Is it necessary to be afraid of vitamin B12 deficiency during metformin treatment?
Abstract
Metformin, a biguanide derivative, is the most frequently used antihyperglycaemic agent in the world. Various adverse effects can occur during the drug therapy. One of them is vitamin B12 deficiency, which may be either asymptomatic (biochemical) or may lead to neurological and/or haematological disorders. Causal diagnosis of these disorders is hampered due to the fact that nervous system symptoms are similar to neurological complications developing over the course of diabetes mellitus. It is estimated that 5.8 to 33% of metformin treated patients have a low (below the reference level) serum vitamin B12 concentration. The interrelation between vitamin B12 deficiency and metformin usage has been known for decades and over that time many studies have been carried out to assess the issue. Unfortunately, these studies were mainly observational, retrospective and performed on nonhomogeneous groups of patients. Recently a meta-analysis of studies concerning only diabetic patients was performed and it demonstrated the existence of a relationship between metformin treatment and vitamin B12 deficiency. Nevertheless, further well-designed, large-scale, randomized studies performed on a homogenous group of patients and employing homogenous criteria for diagnosing vitamin B12 deficiency are necessary in order to decide whether serum vitamin B12 concentration should be routinely checked among metformin treated patients.
Keywords: metforminvitamin B12type 2 diabetes mellitus
References
- Standards of Medical Care in Diabetes-2016: Summary of Revisions. Diabetes Care. 2016; 39 Suppl 1: S4–S5.
- Polskie Towarzystwo Diabetologiczne. Zalecenia kliniczne dotyczące postępowania u chorych na cukrzycę 2016. Stanowisko Polskiego Towarzystwa Diabetologicznego. Clinical Diabetology. 2016; 5(Suppl A).
- Ruston D, Hoare J, Henderson L. The National Diet & Nutrition Survey: adults aged 19 to 64 years: Nutritional status (anthropometry and blood analytes), blood pressure and physical activity. TSO, London 2004.
- Adams JF, Clark JS, Ireland JT, et al. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia. 1983; 24(1): 16–18.
- Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004; 171(3): 251–259.
- Eussen SJ, Nilsen RM, Midttun Ø, et al. North-south gradients in plasma concentrations of B-vitamins and other components of one-carbon metabolism in Western Europe: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. Br J Nutr. 2013; 110(2): 363–374.
- Wyckoff KF, Ganji V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post folic acid fortification period than in the pre folic acid fortification period. Am J Clin Nutr. 2007; 86(4): 1187–1192.
- Carmel R. Mandatory fortification of the food supply with cobalamin: an idea whose time has not yet come. J Inherit Metab Dis. 2011; 34(1): 67–73.
- Pflipsen MC, Oh RC, Saguil A, et al. 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): 528–534.
- Reinstatler L, Qi YP, Williamson RS, et al. Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care. 2012; 35(2): 327–333.
- Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database Syst Rev. 2003(3): CD004326.
- Bottiglieri T, Laundy M, Crellin R, et al. Homocysteine, folate, methylation, and monoamine metabolism in depression. J Neurol Neurosurg Psychiatry. 2000; 69(2): 228–232.
- Sadeghian S, Fallahi F, Salarifar M, et al. Tehran Heart Center. Homocysteine, vitamin B12 and folate levels in premature coronary artery disease. BMC Cardiovasc Disord. 2006; 6: 38.
- Selhub J. Public health significance of elevated homocysteine. Food Nutr Bull. 2008; 29(2 Suppl): S116–S125.
- Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003; 67(5): 979–986.
- O'Leary F, Samman S. Vitamin B12 in health and disease. Nutrients. 2010; 2(3): 299–316.
- Andrès E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002; 162(19): 2251–2252.
- Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000; 23(9): 1227–1231.
- Kos E, Liszek MJo, Emanuele MA, et al. Effect of metformin therapy on vitamin D and vitamin B₁₂ levels in patients with type 2 diabetes mellitus. Endocr Pract. 2012; 18(2): 179–184.
- de Jager J, Kooy A, Lehert P, 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: c2181.
- Leung S, Mattman A, Snyder F, et al. Metformin induces reductions in plasma cobalamin and haptocorrin bound cobalamin levels in elderly diabetic patients. Clin Biochem. 2010; 43(9): 759–760.
- Wulffelé MG, Kooy A, Lehert P, et al. 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. 2003; 254(5): 455–463.
- Niafar M, Hai F, Porhomayon J, et al. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015; 10(1): 93–102.
- Aroda VR, Edelstein SL, Goldberg RB, et al. Diabetes Prevention Program Research Group. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016; 101(4): 1754–1761.
- DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995; 333(9): 541–549.
- Liu Q, Li S, Quan H, et al. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014; 9(6): e100379.
- Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016; 42(5): 316–327.