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.

Keywords: Anemia; Diabetes; Metformin; Metformin-induced cobalamin deficiency; Neuropathy; Prediabetes; Screening criteria; Type 2 diabetes; Vitamin B12 deficiency.

Figure 1

Postulated mechanisms accounting for metformin-induced vitamin B12 deficiency. Metformin may cause vitamin B12 deficiency through one or more of the following mechanisms: (1) Interference with the calcium-dependent binding of the intrinsic factor (IF)-vitamin B12 complex to the cubilin receptor on enterocytes at the ileum level and/or interaction with the cubilin endocytic receptor; (2) Alteration in bile acid metabolism and reabsorption, resulting in impaired enterohepatic circulation of vitamin B12; (3) Reduced IF secretion by gastric parietal cells; (4) Increased liver accumulation of vitamin B12, resulting in altered tissue distribution and metabolism of vitamin B12; and (5) Alteration in small intestine motility, resulting in small intestinal bacterial overgrowth and subsequent inhibition of IF-vitamin B12 complex absorption in the distal ileum. B12: Vitamin B12; BAs: Bile acids; IF: Intrinsic factor.