Metformin and Vitamin B12 Deficiency – What is the Evidence?

  • Bruno Daniel Oliveira Peixoto USF Nova Estação
  • Mariana Abreu Gonçalves
  • Teresa Filipa Ramôa Gonçalves
  • Aníbal Alberto Sá Martins

Sažetak


The widespread adoption of metformin as a primary therapeutic agent for type 2 diabetes has prompted inquiries into its potential impact on vitamin B12 (cobalamin) levels and subsequent deficiency. This study aimed to elucidate this complex relationship and enhance the care provided to patients undergoing metformin treatment. A comprehensive search of meta-analyses, systematic reviews, randomised controlled trials and guidelines published between January 2010 and September 2021 was conducted. MeSH terms 'metformin' and 'vitamin B12,' along with corresponding DeCS terms, guided the search. Varied recommendations from different scientific associations underscore the need for regular monitoring of vitamin B12 levels in patients undergoing long-term metformin therapy. Different durations of metformin exposure, spanning from 6 weeks to 48 months, were associated with decreased vitamin B12 concentrations. Observed decreases in B12 concentrations ranged from 7.7 to 65.8 pmol/L, with percentage reductions ranging from 6.3 % to over 35 %. The evidence highlights a dosage-dependent correlation between higher metformin doses and an increased prevalence of B12 deficiency. The results obtained highlight the association between metformin and B12 deficiency. The prevalence of B12 deficiency under metformin is of a greater magnitude than the one declared on the Summary of Product Characteristics approved by the medicine regulatory agencies. Thus, clinicians should be aware of this possible side effect when prescribing metformin, in order to prevent, monitor and treat if present.

Reference

World Health Organization. Diabetes- Key facts.[Internet]. [Cited: 20-Mar-2021]. Available at: https://www.who.int/news-room/fact-sheets/detail/diabetes/.

American Diabetes Association. Standards of medical care in diabetes-2020 abridged for primary care providers. Clin Diabetes. 2020 Jan;38(1):10-38. doi: 10.2337/cd20-as01.

Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr. Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care. 2012 Feb;35(2):327-33. doi: 10.2337/dc11-1582.

O'Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010 Mar;2(3):299-316. doi: 10.3390/nu2030299.

Tavares Bello C, Capitão RM, Sequeira Duarte J, Azinheira J, Vasconcelos C. [Vitamin B12 Deficiency in Type 2 Diabetes Mellitus]. Acta Med Port. 2017 Oct 31;30(10):719-26. Portuguese. doi: 10.20344/amp.8860..

Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014 Jun 24;9(6):e100379. doi: 10.1371/journal.pone.0100379.

Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycemia in type 2 diabetes, 2018. a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-701. doi: 10.2337/dci18-0033.

LeRoith D, Biessels GJ, Braithwaite SS, Casanueva FF, Draznin B, Halter JB, et al. Treatment of diabetes in older adults: an endocrine society* clinical practice guideline. J Clin Endocrinol Metab. 2019 May 1;104(5):1520-74. doi: 10.1210/jc.2019-00198.

Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE). Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm--2016 executive summary. Endocr Pract. 2016 Jan;22(1):84-113. doi: 10.4158/EP151126.

Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020 Oct;98(4S):S1-S115. doi: 10.1016/j.kint.2020.06.019.

Diabetes Canada Clinical Practice Guidelines Expert Committee; Lipscombe L, Booth G, Butalia S, Dasgupta K, Eurich DT, Goldenberg R, et al. Pharmacologic glycemic management of type 2 diabetes in adults. Can J Diabetes. 2018 Apr;42 Suppl 1:S88-S103. doi: 10.1016/j.jcjd.2017.10.034.

Sahin M, Tutuncu NB, Ertugrul D, Tanaci N, Guvener ND. Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complications. 2007 Mar-Apr;21(2):118-23. doi: 10.1016/j.jdiacomp.2005.10.005.

Gatford KL, Houda CM, Lu ZX, Coat S, Baghurst PA, Owens JA, et al. Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment. Diabetes Obes Metab. 2013 Jul;15(7):660-7. doi: 10.1111/dom.12080.

Leung S, Mattman A, Snyder F, Kassam R, Meneilly G, Nexo E. Metformin induces reductions in plasma cobalamin and haptocorrin bound cobalamin levels in elderly diabetic patients. Clin Biochem. 2010 Jun;43(9):759-60. doi: 10.1016/j.clinbiochem.2010.02.011.

Hassan MH, Abd-Allah GM. Effects of metformin plus gliclazide versus metformin plus glimepiride on cardiovascular risk factors in patients with type 2 diabetes mellitus. Pak J Pharm Sci. 2015 Sep;28(5):1723-30. PMID: 26408873.

Lohmann AE, Liebman MF, Brien W, Parulekar WR, Gelmon KA, Shepherd LE, et al; From the CCTG, Alliance, SWOG, ECOG, NSABP Cooperative Groups. Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32. Breast Cancer Res Treat. 2017 Jul;164(2):371-8. doi: 10.1007/s10549-017-4265-x.

Hansen CS, Jensen JS, Ridderstråle M, Vistisen D, Jørgensen ME, Fleischer J. Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes. J Diabetes Complications. 2017 Jan;31(1):202-8. doi: 10.1016/j.jdiacomp.2016.08.025.

Yang W, Cai X, Wu H, Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes. 2019 Sep;11(9):729-43. doi: 10.1111/1753-0407.12900.

Niafar M, Hai F, Porhomayon J, Nader ND. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015 Feb;10(1):93-102. doi: 10.1007/s11739-014-1157-5.

Griffin SJ, Bethel MA, Holman RR, Khunti K, Wareham N, Brierley G, et al. Metformin in non-diabetic hyperglycaemia: the GLINT feasibility RCT. Health Technol Assess. 2018 Apr;22(18):1-64. doi: 10.3310/hta22180.

Li X, Fang Z, Yang X, Pan H, Zhang C, Li X, et al. The effect of metformin on homocysteine levels in patients with polycystic ovary syndrome: A systematic review and meta-analysis. J Obstet Gynaecol Res. 2021 May;47(5):1804-16. doi: 10.1111/jog.14725.

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 Nov;42(5):316-27. doi: 10.1016/j.diabet.2016.03.008.

Kancherla V, Elliott JL Jr, Patel BB, Holland NW, Johnson TM 2nd, Khakharia A, et al. Long-term metformin therapy and monitoring for vitamin b12 deficiency among older veterans. J Am Geriatr Soc. 2017 May;65(5):1061-6. doi: 10.1111/jgs.14761.

Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, et al; Diabetes Prevention Program Research Group. Long-term metformin use and vitamin b12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab. 2016 Apr;101(4):1754-61. doi: 10.1210/jc.2015-3754.

Mastroianni A, Ciniselli CM, Panella R, Macciotta A, Cavalleri A, Venturelli E, et al. Monitoring vitamin b12 in women treated with metformin for primary prevention of breast cancer and age-related chronic diseases. Nutrients. 2019 May 7;11(5):1020. doi: 10.3390/nu11051020.

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. BMJ. 2010 May 20;340:c2181. doi: 10.1136/bmj.c2181.

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2024/06/28
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