Metformin Use and Vitamin B12 Deficiency: Managing the Risks

Metformin is the first-line medication for treatment of type 2 diabetes mellitus (T2DM). This commonly used medication has also been associated with lowering serum vitamin B₁₂ levels. Although the British National Formulary documented this connection in the 1970s with a constellation of studies supporting this effect, recognition of this by most prescribers is lacking.^1-17

Three theoretical mechanisms of action regarding the contribution of metformin to the lowering of B₁₂, a water-soluble vitamin, have been postulated; it may be one or any combination of these that contributes to a diminished B₁₂ level. The first posits that this is due to blocking by metformin of the calcium channels in the distal ileum that normally allow absorption of the vitamin B₁₂-intrinsic factor (B₁₂-IF) complex by altering the membrane potential.² The hydrophobic tail of metformin binds to the hydrocarbon core of the cell membrane, imparting a net positive charge; this, in turn, repels calcium that is necessary for transporting B₁₂ across the ileal-lumen interface.¹⁸ The second mechanism details the modification of normal bacterial flora, resulting in bacterial overgrowth and impeded passage of B₁₂-IF into the bloodstream.¹⁹ A third pathway describes metformin changing the B₁₂-IF complex by binding to it structurally.¹⁹ Each of these potential influences lessens the amount of B₁₂ that passes through the distal ileal wall.¹³

Though poorly understood, low vitamin B₁₂ levels cause a diminution of the myelin that coats the peripheral nerves, perhaps through the attenuated methylation of myelin, which subsequently disrupts the transmission of action potentials. Nonhomogeneous myelin manifests as peripheral neuropathy.⁸ Vitamin B₁₂ functions as a coenzyme in the transfer of a methyl group from 5-methyl-tetrahydrofolate to tetrahydrofolate, creating methionine with the enzyme methionine synthase.²⁰ Methionine and adenosine triphosphate are essential in assembling 5-adenosyl methionine, which is the primary methyl donor in the methylation reactions involving amines, proteins, and phospholipids (including sphingomyelin) in the myelin sheath. Thus, a deficiency of B₁₂ leads to diminished methylation in myelin and, subsequently, the development of peripheral neuropathy.²⁰ Once this process occurs, it is extremely difficult to reverse and correct. Low vitamin B₁₂ levels that are symptomatic exhibit a confounding clinical similarity to diabetic peripheral neuropathy.⁵

Vitamin B₁₂ also functions as a coenzyme that connects lipid to carbohydrate metabolism in the mitochondria by converting methylmalonic acid to succinate through the enzyme methylmalonyl-coenzyme A mutase.²⁰ A deficiency in vitamin B₁₂ can therefore result in symptoms of malaise and fatigue.

Coexisting factors can affect the absorption of vitamin B₁₂ in patients with T2DM. Patients who are vegetarian are known to be at risk for low vitamin B₁₂ levels because of the absence of protein-bound vitamin B₁₂ in plant-based foods.¹ Additionally, the concomitant use of metformin with proton pump inhibitors and/or H₂-antagonist medications can cause as much as a 65% and 25% reduction, respectively, in absorption of vitamin B₁₂. This is due to the decrease in gastric hydrochloric acid, which is needed to cleave vitamin B₁₂ from protein that is ingested.⁴ Similarly, alcohol use can deleteriously influence vitamin B₁₂ levels.⁵

Until recently, no published guidelines existed regarding the monitoring and supplementation with exogenous cyanocobalamin, the manufactured form of vitamin B₁₂, in patients with T2DM on long-term treatment with metformin.^14,21 In 2018, the American Association of Clinical Endocrinologists and the American College of Endocrinology endorsed a comprehensive management algorithm for T2DM that calls for assessing the status of vitamin B₁₂ levels in patients taking metformin and instituting supplementation if neuropathy develops.²²

This article originally appeared on Clinical Advisor