DOI: http://dx.doi.org/10.18203/2349-3933.ijam20183459

Correlation of Vit B12 levels with metformin usage among type 2 diabetic patients in a tertiary care hospital

Vishnu A. Nareddy, Indeevar P. Boddikuri, Shaik K. Ubedullah, Abhinaya Papareddy, Manoj Kumar Miriyam

Abstract


Background: T2DM is a metabolic disorder that is increasingly becoming a public health concern. The disease is associated with a variety of systemic macrovascular and microvascular complications. Diabetic peripheral neuropathy (DPN) is the most common complication, and it may eventually develop in up to 50% of patients. It is assumed that prolonged use of metformin causes vitamin B12 deficiency. The clinical presentation of vitamin B12 deficiency generally includes haematological and neurological manifestations. The aim of the study is to correlate vit b12 levels in relation to duration of usage of metformin for a period of more than 1 year.

Methods: The study was conducted from November 2017 to June 2018 for a period of 7 months which included 50 subjects from both sex groups, aged 18 years and above, on metformin with subjective evidence of neuropathy and compared with vit b12 levels.

Results: The study results indicate that there is no significant drop in vit b12 levels in metformin users in significant proportions to cause vitb12 deficient-neuropathy. The p value being 0.658 comparing vit b12 with metformin usage years (<2 yrs, 2-5yrs, 5-8yrs, ≥8yrs).

Conclusions: This cross-sectional study indicates that diabetic patients who were on metformin were not having any vit b12 deficiency, though all patients had subjective neuropathy. This suggests that neuropathy is not related to metformin induced Vit B12 deficiency. Therefore, prescribing of vit b12 supplementation in any long term metformin treated patients is no longer necessary and reduces patients financial burden.


Keywords


Metformin, Peripheral neuropathy, Type 2 diabetes mellitus, Vitamin B12

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References


Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010 Oct 1;33(10):2285-93.

Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B (12) deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab. 2016;42:316-27.

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.

Ko SH, Ko SH, Ahn YB, Song KH, Han KD, Park YM, et al. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci. 2014;29:965-72.

Mazokopakis EE, Starakis IK. Recommendations for diagnosis and management of metformin-induced vitamin B12 (Cbl) deficiency. Diabetes Res Clin Pract. 2012;97:359-67.

Kumthekar AA, Gidwani HV, Kumthekar AB. Metformin associated B12 deficiency. J Assoc Physicians India. 2012;60:58-60

De Jager J, Kooy A, Lehert P, Wulffelé MG, Van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181.

Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Internal Med. 2006 Oct 9;166(18):1975-9.

Nervo M, Lubini A, Raimundo FV, Faulhaber GA, Leite C, Fischer LM et al. Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Revista Da Associacao Medica Brasileira. 2011 Feb;57(1):46-9.

Sparre Hermann L, Nilsson BO, Wettre S. Vitamin B12 status of patients treated with metformin: a cross-sectional cohort study. Br J Diab Vascu Dis. 2004 Nov;4(6):401-6.

Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Seaquist D, Topolski R. The prevalence of vitamin B12 deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med. 2009 Sep 1;22(5):528-34.

Russo GT, Di Benedetto A, Magazzù D, Giandalia A, Giorda CB, Ientile R et al. Mild hyperhomocysteinemia, C677T polymorphism on methylenetetrahydrofolate reductase gene and the risk of macroangiopathy in type 2 diabetes: a prospective study. Acta Diabetol. 2011 Jun 1;48(2):95-101.

Shaw RJ, Lamia KA, Vasquez D. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642-6.

El-Mir MY, Nogueira V, Fontaine E. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000, 275: 223-228. 10.1074/jbc.275.1.223.

Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine. 1991 Jul;70(4):229-45.

Ismail II, John JK, Ibrahim M. Neurological, hematological and dermatological manifestations of vitamin deficiency secondary to pernicious anemia. J Neurol Stroke. 2015;3(3):00095.

Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003 Mar 1;67(5):979-86.

Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australasian Med J. 2014;7(1):45-48.

Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D. How prevalent is vitamin B12 deficiency among vegetarians?. Nutri Rev. 2013 Feb 1;71(2):110-7.

Mao-Ying QL, Kavelaars A, Krukowski K, Huo XJ, Zhou W, Price TJ et al. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PloS One. 2014 Jun 23;9(6):e100701.

Melemedjian OK, Khoutorsky A, Sorge RE, Yan J, Asiedu MN, Valdez A et al. mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. PAIN®. 2013;154(7):1080-91.

Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A et al. Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Molecular Pain. 2011 Dec;7(1):70.

Ullah I, Ullah N, Naseer MI, Lee HY, Kim MO. Neuroprotection with metformin and thymoquinone against ethanol induced apoptotic neuro-degeneration in prenatal rat cortical neurons. BMC Neurosci. 2012 Dec;13(1):11.

Wang J, Gallagher D, DeVito LM, Cancino GI, Tsui D, He L et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell. 2012 Jul 6;11(1):23-35.

El-Mir MY, Detaille D, Gloria R, Delgado-Esteban M, Guigas B, Attia S, Fontaine E, Almeida A, Leverve X. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Molecular Neurosci. 2008 Jan;34(1):77-87.

Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S. Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience. 2014 Sep 26;277:747-54.

Pop-Busui R, Boulton AJ, Feldman EL, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40:136-54.

Kang D, Yun JS, Ko SH, Lim TS, Ahn YB, Park YM, et al. Higher prevalence of metformin-induced vitamin B12 deficiency in sulfonylurea combination compared with insulin combination in patients with type 2 diabetes: a cross-sectional study. PLoS One. 2014;9:e109878.

den Elzen WP, Groeneveld Y, de Ruijter W, Souverijn JH, le Cessie S, Assendelft WJ, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 2008;27:491-7.

Taylor A, Westveld AH, Szkudlinska M, Guruguri P, Annabi E, Patwardhan A et al. The use of metformin is associated with decreased lumbar radiculopathy pain. J Pain Res. 2013;6:755-763.

Ma J, Yu H, Liu J, Chen Y, Wang Q, Xiang L. Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur J Pharmacol. 2015;764:599-606.

Roy Chowdhury SK, Smith DR, Saleh A, Schapansky J, Marquez A, Gomes S et al. Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain. 2012 May 4;135(6):1751-66.