VITAMIN B12 LEVELS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS ON METFORMIN

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K.S. Akinlade¹, S.O. Agbebaku¹, S.K. Rahamon¹, and W.O. Balogun²

1. Department of Chemical Pathology, University of Ibadan/University College Hospital, Ibadan, Nigeria.
2. Department of Medicine, University of Ibadan/University College Hospital, Ibadan, Nigeria.

Abstract

Background: Due to the clinical benefits of metformin, its associated side effects such as vitamin B12 deficiency are usually overlooked and rarely investigated.

Objective: This study was carried out to determine the serum level of vitamin B12 in Nigerian patients with type 2 diabetes mellitus (T2DM) on metformin.

Methods: Serum vitamin B12 level was determined using high performance liquid chromatography (HPLC) in 81 T2DM patients who have been on metformin for 5 years or more. Vitamin B12 deficiency was defined as serum concentration of <200 pg/dl, borderline deficiency as 200 – 300 pg/dl and >300 pg/dl as normal. Differences in vitamin B12 levels between different groups were assessed using Mann WhitneyU test andP<0.05 was considered as statistically significant.

Results: Vitamin B12 deficiency and borderline deficiency were recorded in 8.6% and 26.0% of the patients respectively. Vitamin B12 level was significantly lower in patients who have been on metformin for >10 years compared with patients with <10 years history of metformin use. Similarly, patients who were on metformin at a dose of >1000 mg/day had significantly lower vitamin B12 level when compared with patients on <1000 mg/day.

Conclusion: Low serum vitamin B12 level is associated with longer duration and higher dose of metformin use. Therefore, routine determination of vitamin B12 level in patients with T2DM on high dose of metformin and those with prolonged use of metformin might help in identifying patients that would benefit from vitamin B12 supplements.

Keywords: Metformin, Type 2 diabetes mellitus, Vitamin B12 deficiency.

Introduction

Metformin is the most prescribed anti-diabetic drug in patients with type 2 diabetes mellitus (T2DM) and hence, considered a cornerstone in the treatment of T2DM.¹ It is an anti hyperglycaemic agent that is usually well tolerated in most of the patients (except for mild gastrointestinal side effects) and it is characterized by excellent improvement in the cardiovascular morbidity and mortality associated with T2DM.²

Due to the numerous clinical benefits associated with metformin, some side effects with potential adverse health effects associated with its use are usually ignored and rarely investigated. One of such side effects is vitamin B12 deficiency.^{3, 4}

Vitamin B12, also called cobalamin, is a water-soluble vitamin involved in the optimal functioning of the hemopoetic, neuro-cognitive and vascular systems. It is involved in DNA synthesis, fatty acid metabolism and energy production.⁵ Vitamin B12 exerts its physiological effects by facilitating the methylation of homocysteine to methionine which is later activated into S-adenosyl methionine that donates its methyl group to methyl acceptors.⁶. Similarly, vitamin B12 mediates the conversion of methyl malonyl coenzyme A (coA) to succinyl coA, a process when hindered, results in accumulation of serum methylmalonic acid (MMA) thereby causing defective fatty acid synthesis of the neuronal membranes.⁷

Reports have shown that there is an association between metformin use and vitamin B12 deficiency.^3,4 However, the mechanism through which metformin induces vitamin B12 deficiency (VBD) in patients with T2DM is presently unclear. Some of the suggested mechanisms include alteration in small bowel motility, which stimulates bacterial overgrowth and consequential vitamin B12 deficiency. Others include competitive inhibition or inactivation of vitamin B12
absorption, alteration in intrinsic factor levels and interaction with the cubulin endocytic receptor. Also, inhibition of the calcium dependent absorption of vitamin B12–intrinsic factor (IF) complex at the terminal ileum has been suggested as one of the mechanisms.^{8 ,9, 10}

Although decrease in vitamin B12 levels following metformin use typically starts as early as the 4th month,¹¹ clinical features of vitamin B12 deficiency become apparent by 5 years owing to the large body stores in the liver that are not quickly depleted.¹⁰ This is however influenced by increasing age and dose of metformin.^{12, 13}

Assessment of vitamin B12 deficiency in patients with T2DM is of clinical importance. It can present as peripheral neuropathy and may be mistaken for diabetic neuropathy in patients on metformin treatment.¹⁴ Also, low vitamin B12 levels have been reported to be associated with poor nerve conduction velocities and poorer responses to light touch by monofilament detection.¹⁵ This may lead to unnecessary use of anticonvulsants, tricyclic antidepressants and other medications for diabetic neuropathy.^{14, 16, 17}

Usually, the established clinical benefits of metformin use in patients with type 2 diabetes mellitus (T2DM) make its side effects to be overlooked and rarely investigated especially, in Nigeria. This study was therefore, carried out to evaluate the serum levels of vitamin B12 in patients with T2DM on metformin.