Published: 2020-07-24

Review for the management of vitamin B12 deficiency in diabetic patients on metformin

Saad Thamer Sedeeq, Zohor Ahmed Kamaleldin Mohamed, Al Anoud Saleh Al Fehaidi, Mohammad Jamil Mohammad Al Tamimi, Mohamed Abd Elhamid, Amina Ali Mohamed Muktar, Ehab Hamed


Long-term usage of Metformin is associated with lower serum vitamin B12 levels. The lower than normal levels could worsen neurological complications of diabetes, including diabetic neuropathy and poor cognition. Guidelines advise periodic monitoring of vitamin B12 but do not specify frequency, treatment targets or treatment modality. This commentary aims to review the prevalence and the severity of the presentation and to provide evidence-based answers to those clinical questions not answered by current guidelines.


Diabetes mellitus, Diabetic neuropathies, Metformin, Prevalence, Vitamin B12 deficiency

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Tomkin GH, Hadden DR, Weaver JA, Montgomery DAD. Vitamin-B12 Status of Patients on Long-term Metformin Therapy. Br Med J. 1971;2(5763):685.

Houlden RL. Diabetes Canada 2018 Clinical Practice Guidelines. Can J Diabetes. 2018;28z;42:S1-5.

National Insitute of Clinical and Health Excellence. Overview. Type 2 diabetes in adults: management. Guidance. NICE. 2015 Dec. Available at: Accessed on 28 March 2020.

Johnson EL, Feldman H, Butts A, Billy CDR, Dugan J, Leal S, et al. Standards of medical care in diabetes-2019 abridged for primary care providers. Clin Diabetes. 2019 Jan 1;37(1):11-34.

Scottish Intercollegiate Guidelines Network (SIGN). SIGN 154. Pharmacological management of glycaemic control in people with type 2 diabetes. 2017 November):1-57. Available at: Accessed on 23 December 2019.

Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Annals Inter Med. 2002;137(1):25-33.

Ahmed MA. Metformin and Vitamin B12 deficiency: Where do we stand? J Pharm Pharm Sci. 2016 Oct 25;19(3):382-98.

Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by Metformin. Diabetes Care. 2000;23(9):1227-31.

Liu Q, Li S, Quan H, Li J. Vitamin B12 status in Metformin treated patients: Systematic review. PLoS One. 2014 Jun 24;9(6).

Niafar M, Hai F, Porhomayon J, Nader ND. The role of Metformin on vitamin B12 deficiency: a meta-analysis review. Int Emerg Med. Springer-Verlag Italia s.r.l. 2014;10:93-102.

Aparicio-Ugarriza R, Palacios G, Alder M, González-Gross M. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. Clinical Chemistry and Laboratory Medicine. Walter de Gruyter GmbH. 2015;53:1149-59.

Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, et al. Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab. 2020;101(4):1754-61.

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 29;340(7757):1177.

Wolffenbuttel BHR, Wouters HJCM, Heiner-Fokkema MR, van der Klauw MM. The Many Faces of Cobalamin (Vitamin B12) Deficiency. Mayo Clin Proc Innov Qual Outcomes. 2019 Jun;3(2):200-14.

Niafar M, Hai F, Porhomayon J, Nader ND. The role of Metformin on vitamin B12 deficiency: a meta-analysis review. Internal and Emergency Medicine. Springer-Verlag Italia s.r.l. 2014;10:93-102.

Langan RC, Goodbred AJ. Vitamin B12 Deficiency: Recognition and Management. Am Fam Physician. 2017;96(6):384-9.

Kim J, Ahn CW, Fang S, Lee HS, Park JS. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore). 2019 Nov 1;98(46):e17918.

Devalia V, Hamilton MS, Molloy AM. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496-513.

Sun Y, Lai M-S, Lu C-J. Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials. Acta Neurol Taiwan [Internet]. 2005;14(2):48-54.

Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, et al. Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin. Diabetes Care 2013;36(10):2981-7.

Hamed E, Monem MA. A Review of Diabetic Peripheral Neuropathy Management given Recent Guidelines Updates. Arch Gen Intern Med. 2018;02(04).

Alvarez M, Sierra OR, Saavedra G, Moreno S. Vitamin B12 deficiency and diabetic neuropathy in patients taking Metformin: A cross-sectional study. Endocr Connect. 2019;8(10):1324-9.

Gupta K, Jain A, Rohatgi A. An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy. Diabetes Metab Syndr Clin Res Rev. 2018;12(1):51-8.

Kothiwale V, Chafekar ND, Babaliche P, Chougule NA. 576-P: Prevalence of Vitamin B12 Deficiency and Clinical Neuropathy with Metformin Use in Type 2 Diabetes Mellitus Patients. Diabetes. 2019;68(Suppl 1):576.

Singh AK, Kumar A, Karmakar D, Jha RK. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med. 2013 Oct;59(4):253-7.

Ahmed MA, Muntingh G, Rheeder P. Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy. BMC Pharmacol Toxicol. 2016;17(1):44.

Elhadd T, Ponirakis G, Dabbous Z, Siddique M, Chinnaiyan S, Malik RA. Metformin use is not associated with B 12 deficiency or neuropathy in patients with type 2 diabetes Mellitus in Qatar. Front Endocrinol (Lausanne). 2018;9.

Chen S, Lansdown AJ, Moat SJ, Ellis R, Goringe A, Dunstan FDJ, et al. An observational study of the effect of Metformin on B12 status and peripheral neuropathy. Br J Diabetes Vasc Dis. 2012;12(4):189-93.

Jayabalan B, Low LL. Vitamin B supplementation for diabetic peripheral neuropathy. Singapore Med J. Singapore Medical Asso. 2016;57:55-9.

Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes - Systematic overview of prospective observational studies. Vol. 48, Diabetologia. Springer. 2005;48:2460-9.

Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: A systematic review. Vol. 5, Lancet Neurol. Elsevier. 2006;5:64-74.

O’Leary F, Allman-Farinelli M, Samman S. Vitamin B12 status, cognitive decline and dementia: A systematic review of prospective cohort studies. Vol. 108, Br J Nutrition. Cambridge University Press. 2012;108:1948-61.

Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: Systematic review and meta-analysis. BMC Public Health 2014;14(1):643.

Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database Syst Rev. 2003;21:(3).

Davies SR. How do vitamin B supplements compare with placebo/no treatment for people with mild cognitive impairment? Cochrane Clin Answers. Available at:

Mccleery J, Abraham RP, Denton DA, Rutjes AWS, Chong LY, Al-Assaf AS, et al. vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment. Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd; 2018:2018.

Malouf R, Evans JG. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database of Systematic Reviews. John Wiley and Sons Ltd; 2008.

Andrès E, Zulfiqar A-A, Serraj K, Vogel T, Kaltenbach G. Systematic Review and Pragmatic Clinical Approach to Oral and Nasal Vitamin B12 (Cobalamin) Treatment in Patients with Vitamin B12 Deficiency Related to Gastrointestinal Disorders. J Clin Med. 2018 Sep 26;7(10):304.

Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database of Syst Rev. 2018;3(3):CD004655.