Internal and Emergency Medicine

, Volume 10, Issue 1, pp 93–102 | Cite as

The role of metformin on vitamin B12 deficiency: a meta-analysis review

  • Mitra Niafar
  • Faizi Hai
  • Jahan Porhomayon
  • Nader Djalal NaderEmail author


Metformin is the only biguanide oral hypoglycemic drug, that is used to treat patients with type-2 diabetes mellitus. There are some reports of metformin being associated with decreased serum levels of vitamin B12 (VB12). The objective of this study is to systematically analyze the impact of metformin on the frequency of VB12 deficiency and serum levels of VB12. A search of various databases provided 18 retrospective cohort studies and 11 randomized controlled trials. Pooled estimates of odds ratio with 95 % confidence interval using random effect model were conducted. Studies were examined for heterogeneity, publication bias and sensitivity analysis. Separate analysis of randomized control trials (RCTs) including both low-risk and high-risk bias was also conducted. 29 studies were selected with a total of 8,089 patients. 19 studies were rated intermediate or high quality. Primary outcome suggested increased incidence of VB12 deficiency in metformin group (OR = 2.45, 95 % CI 1.74–3.44, P < 0.0001.) Heterogeneity was relatively high (I 2 = 53 %), with minor publication bias. Secondary outcome suggested lower serum VB12 concentrations in metformin group (Mean difference = −65.8, 95 % CI −78.1 to −53.6 pmol/L, P < 0.00001) with high heterogeneity (I 2 = 98 %,) and low publication bias. RCTs analysis of low-and high-risk group revealed similar trends. We conclude that metformin treatment is significantly associated with an increase in incidence of VB12 deficiency and reduced serum VB12 levels.


Cyanocobalamin Neuropathy Metformin Diabetes Mellitus type-2 Vitamin B12 Cobalamin deficiency 


