Metformin Use and Vitamin B12 Deficiency: Managing the Risks

With the direct correlation between metformin use and vitamin B12 deficiency established, implementation of guidelines for B12 screening should be considered.

Preconception probiotics, micronutrients, and myo-inositol supplementation reduced preterm birth, but not gestational glycemia. These findings from a double-blind, randomized controlled trial were published in Diabetes Care.

Women (N=1729) planning to conceive during the next 6 months were recruited from centers in Singapore, New Zealand, and the UK between 2015 and 2017 for the Nutritional Intervention Preconception and During Pregnancy to Maintain Healthy Glucose Metabolism and Offspring Health (NIPPER) study.

Participants were randomly assigned in a 1:1 ratio to receive daily 400 mg folic acid, 12 mg iron, 150 mg calcium, 150 mg iodine, and 720 mg b-carotene alone or with 4 g myo-inositol, 10 mg vitamin D, 1.8 mg riboflavin, 2.6 mg vitamin B6, 5.2 mg vitamin B12, 10 mg zinc, and probiotics (Lactobacillus rhamnosus and Bifidobacterium animalis). Pregnancy outcomes and gestational glycemia were assessed.

A total of 34% of each cohort (n=588) reached 28 weeks’ gestation. Among those who reached 28 weeks, the control and intervention cohorts comprised women with mean ages of 30.14 (±3.30) and 30.53 (±3.40) years. Their median BMI was 23.75 (interquartile range [IQR], 21.34-27.5) and 23.65 (IQR, 21.16-26.23) kg/m2, and 27.2% and 19.1% had a family history of diabetes, respectively.

The participants were assessed by an oral glucose tolerance test (OGTT) at 3 time points. No significant group differences were observed (all P >.017).

Among women who were overweight or obese at the time of conception, 2-hour glycemia was higher among the intervention cohort (adjusted b, 0.076; 95% CI, 0.020-0.131 loge mmol/L). This significant difference did not associate with an increased risk for gestational diabetes.

Fewer women in the intervention group delivered their baby before 37 weeks (adjusted risk ratio [aRR], 0.43; 95% CI, 0.22-0.82). The group differences were more pronounced between 34 and 36 weeks (aRR, 0.41; 95% CI, 0.20-0.85) and for preterm prelabor rupture of membranes (aRR, 0.39; 95% CI, 0.16-0.97).

Major postpartum hemorrhage incidence (>1-L blood loss) was reduced among the intervention recipients (aRR, 0.44; 95% CI, 0.20-0.94).

This study may have been limited by its lack of diversity and small percentage of women who were not overweight or obese prior to conception.

These findings suggested supplementation with probiotics, micronutrients, and myo-inositol did not decrease likelihood of developing gestational diabetes but did decrease preterm deliveries.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of authors’ disclosures.


Godfrey KM, Barton SJ, El-Heis S, et al; NiPPeR Study Group. Myo-inositol, probiotics, and micronutrient supplementation from preconception for glycemia in pregnancy: NiPPeR international multicenter double-blind randomized controlled trial. Diabetes Care. Published online March 29, 2021. doi:10.2337/dc20-2515 

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