Metformin causing vitamin B12 (B12) deficiency has become a traditional myth in medical literature (1,2). But what evidence do we have? The possibility to measure holotranscobalamin (active B12) and the metabolic marker, methylmalonic acid (MMA), has changed the practice of diagnosing B12 deficiency in recent years. We have learned that not all low plasma B12 means a “deficiency” and not all high plasma B12 mean “sufficiency.” When B12 is internalized and is able to maintain the B12-dependent intercellular enzyme activities (methionine synthase and methylmalonyl-CoA mutase), plasma total homocysteine (tHcy) and MMA will be within the reference range. This revolution in diagnosing B12 deficiency has provided convincing evidence that metformin is not as bad as its reputation.
In the National Health and Nutrition Examination Survey (NHANES), which included 1,621 patients with diabetes (575 were taking metformin) (1), mean serum B12 was lower (geometric mean 318 vs. 387 pmol/L, respectively) and plasma tHcy was slightly lower in patients taking metformin (9.8 vs. 10.4 µmol/L; P = 0.1015) compared with patients not taking metformin (1). This report from the NHANES study has the advantage of minimizing the effect of folate on plasma tHcy because it was conducted after starting folic acid fortification in the U.S. (mean serum folate ∼40 nmol/L) (1). Vitamin B12 became a major determinant of plasma tHcy after folic acid fortification in the U.S. Despite the obvious effect of metformin on lowering plasma B12, concentrations of tHcy were not elevated as would be expected (1). Similarly, one follow-up study (2) showed that using 850 mg/day metformin (compared with insulin) over a mean of 3.4 years in 390 patients with type 2 diabetes lowered plasma B12, but tHcy was not significantly higher than the insulin group (2). We provided further evidence that patients who were taking metformin had lower serum B12 and holotranscobalamin but comparable metabolic markers: tHcy, MMA, and methylation index (S-adenosylmethionine/S-adenosylhomocysteine) (3). A recent study confirmed these observations, where lowering serum B12 was not associated with increased serum MMA in women with polycystic ovary syndrome taking metformin over 6 months (4). Therefore, the B12-dependent reactions are well functioning in large numbers of metformin-treated patients despite low serum B12. Low serum B12 alone without disturbances in the metabolic markers has no diagnostic value. In contrast, higher serum B12 in non–metformin treated patients may give the wrong impression that B12 deficiency is less common. Metformin has been also accused of lowering B12 absorption in one study that used metformin together with calcium without controlling for a potential independent effect of calcium on B12 absorption (5). All available evidence suggests that with metformin therapy, lowering plasma B12 (if not associated with increased metabolites) would mean increased cellular uptake of B12. In line with this view, it was recently shown that animals treated with metformin accumulate more B12 in the liver, which may explain lowering plasma B12 levels (6).
Taken together, there is no evidence that pathological levels of the biochemical markers of B12 are more common in metformin-treated compared with non–metformin-treated patients, despite lowering B12 in serum or plasma. This letter aims to raise the consciousness of medical practitioners of the common misleading statements on metformin causing vitamin B12 deficiency. A combined assay of vitamin B12 (i.e., active B12) and MMA can identify the deficiency in suspected cases.
Article Information
Duality of Interest. The author was the principal investigator in one study (ref. 3) that was partly supported by Merck Serono. The funding was declared in the original article. The company had no role in the study design, interpretation of the results, or drafting of the manuscript. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. R.O. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