Conflict of interest



  1. 1.
    Cho NM (ed) (2013) Diabetic atlas, 6th edn. International Diabetes Federation, BruccelGoogle Scholar
  2. 2.
    Home P (ed) (2005) Global guidelines for type-2 diabetes. International Diabetes Federation, Inc., BrusselsGoogle Scholar
  3. 3.
    American Diabetes Association (2014) Standards of medical care in diabetes–2014. Diabetes Care 37(Suppl 1):S14–S80. doi: 10.2337/dc14-S014 CrossRefGoogle Scholar
  4. 4.
    Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS (1983) Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia 24(1):16–18PubMedCrossRefGoogle Scholar
  5. 5.
    Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Seaquist D, Topolski R (2009) The prevalence of vitamin B(12) deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med JABFM 22(5):528–534. doi: 10.3122/jabfm.2009.05.090044 CrossRefGoogle Scholar
  6. 6.
    Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP Jr (2012) Association of biochemical B(1)(2) deficiency with metformin therapy and vitamin B(1)(2) supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care 35(2):327–333. doi: 10.2337/dc11-1582 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Da Silva L, McCray S (2009) Vitamin B12: no one should be without it. Pract Gastroentrol 33(1):39–46Google Scholar
  8. 8.
    Saperstein DS, Barohn RJ (2002) Peripheral neuropathy due to cobalamin deficiency. Curr Treat Option Neurol 4(3):197–201CrossRefGoogle Scholar
  9. 9.
    Downs SH, Black N (1998) The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Commun H. 52(6):377–384CrossRefGoogle Scholar
  10. 10.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188PubMedCrossRefGoogle Scholar
  11. 11.
    Sterne JA, Gavaghan D, Egger M (2000) Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 53(11):1119–1129PubMedCrossRefGoogle Scholar
  12. 12.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101PubMedCrossRefGoogle Scholar
  13. 13.
    Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V (2000) Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 23(9):1227–1231PubMedCrossRefGoogle Scholar
  14. 14.
    Berchtold P, Dahlqvist A, Gustafson A, Asp NG (1971) Effects of a biguanide (Metformin) on vitamin B 12 and folic acid absorption and intestinal enzyme activities. Scand J Gastroenterol 6(8):751–754PubMedCrossRefGoogle Scholar
  15. 15.
    Buysschaert M, Dramais AS, Wallemacq PE, Hermans MP (2000) Hyperhomocysteinemia in type 2 diabetes: relationship to macroangiopathy, nephropathy, and insulin resistance. Diabetes Care 23(12):1816–1822PubMedCrossRefGoogle Scholar
  16. 16.
    Calvo Romero JM, Ramiro Lozano JM (2012) Vitamin B(12) in type 2 diabetic patients treated with metformin. Endocrinologia y nutricion : organo de la Sociedad Espanola de. Endocrinologia y Nutricion 59(8):487–490. doi: 10.1016/j.endonu.2012.06.005 PubMedCrossRefGoogle Scholar
  17. 17.
    Carlsen SM (2007) [Metformin and vitamin B 12 deficiency]. Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke 127(6):764 (author reply PubMed PMID: 17363994)Google Scholar
  18. 18.
    Carlsen SM, Folling I, Grill V, Bjerve KS, Schneede J, Refsum H (1997) Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease. Scand J Clin Lab Invest 57(6):521–527PubMedCrossRefGoogle Scholar
  19. 19.
    Carpentier JL, Bury J, Luyckx A, Lefebvre P (1976) Vitamin B 12 and folic acid serum levels in diabetics under various therapeutic regimens. Diabete metab 2(4):187–190PubMedGoogle Scholar
  20. 20.
    Diakoumopoulou E, Tentolouris N, Kirlaki E, Perrea D, Kitsou E, Psallas M et al (2005) Plasma homocysteine levels in patients with type 2 diabetes in a Mediterranean population: relation with nutritional and other factors. Nutr Metab Cardiovasc Dis NMCD 15(2):109–117. doi: 10.1016/j.numecd.2004.01.001 CrossRefGoogle Scholar
  21. 21.
    Gastaldi G, Mura T, Sultan A, Piot C, Cristol JP, Renard EM (2011) Vit B12 deficiency and silent myocardial ischemia in type 2 diabetic patients. Diabetologia 54:S500–S501Google Scholar
  22. 22.
    Hermann LS, Nilsson B, Wettre S (2004) Vitamin B12 status of patients treated with metformin: a cross-sectional cohort study. Br J Diabetes Vasc Dis 4:401–406CrossRefGoogle Scholar
  23. 23.
    Kilicdag EB, Bagis T, Tarim E, Aslan E, Erkanli S, Simsek E et al (2005) Administration of B-group vitamins reduces circulating homocysteine in polycystic ovarian syndrome patients treated with metformin: a randomized trial. Hum Reprod 20(6):1521–1528. doi: 10.1093/humrep/deh825 PubMedCrossRefGoogle Scholar
  24. 24.
    Kilicdag EB, Bagis T, Zeyneloglu HB, Tarim E, Aslan E, Haydardedeoglu B et al (2005) Homocysteine levels in women with polycystic ovary syndrome treated with metformin versus rosiglitazone: a randomized study. Hum Reprod 20(4):894–899. doi: 10.1093/humrep/deh700 PubMedCrossRefGoogle Scholar
  25. 25.
