Metformin and B12 deficiency

Today at VA Morning Report, a question came up about metformin and B12 deficiency and how often to screen for B12 deficiency in patients being treated with metformin. The short answer is that there are no set guidelines. The long answer is:

Metformin has been reported to cause a decrease in serum B12 concentrations. Cross-sectional studies report a wide range of prevalence of biochemical vitamin B12 deficiency with metformin exposure, ranging from 5.8% to as high as 40%. Though the exact mechanism is not known, it is thought to be caused by B12 malabsorption: it is thought that metformin interferes with the calcium-dependent membrane action responsible for vitamin B12-intrinsic factor absorption in the terminal ileum.

A recent report from the Diabetes Prevention Program (DPP) / DPP outcomes study (DPPOS) assessed the risk of B12 deficiency with metformin. The study contained adult participants from 27 centers in the US. Patients treated with metformin 850 mg BID vs placebo. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764). Low B12 (≤ 203 pg/mL) occurred more often in the Metformin group than the Placebo group at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in metformin group at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Anemia prevalence was higher in metformin group but did not differ by B12 status. The prevalence of neuropathy was higher in the metformin group with low B12 levels. In the patients with biochemical B12 deficiency, homocysteine levels were was elevated consistent with true B12 tissue deficiency.

Several researchers globally have made recommendation to screen those with T2DM on metformin for B12 deficiency. The group above proposed screening for B12 deficiency prior to initiating metformin (>/= 3-4 years), use of high doses of metformin (>/= 2 g/day), clinically worsening diabetic distal polyneuropathy in the presence or absence of anemia. The most recent American Diabetes Association Standards of Medical Care in Diabetes – 2018 makes the following statement: “Long-term use of metformin may be associated with biochemical vitamin B12 deficiency, and periodic measurement of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy.” (Grade B). No formal recommendations have been provided by USPSTF.

Please refer to this article for more information! Vanita R. Aroda et al and the Diabetes Prevention Program Research Group. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016 Apr; 101(4): 1754–1761.