Vitamin B12 levels in type 2 diabetic patients on Metformin compared to those never on Metformin: a cross‑sectional study in Tunisia Section Original articles

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Imen ROJBI
Mehdi Kalthoum
Sabrine Mekni
Kahena Bouzid
Karima Khiari
Ibtissem Ben Nacef

Abstract

Introduction : Recent studies suggest that long-term use of metformin may decrease the plasma level of Vitamin B12.


Aim: To assess the Vitamin B12 status in Tunisian patients treated with metformin and to study its association with the dose, the duration of metformin use, and the clinical and biological parameters.


Methods: It was a cross-sectional, comparative study on 200 type 2 diabetic (T2D) patients. A vitamin B12 assay was performed with a neurological examination and a Complete blood count.


Results: The mean level of Vitamin B12 assayed in our population was 398.5±188.3 pg/ml. The serum Vitamin B12 levels were 356.9±153.5 pg/ml in the metformin group and 460.9±218.6 pg/ml in the no metformin group (p <0.01). Metformin intake was associated with an increased prevalence of Vitamin B12 deficiency and borderline level. The level of Vitamin B12 was correlated with the duration and the dose of metformin. Vitamin B12 deficiency was significantly associated with anemia, macrocytosis, and diabetic neuropathy. Multivariate analysis concluded that Vitamin B12 deficiency was significantly associated with the duration, cumulative metformin dose, clinical neuropathy, anemia, and macrocytosis.


Conclusion: Our study showed an association of Vitamin B12 deficiency with the dose and duration of metformin intake in Tunisian T2D patients, with hematological and neurological repercussions.

Keywords:

Metformin, Anemia, Diabetic neuropathy

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References

  1. Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P. Metformin - The gold standard: a scientific handbook. Chichester: Wiley 2007.
  2. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet.1998;352(9131):854–65.
  3. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2020 . Diabetes Care. 2020;43(Suppl 1):98-110.
  4. World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia [Internet]. World Health Organization [cited 2020 Dec 18]. Available from: https://apps.who.int/iris/handle/10665/43588
  5. Bo S, Benso A, Durazzo M, Ghigo E. Does use of metformin protect against cancer in Type 2 diabetes mellitus? J Endocrinol Invest. 2012;35(2):231–5.
  6. Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330(7503):1304–5.
  7. Feng T, Sun X, Howard LE, Vidal AC, Gaines AR, Moreira DM, et al. Metformin use and risk of prostate cancer: results from the REDUCE study. Cancer Prev Res Phila Pa. 2015;8(11):1055–60.
  8. 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):327–33.
  9. 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;340:2181.
  10. Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age Ageing. 2006;35(2):200–1.
  11. Bell DSH. Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy. South Med J. 2010;103(3):265–7.
  12. Lin H-Y, Chung C-Y, Chang C-S, Wang M-L, Lin J-S, Shen M-C. Hyperhomocysteinemia, deep vein thrombosis and vitamin B12 deficiency in a metformin-treated diabetic patient. J Formos Med Assoc Taiwan Yi Zhi. 2007;106(9):774–8.
  13. De Groot-Kamphuis DM, van Dijk PR, Groenier KH, Houweling ST, Bilo HJG, Kleefstra N. Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using metformin. Neth J Med. 2013;71(7):386–90.
  14. Donnelly LA, Dennis JM, Coleman RL, Sattar N, Hattersley AT, Holman RR, et al. Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study. Diabetes Care. 2020;43(10):2493–9.
  15. Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2010;33(1):156–61.
  16. Gilligan MA. Metformin and vitamin B12 deficiency. Arch Intern Med. 2002;162(4):484–5.
  17. 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;11(9):729–43.
  18. Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia. 1983;24(1):16–8.
  19. 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.
  20. 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. 2016;101(4):1754–61.
  21. Miyan Z, Waris N. Association of vitamin B12 deficiency in people with type 2 diabetes on metformin and without metformin: a multicenter study, Karachi, Pakistan. BMJ Open Diabetes Res Care. 2020;8(1):e001151.
  22. 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. 2018;12(1):51–8.
  23. Callaghan TS, Hadden DR, Tomkin GH. Megaloblastic anaemia due to vitamin B12 malabsorption associated with long-term metformin treatment. Br Med J. 1980;280(6225):1214–5.
  24. Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megaloblastic anaemia? Aust Fam Physician. 2003;32(5):383–4.
  25. Wulffelé MG, Kooy A, de Zeeuw D, Stehouwer CDA, Gansevoort RT. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004;256(1):1–14.
  26. Hermann L, Nilsson B, Wettre S. Vitamin B12 status of patients treated with metformin: A cross-sectional cohort study. Br J Diabetes Vasc Dis. 2004;4:401–6.
  27. Pongchaidecha M, Srikusalanukul V, Chattananon A, Tanjariyaporn S. 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 Thail Chotmaihet Thangphaet. 2004;87(7):780–7.
  28. 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;21(2):118–23.
  29. 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 JABFM. 2009;22(5):528–34.
  30. Calvo Romero JM, Ramiro Lozano JM. Vitamin B(12) in type 2 diabetic patients treated with metformin. Endocrinol Nutr Organo Soc Espanola Endocrinol Nutr. 2012;59(8):487–90.
  31. Iftikhar R, Kamran SM, Qadir A, Iqbal Z, bin Usman H. Prevalence of vitamin B12 deficiency in patients of type 2 diabetes mellitus on metformin: a case control study from Pakistan. Pan Afr Med J. 2013;16:67.
  32. Sato Y, Ouchi K, Funase Y, Yamauchi K, Aizawa T. Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocr J. 2013; 60(12):1275–1280.
  33. 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;59(4):253–7.
  34. Adaikalakoteswari A, Jayashri R, Sukumar N, Venkataraman H, Pradeepa R, Gokulakrishnan K, et al. Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes. Cardiovasc Diabetol. 2014;13:129.
  35. Niafar M, Hai F, Porhomayon J, Nader ND. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015;10(1):93–102.
  36. Zbadi R, Derrou S, Ouleghzal H, Safi S. Vitamine B12 chez une population de patients diabétiques traités par metformine. Ann Endocrinol. 2016;77(4):325–6.