DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

The NPRA has updated information about this safety issue. See the NPRA Safety Alerts published on 4 March 2024.

Overview

Metformin is a biguanide antihyperglycemic agent indicated for the treatment of type 2 diabetes mellitus and a reduction in the risk or delay of the onset of type 2 diabetes mellitus in adult, overweight patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), and/or increased HbA1C.^1-2 In Malaysia, there are currently 96 products containing metformin as a single active ingredient or a component of fixed-dose combinations registered with the Drug Control Authority (DCA).³

Vitamin B12, also referred to as cobalamin, is a water-soluble vitamin that is naturally present in foods of animal origin such as meat, dairy, and eggs.⁴ Vitamin B12 deficiency is defined as a reduced serum B12 level of ≤300 pg/mL (221 pmol/L).⁵

Background of the Safety Issue

In June 2022, the National Pharmaceutical Regulatory Agency (NPRA) picked up new information on vitamin B12 deficiency associated with the use of metformin from the Medicines and Healthcare products Regulatory Agency (MHRA), United Kingdom.⁶

Reduced vitamin B12 absorption with decreased serum levels was documented as a very rare adverse effect of long-term treatment with metformin.^1,2,6 However, this known adverse effect of metformin was reassessed within Europe with input from the MHRA following published literature which indicated that its frequency is higher than previously thought.^6-7 The MHRA concluded that there is a need to update product information of all metformin-containing products to reflect that vitamin B12 deficiency is now regarded as a common adverse drug reaction, and may affect up to 1 in 10 people who take metformin.⁶

Several oversea studies have shown that the occurrence of vitamin B12 deficiency is common among patients on metformin (ranging from 4.3% to 30%), and the risk increases with a higher dose, longer treatment duration, and in patients with risk factors for vitamin B12 deficiency.^6,8-17 

Correspondingly, a local study by Krishnan et al. (2020) indicates that the prevalence of vitamin B12 deficiency was substantially high (28.3%) among the metformin-treated population.⁵ In that study, race and duration of metformin use were reported as the most consistently associated factors with vitamin B12 deficiency. Non-Malay race (Chinese or Indian) was associated with an approximately four-fold increased risk, whereas the duration of metformin use of more than five years conferred a greater than two-fold increased risk for vitamin B12 deficiency.

The exact mechanism underlying metformin-induced vitamin B12 deficiency has not yet been fully elucidated.^5,8 However, it is postulated to occur mainly through changes in vitamin B12 absorption and metabolism, most possibly due to interference with calcium-dependent absorption of the vitamin B12-intrinsic factor complex at the terminal ileum.

Vitamin B12 deficiency can be asymptomatic or associated with haematologic (such as megaloblastic anaemia), neurologic (such as peripheral neuropathy), and psychiatric disorders (such as impaired memory and irritability) that can usually be reversed by early diagnosis and treatment.¹⁸ The peripheral neuropathy caused by vitamin B12 deficiency might also be mistaken for diabetic neuropathy.⁵ Thus, it is important for patients with anaemia or neuropathy induced by vitamin B12 deficiency to be diagnosed and treated as soon as possible to prevent the development of permanent symptoms.⁶

Adverse Drug Reaction Reports¹⁹

The NPRA had received a total of 5,174 reports with 8,893 adverse events suspected to be related to metformin-containing products. The most frequently reported adverse events were diarrhoea (1,630), nausea (690), dizziness (679), vomiting (598), and pruritus (424). Of these, there were three (3) reports of anaemia vitamin B12 deficiency.

Advice for Healthcare Professionals:

• Both local and oversea studies revealed that metformin can commonly decrease serum vitamin B12 levels and lead to vitamin B12 deficiency.
• Be vigilant with the risk of vitamin B12 deficiency following metformin use as the risk increases with a higher metformin dose, longer treatment duration, and in patients with risk factors.
• Perform serum vitamin B12 level tests when metformin-induced vitamin B12 deficiency is suspected. Consider periodic vitamin B12 monitoring in patients with risk factors.
• Educate patients on metformin therapy to seek medical attention if they develop signs and symptoms suggestive of low vitamin B12 level, including new or worsening symptoms of extreme tiredness, a sore and red tongue, pins and needles sensation, or pale or yellow skin.

• Treat vitamin B12 deficiency promptly in accordance with the latest clinical guidelines and continue metformin therapy for as long as it is tolerated and not contraindicated.
• Report all suspected adverse events associated with products containing metformin to the NPRA.

