Multivitamins Could Prevent Metformin-Induced B12 Deficiency


Long-term metformin use reduces serum vitamin B12 variably.

Long-term metformin use reduces serum vitamin B12 variably.

Metformin is a common first-line treatment for type 2 diabetes, though it’s being studied for other indications, including cancer and aging retardation. However, no consensus defines vitamin B12 serum levels and the biomarkers indicating deficiency. The National Health and Nutrition Examination Survey recommends measuring a direct biomarker (serum B12 or holotranscobalamin) and a functional biomarker (methylmalonic acid or total homocysteine) to identify vitamin B12 deficiency.

Metformin-induced vitamin B12 deficiency is similar to pernicious anemia in that both are slow to develop, chronic, and can cause neurologic disability. However, pernicious anemia due to total vitamin B12 absorption failure is more severe and irreversibly disabling without treatment.

Vitamin B12 supplementation far in excess of the dietary reference intake of 2.4 mcg/day (eg, 1000 mcg per day) reverses vitamin B12 deficiency secondary to insufficient dietary intake or absorption. The authors of a 2015 review suggested that supplementation with 6 mcg/day to 25 mcg/day can protect against metformin-induced vitamin B12 deficiency.

Multivitamins prevent metformin-induced vitamin B12 deficiency in diabetic metformin users, and vitamin B12 deficiency is more common in metformin users than in nonmetformin user diabetic patients. Results from a recent study affirm metformin use’s association with low serum vitamin B12 in diabetic older adults, and that deficiency responds to multivitamin use.1

The study included 2510 older adult enrollees (>50 years) from the much larger REGARDS Study. The authors defined low vitamin B12 as serum levels <148 pmol/L and borderline low levels as 148 pmol/L to 221 pmol/L.1

Metformin users took multivitamins less often than patients without diabetes. This was surprising because providers have understood metformin’s risks for years (although the study started in 2003), and it seems that clinicians should be encouraging patients to take multivitamins. In this study, multivitamins contained 6 mcg to 25 mcg vitamin B12 per dose.

Previous study results suggest calcium carbonate supplementation as a prophylactic for deficiency and that histamine-2 receptor blockers and proton pump inhibitors increase the risk of deficiency. However, the current researchers didn’t find a relationship between acid-suppression and vitamin B12 deficiency.

Future studies should assess metformin’s impact on serum vitamin B12 levels by dose and duration. The optimal multivitamin vitamin B12 content for metformin-induced deficiency is currently unknown.


1. Kancherla V, et al. Multivitamin use and serum vitamin B12 concentrations in older-adult metformin users in REGARDS, 2003-2007. PLOS One. 2016;11(8):e0160802.

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