Long-term metformin therapy and vitamin B12 deficiency: an association to bear in mind

Abstract

To date, metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile. Indeed, metformin is the most widely used oral insulin-sensitizing agent, being prescribed to more than 100 million people worldwide, including patients with prediabetes, insulin resistance, and polycystic ovary syndrome. However, over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency. Of note, evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status. Vitamin B12 (also referred to as cobalamin) is a water-soluble vitamin that is mainly obtained from animal-sourced foods. At the cellular level, vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection. Thus, vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities ( e.g. , megaloblastic anemia and formation of hypersegmented neutrophils), progressive axonal demyelination and peripheral neuropathy. Nevertheless, no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy, and vitamin B12 deficiency remains frequently unrecognized in such individuals. Therefore, in this “field of vision” article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients, which could serve as a practical guide for identifying individuals at high risk for this condition. Moreover, we discuss additional relevant topics related to this field, including: (1) The lack of consensus about the exact definition of vitamin B12 deficiency; (2) The definition of reliable biomarkers of vitamin B12 status; (3) Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis; and (4) Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency. Finally, we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency, particularly when this condition is induced by metformin.

Metformin‐induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic and cardiac neuropathy in the patient with diabetes

“…The combined intrinsic factor-vitamin B12 complex in the terminal ileum attaches to the cubam receptor on the enterocytes, which results in absorption of B12 by endocytosis, a process that is calcium dependent. [7][8][9] After absorption 20%-25% of vitamin B12 is circulated bound to transcobalamin and 70% (estimated to be 2500 pg) is stored in the liver bound to haptocorrin. A portion of haptocorrin is regularly secreted in bile and is reabsorbed through the enterohepatic circulation.…”

“…These tetrahydrofolate intermediaries are utilized in the synthesis of the pyrimidine bases of both RNA and DNA. Therefore, when there is a deficiency of vitamin B12 there is an accumulation of homocysteine and impaired the synthesis of DNA, which in turn leads to ineffective erythropoiesis (megaloblastic anaemia, generation of hypersegmented neutrophils and pancytopenia) 9,10 …”

Metformin: Sex/Gender Differences in Its Uses and Effects—Narrative Review

“…The long-term administration of MTF significantly lowers vitamin B12 levels [ 59 , 60 , 61 ]. Vitamin B12 deficiency with MTF is rarely symptomatic; it is linked to a reduction in the intestinal absorption of cobalamin and can be reversed by the discontinuation of MTF or with oral B12 supplementation.…”

Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges

“…In a recent retrospective cohort study on patients with more than 1 year of metformin consumption, around 3.3% of the subjects displayed a significant VitB12 deficiency, with the highest correlation in people over 80 years old (63%) [ 86 ]. Although the precise mechanism of metformin inhibition of VitB12 uptake has not been fully elucidated, it might depend on an interference with the calcium-dependent binding of the gastric intrinsic factor-VitB12 complex with the cubilin receptors on enterocytes at the level of the ileum, a direct interaction between metformin and the cubilin receptor, which blocks VitB12 uptake, or a dysregulated intestinal microbiota outgrowth, which potentially affects cubilin receptor accessibility by VitB12 [ 87 ].…”

“…On these premises, the VitB12 deficiency and the gastro-intestinal alterations induced by metformin consumption should be taken into consideration during prolonged therapies with metformin. This is especially relevant when high dosages are required to ensure a proper bioavailability of the drug in the brain because they might exacerbate VitB12 depletion in elderly individuals who already have an increased risk of VitB12 deficiency at the age of PD clinical onset [ 87 ]. In addition, despite the putative role of metformin in counteracting α-syn spreading, it might have an indirect pro-aggregating action on the enteric α-syn, thus accelerating the early events of PD pathology.…”