Metformin and Anemia

The list of causes of anemia are many, making the work up timely and at times invasive, where patients may require endoscopic procedures and occasionally bone marrow evaluation. B12 deficiency is a common problem and in itself has a long list of contributors, ranging from common (pernicious anemia) to zebra (nitrous oxide toxicity). The case of anemia discussed today involved a patient with DM2 who was taking metformin, which raised the question of metformin induced B12 deficiency. Given the widespread use of metformin in the treatment of diabetes, I felt a review of the literature surrounding this topic would be useful.


Metformin is from the biguanide class of oral hypoglycemics, which decrease hepatic gluconeogenesis and insulin dependant glucose utilization in peripheral tissues. It is supported as first line therapy for diabetes by the American Diabetes Association consensus guidelines and has become the most commonly used medication in this disease. Metformin results in decreased intestinal absorption in upwards of 30% of patients through a reduction in  intestinal absorption. A randomized study involving nearly 400 patients randomized diabetics on insulin to metformin or placebo and monitored their B12, folate and homocysteine levels for 4 years. Compared to placebo, metformin resulted in decreased B12 levels and increased homocysteine levels. There was no difference in folate concentration when controlling for BMI and smoking. They felt that the number needed to harm was roughly 9 individuals per 4.3 years. B12 deficiency was found to be progressive, worsening over time in these patients where some did reach levels requiring supplementation.

The mechanism was initially felt to be related to impaired bowel motility and subsequent bacterial overgrowth. However, B12 deficiency has been identified in the absence of bacterial overgrowth bringing this mechanism into question. Metformin is known to have activity against calcium absorption at the intestinal wall. As well, intrinsic factor absorption is calcium dependent, which raised the idea that calcium alterations may be involved in the mechanism of B12 deficiency. A study published in Diabetes Care looked at B12 levels in diabetics newly started on metformin. B12 levels dropped significantly after three months of therapy as did B12 precursors. Supplimentation with calcium led to an increase in B12 precursor within a month, with a non-significant increase in total B12 levels. There was no evidence of bacterial overgrowth in the study population as tested with hydrogen breath testing.

Rarely will the B12 deficiency associated with metformin result in hematologic or neurologic complications, though there are case reports of peripheral neuropathy from B12 deficiency. Neuropathy may be under diagnosed as well, given diabetic neuropathy presents in a similar fashion to B12 deficiency and is a common complaint amongst diabetics.

Below is the article linking calcium supplimentation and improved B12 levels.

B12 deficiency and metformin