamin B12 deficiency, and its clinical implications like peripheral neuropathy. These studies collectively underscore the importance of monitoring vitamin B12 levels in diabetic patients on long-term metformin therapy. Thank you for your suggestions, we’ve also added some of the systematic reviews in the Introduction and Discussion part[2–4]. Additionally, the association between metformin-induced vitamin B12 deficiency and peripheral neuropathy, as discussed in several articles on PubMed, is a critical aspect that should be addressed in your manuscript. The prevalence of vitamin B12 deficiency among diabetic patients on metformin and its potential impact on peripheral neuropathy is a significant area of concern, and your study could benefit from discussing these findings. Thank you so much for pointing out this weakness in our study. The peripheral neuropathy complication is often observed in diabetic patients with vitamin B12 deficiency. However, due to the lack of resources (funding and the participation of a neurologist), we could not make a definitive diagnosis of peripheral neuropathy in the studied population. This is obviously a major drawback of this study, and we also admit that in the Discussion part. Regarding the use of homocysteine (HCY) and methylmalonic acid (MMA) as indicators of vitamin B12 deficiency in tissues, these are reliable markers for diagnosing vitamin B12 deficiency at the tissue level. Their omission in the experimental design of your study is a point that should be addressed. The rationale for not including these markers should be clarified, considering their relevance in understanding the biochemical and clinical implications of vitamin B12 deficiency. Thank you for your suggestions, we’ve also added the information regarding the importance of homocysteine (HCY) and methylmalonic acid (MMA) as indicators of vitamin B12 deficiency in tissues in Discussion part, we also acknowledge that the increase of both methylmalonic acid and homocysteine levels can cause of worsen diabetic peripheral neuropathy[5,6]. As we previously stated, due to the lack of resources, we could not measure these important markers. It is also advisable to incorporate open-access references, as they would align with the broader accessibility goals of current scientific research. The inclusion of such references would not only enhance the credibility of your manuscript but also ensure its wider reach and impact. Finally, conducting a current literature search through databases like PubMed would provide the most recent and relevant studies, ensuring that your manuscript reflects the current understanding and research trends in this field. https://pubmed.ncbi.nlm.nih.gov/?term=metformin+b12+deficiency&sort=date Thank you for your suggestions, we’ve added more open access references in the recent years on Pubmed[4,7,8], we hope that this information could reflect the current understanding and research trends in this field. References: 1. de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. The BMJ. 2010;340: c2181. doi:10.1136/bmj.c2181 2. Khattab R, Albannawi M, Alhajjmohammed D, Alkubaish Z, Althani R, Altheeb L, et al. Metformin-Induced Vitamin B12 Deficiency among Type 2 Diabetes Mellitus’ Patients: A Systematic Review. Curr Diabetes Rev. 2023;19: e180422203716. doi:10.2174/1573399818666220418080959 3. Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016;42: 316–327. doi:10.1016/j.diabet.2016.03.008 4. Kakarlapudi Y, Kondabolu SK, Tehseen Z, Khemani V, J SK, Nousherwani MD, et al. Effect of Metformin on Vitamin B12 Deficiency in Patients With Type 2 Diabetes Mellitus and Factors Associated With It: A Meta-Analysis. Cureus. 2022;14. doi:10.7759/cureus.32277 5. Wile DJ, Toth C. Association of Metformin, Elevated Homocysteine, and Methylmalonic Acid Levels and Clinically Worsened Diabetic Peripheral Neuropathy. Diabetes Care. 2009;33: 156–161. doi:10.2337/dc09-0606 6. Bell DSH. Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes. Diabetes Obes Metab. 2022;24: 1423–1428. doi:10.1111/dom.14734 7. Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PloS One. 2014;9: e100379. doi:10.1371/journal.pone.0100379 8. Hurley-Kim K, Vu CH, Dao NM, Tran LC, McBane S, Lee J, et al. Effect of Metformin Use on Vitamin B12 Deficiency Over Time (EMBER): A Real-World Evidence Database Study. Endocr Pract. 2023;29: 862–867. doi:10.1016/j.eprac.2023.06.013 Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0302500.r002
5 Apr 2024 Decision Letter - Joseph Alan Bauer, Editor VITAMIN B12 DEFICIENCY IN DIABETIC PATIENTS TREATED WITH METFORMIN: A CROSS-SECTIONAL STUDY PONE-D-24-00863R1 Dear Dr. Do, 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, Joseph Alan Bauer, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0302500.r003

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