References:

1. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). GLUCOPHAGE 500mg (metformin) package insert [Internet]. 2018 Jun [cited 2022 Aug 26]. Available from: http://www.npra.gov.my 
2. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian Product Registration Database (QUEST). GLUCOPHAGE XR 500mg (metformin) package insert [Internet]. 2018 Oct [cited 2022 Aug 26]. Available from: http://www.npra.gov.my 
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2022 [cited 2022 Aug 26]. Available from: http://www.npra.gov.my
4. Ankar A, Kumar A. Vitamin B12 deficiency [Internet]. 2021 [cited 2022 Aug 26]. Available from: https://pubmed.ncbi.nlm.nih.gov/28722952/
5. Krishnan GD, Zakaria MH, Yahaya N. Prevalence of vitamin B12 deficiency and its associated factors among patients with type 2 diabetes mellitus on metformin from a district in Malaysia. J ASEAN Fed Endocr Soc. 2020; 35(2):163-168. Available from: https://doi.org/10.15605/jafes.035.02.03
6. United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA). Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk [Internet]. 2022 Jun 20 [cited 2022 Aug 26]. Available from: https://www.gov.uk/drug-safety-update/metformin-and-reduced-vitamin-b12-levels-new-advice-for-monitoring-patients-at-risk#:~:text=metformin%20can%20commonly%20reduce%20vitamin,
   factors%20for%20vitamin%20B12%20deficiency
7. Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, Bray GA, Schade DS, Temprosa MG, White NH, Crandall JP. Long-term metformin use and vitamin b12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016; 101(4):1754–1761. Available from: https://doi.org/10.1210/jc.2015-3754
8. Infante M, Leoni M, Caprio M, Fabbri A. Long-term metformin therapy and vitamin B12 deficiency: an association to bear in mind. World J Diabetes. 2021; 12(7):916–931. Available from: https://doi.org/10.4239%2Fwjd.v12.i7.916
9. Ko SH, Ko SH, Ahn YB, Song KH, Han KD, Park YM, Ko SH, Kim HS. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci. 2014; 29(7):965-72. Available from: https://doi.org/10.3346/jkms.2014.29.7.965
10. Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Seaquist D, Topolski R. The prevalence of vitamin B (12) deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med. 2009; 22(5):528-34. Available from: https://doi/org/10.3122/jabfm.2009.05.090044
11. Beulens JWJ, Hart HE, Kuijs R, Kooijman-Buiting AMJ, Rutten GEHM. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol. 2015; 52(1):47-53. Available from: https://doi.org/10.1007/s00592-014-0597-8
12. de Jager J, Kooy A, Lehert P, Wulffelé MG, der Kolk JV, Bets D, Verburg J, Donker AJM, Stehouwer CDA. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010; 340:c2181. Available from: https://doi.org/10.1136/bmj.c2181
13. Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971; 2(5763):685-7. Available from: https://doi.org/10.1136/bmj.2.5763.685
14. Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP. Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements. Diabetes Care. 2012; 35(2): 327–333. Available from: https://doi.org/10.2337%2Fdc11-1582
15. Rose ZWT, Szeto CC, Chan MHM, Ma KK, Chow KM. Risk factors of vitamin B (12) deficiency in patients receiving metformin. Arch Intern Med. 2006; 166(18):1975-9. Available from: https://doi.org/10.1001/archinte.166.18.1975
16. Almatrafi SB, Bakr ESH, Almatrafi AA, Altayeb MM. Prevalence of vitamin B12 deficiency and its association with metformin-treated type 2 diabetic patients: A cross sectional study. Human Nutrition & Metabolism. 2022; 27: 200138. Available from: https://doi.org/10.1016/j.hnm.2022.200138
17. Nervo M, Lubini A, Raimundo FV, Faulhaber GAM, Leite C, Fischer LM, Furlanetto TW. Vitamin B12 in metformin treated diabetic patients: a cross-sectional study in Brazil. Rev Assoc Med Bras. 2011; 57(1):46-9. Available from: https://doi.org/10.1590/S0104-42302011000100015
18. Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam Physician. [Internet] 2003 [cited 2022 Aug 26]; 67(5):979-86. Available from: https://pubmed.ncbi.nlm.nih.gov/12643357/
19. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2022 [cited 2022 Aug 26]. Available from: https://www.npra.gov.my (access restricted).

Written by: Ng Chiew Seng
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Noor'ain Shamsuddin, Dr Azuana Ramli