    Kocaciftci G, Aydogan U, Akbulut H, Parildar H, Aydogdu A, Yaman H et al (2013) The effects of metformin and metformin plus calcium treatments on serum vitamin B12 levels. Nobel Med 9(3):58–63Google Scholar
  26. 26.
    Lim SS, Norman RJ, Clifton PM, Noakes M (2011) The effect of comprehensive lifestyle intervention or metformin on obesity in young women. Nutr Metab Cardiovasc Dis NMCD 21(4):261–268. doi: 10.1016/j.numecd.2009.10.006 Google Scholar
  27. 27.
    Niafar M, Jamali B, Lotfi-Bakhshaieshi N, Aghamohammadzadeh N, Nader ND (2014) Effect of Metformin on Serum Vitamin B12 Level in Patients with Type 2 Diabetes Mellitus. Diabetes Tech Therap. Submitted (under review)Google Scholar
  28. 28.
    Pongchaidecha M, Srikusalanukul V, Chattananon A, Tanjariyaporn S (2004) Effect of metformin on plasma homocysteine, vitamin B12 and folic acid: a cross-sectional study in patients with type 2 diabetes mellitus. J Med Assoc Thai Chotmaihet Thangphaet 87(7):780–787Google Scholar
  29. 29.
    Sahin M, Tutuncu NB, Ertugrul D, Tanaci N, Guvener ND (2007) Effects of metformin or rosiglitazone on serum concentrations of homocysteine, folate, and vitamin B12 in patients with type 2 diabetes mellitus. J Diabetes Complications 21(2):118–123. doi: 10.1016/j.jdiacomp.2005.10.005 PubMedCrossRefGoogle Scholar
  30. 30.
    Sato Y, Ouchi K, Funase Y, Yamauchi K, Aizawa T (2013) Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocr J 60(12):1275–1280PubMedCrossRefGoogle Scholar
  31. 31.
    Simsek A, Aydogan U, Cigerli O, Yaman H, Saglam K (2013) The Effect Effect of Metformin Treatment on Serum Total Vitamin B-12. Homocysteine and Transcobalamin Levels. Nobel Med 9(3):14–21Google Scholar
  32. 32.
    Singh AK, Kumar A, Karmakar D, Jha RK (2013) Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med 59(4):253–257. doi: 10.4103/0022-3859.123143 PubMedCrossRefGoogle Scholar
  33. 33.
    Crandall M, Zarzaur B, Tinkoff G (2013) American Association for the Surgery of Trauma Prevention Committee topical overview: National Trauma Data Bank, geographic information systems, and teaching injury prevention. Am J Surg 206(5):709–713. doi: 10.1016/j.amjsurg.2013.07.002 PubMedCrossRefGoogle Scholar
  34. 34.
    de Jager J, Kooy A, Lehert P, Wulffele MG, van der Kolk J, Bets D et al (2010) Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 340:c2181. doi: 10.1136/bmj.c2181 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Long AN, Atwell CL, Yoo W, Solomon SS (2012) Vitamin B(12) deficiency associated with concomitant metformin and proton pump inhibitor use. Diabetes Care 35(12):e84. doi: 10.2337/dc12-0980 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    O’Loughlin S (2013) Wan Mahmoud WA, Kyaw Tun T, McDermott JH, Sreenan S. Vitamin B12 deficiency in diabetes patients treated with metformin. Ir J Med Sci 182:S417–S418Google Scholar
  37. 37.
    Radfar M, Doost MJ, Hadjibabaie M, Larijani B (2011) Vitamin B12 levels in type 2 diabetic patients receiving metformin. Int J Clin Pharm-Net. 33(2):339Google Scholar
  38. 38.
    Wile DJ, Toth C (2010) Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes care 33(1):156–161. doi: 10.2337/dc09-0606 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B et al (2003) Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med 254(5):455–463PubMedCrossRefGoogle Scholar
  40. 40.
    Andres E, Vidal-Alaball J, Federici L, Loukili NH, Zimmer J, Kaltenbach G (2007) Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, and treatment with special focus on oral cobalamin therapy. Eur J Intern Med 18(6):456–462. doi: 10.1016/j.ejim.2007.02.013 PubMedCrossRefGoogle Scholar
  41. 41.
    Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM (2006) Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med 166(18):1975–1979. doi: 10.1001/archinte.166.18.1975 PubMedCrossRefGoogle Scholar
  42. 42.
    Institute of Medicine Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate Other B Vitamins and Choline USA (1998) Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. The National Academies Collection: Reports funded by National Institutes of Health. Washington (DC)Google Scholar
  43. 43.
    Carmel R, Rasmussen K, Jacobsen DW, Green R (1996) Comparison of the deoxyuridine suppression test with serum levels of methylmalonic acid and homocysteine in mild cobalamin deficiency. Br J Haematol 93(2):311–318PubMedCrossRefGoogle Scholar
  44. 44.
    Obeid R, Jung J, Falk J, Herrmann W, Geisel J, Friesenhahn-Ochs B et al (2013) Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes. Biochimie 95(5):1056–1061. doi: 10.1016/j.biochi.2012.10.028 PubMedCrossRefGoogle Scholar

Copyright information

© SIMI (outside the USA) 2014

Authors and Affiliations

  • Mitra Niafar
    • 1
  • Faizi Hai
    • 2
  • Jahan Porhomayon
    • 2
  • Nader Djalal Nader
    • 2
    Email author
  1. 1.Tabriz University of Medical Sciences, Bone Research CenterTabrizIran
  2. 2.University at BuffaloBuffaloUSA

Personalised recommendations