Analysis of risk factors for vitamin B12 deficiency in patients with type 2 diabetes mellitus and its relation to the use of metformin
Abstract
Background. The use of metformin has been associated with vitamin B12 deficiency in patients with type 2 diabetes mellitus. Objective. The present study evaluates the relationship between vitamin B12 deficiency and its risk factors. Moreover, it investigates the relationship between established deficiency and clinically detectable peripheral neuropathy.
Material and methods. A cross-sectional study involving patients with type 2 diabetes mellitus who were assisted at a public health care service, which is a reference center in Diabetes. Peripheral neuropathy was detected by Neuropathy Symptom Score, Vibration Sensitivity Test, Achilles Reflex and Monofilament Test. Vitamin B12 levels were determined by means of two laboratory measurements.
Results. The study included 316 subjects, from which 91% were metformin users. Vitamin B12 deficiency was observed in 14% of participants in the study. All patients with vitamin B12 deficiency used metformin, with an odds ratio of 2.6 for those using doses higher than 1000 mg/day (95% confidence interval: 1.3–5.3, p = 0.009). Vitamin B12 deficiency was also statistically related to the use of angiotensin-converting enzyme inhibitors (p = 0.02). Peripheral neuropathy was observed in 41% of patients and was not related to vitamin B12 deficiency. The prevalence of peripheral neuropathy was lower among metformin users (39% vs. 60%; p = 0.04).
Conclusions. This study demonstrated a dose-dependent association between metformin use and vitamin B12 deficiency, in addition to an association with the use of angiotensin-converting enzyme inhibitors. In contrast, Vitamin B12 deficiency was not related to clinically detected neuropathy.
Keywords: diabetesmetforminvitamin B12diabetic neuropathyangiotensin-converting enzyme inhibitors
References
- Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012; 97(3): 359–367.
- American Diabetes Association. Standards of medical care in diabetes — 2013. Diabetes Care. 2013; 36(Suppl 1): S11–S66.
- Nathan DM, Buse JB, Davidson MB, et al. American Diabetes Association, European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009; 32(1): 193–203.
- Nathan DM, Buse JB, Davidson MB, et al. American Diabetes Association, European Association for the Study of Diabetes. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006; 29(8): 1963–1972.
- Tomkin GH, Hadden DR, Weaver JA, et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971; 2(5763): 685–687.
- 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.
- Ko SH, Ahn YB, Song KH, et al. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci. 2014; 29(7): 965–972.
- 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.
- 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.
- Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc. 1994; 69(2): 144–150.
- Allen RH, Stabler SP, Savage DG, et al. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J. 1993; 7(14): 1344–1353.
- Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. Neurology. 1995; 45(8): 1435–1440.
- Hemmer B, Glocker FX, Schumacher M, et al. Subacute combined degeneration: clinical, electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry. 1998; 65(6): 822–827.
- Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993; 43(4): 817–824.
- Dyck PJ, Litchy WJ, Lehman KA, et al. Variables influencing neuropathic endpoints: the Rochester Diabetic Neuropathy Study of Healthy Subjects. Neurology. 1995; 45(6): 1115–1121.
- Edwards JL, Vincent AM, Cheng HT, et al. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008; 120(1): 1–34.
- Bell DS. Nondiabetic neuropathy in a patient with diabetes. Endocr Pract. 1995; 1(6): 393–394.
- Young MJ, Boulton AJ, MacLeod AF, et al. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993; 36(2): 150–154.
- Moreira R, Castro A, Papelbaum M, et al. Tradução para o português e avaliação da confiabilidade de uma escala para diagnóstico da polineuropatia distal diabética. Arq Bras Endocrinol Metab. 2005; 49(6): 944–950.
- Bakker K, Apelqvist J, Schaper NC, et al. International Working Group on Diabetic Foot Editorial Board. Practical guidelines on the management and prevention of the diabetic foot 2011. Diabetes Metab Res Rev. 2012; 28(Suppl 1): 225–231.
- Tesfaye S, Boulton AJM, Dyck PJ, et al. Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010; 33(10): 2285–2293.
- 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.
- Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016; 42(5): 316–327.
- Ting RZW, Szeto CC, Chan MHM, et al. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med. 2006; 166(18): 1975–1979.
- Beulens JWJ, Hart HE, Kuijs R, et al. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol. 2015; 52(1): 47–53.
- de Groot-Kamphuis DM, van Dijk PR, Groenier KH, et al. Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using metformin. Neth J Med. 2013; 71(7): 386–390.
- Dunstan DF, Rees JA, Chen S, et al. An observational study of the effect of metformin on B12 status and peripheral neuropathy. Br J Diabetes Vascular Dis. 2012; 12: 189–193.
- Obeid R, Jung J, Falk J, et al. Serum vitamin B12 not reflecting vitamin B12 status in patients with type 2 diabetes. Biochimie. 2013; 95(5): 1056–1061.
- Greibe E, Trolle B, Bor MV, et al. Metformin lowers serum cobalamin without changing other markers of cobalamin status: a study on women with polycystic ovary syndrome. Nutrients. 2013; 5(7): 2475–2482.