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

Abstract

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.

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References

  1. 1.

    Cho NM (ed) (2013) Diabetic atlas, 6th edn. International Diabetes Federation, Bruccel

    Google Scholar 

  2. 2.

    Home P (ed) (2005) Global guidelines for type-2 diabetes. International Diabetes Federation, Inc., Brussels

    Google 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

    Article  Google 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):16–18

    CAS  PubMed  Article  Google 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

    Article  Google 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

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. 7.

    Da Silva L, McCray S (2009) Vitamin B12: no one should be without it. Pract Gastroentrol 33(1):39–46

    Google Scholar 

  8. 8.

    Saperstein DS, Barohn RJ (2002) Peripheral neuropathy due to cobalamin deficiency. Curr Treat Option Neurol 4(3):197–201

    Article  Google 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):377–384

    CAS  Article  Google Scholar 

  10. 10.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    CAS  PubMed  Article  Google 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):1119–1129

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101

    CAS  PubMed  Article  Google 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):1227–1231

    CAS  PubMed  Article  Google 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):751–754

    CAS  PubMed  Article  Google 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):1816–1822

    CAS  PubMed  Article  Google 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

    CAS  PubMed  Article  Google 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)

  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):521–527

    CAS  PubMed  Article  Google 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):187–190

    CAS  PubMed  Google 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

    CAS  Article  Google 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–S501

    Google 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 4:401–406

    CAS  Article  Google 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

    CAS  PubMed  Article  Google 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

    CAS  PubMed  Article  Google 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):58–63

    Google 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

    CAS  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)

  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):780–787

    Google 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

    PubMed  Article  Google 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):1275–1280

    CAS  PubMed  Article  Google 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):14–21

    Google 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

    CAS  PubMed  Article  Google 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

    PubMed  Article  Google 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

    PubMed Central  PubMed  Article  Google 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

    CAS  PubMed Central  PubMed  Article  Google 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–S418

    Google 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):339

    Google 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

    CAS  PubMed Central  PubMed  Article  Google 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):455–463

    CAS  PubMed  Article  Google 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

    CAS  PubMed  Article  Google 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

    CAS  PubMed  Article  Google 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)

  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):311–318

    CAS  PubMed  Article  Google 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

    CAS  PubMed  Article  Google Scholar 

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Correspondence to Nader Djalal Nader.

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Niafar, M., Hai, F., Porhomayon, J. et al. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med 10, 93–102 (2015). https://doi.org/10.1007/s11739-014-1157-5

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Keywords

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