Diabetes Medication and Vitamin B12 Levels

Metformin is the most commonly-used drug for the control of blood sugar in diabetics.  In Europe it has been used since the 70’s while it was approved in the United States in 1994.  It is prescribed at daily amounts between 500 mg and 2550 mg, sometimes divided over several  doses.  It is available under several trade names, sometimes in combination with other drugs.  An example are the pair Glucophage and Glucovance.  Glucophage (“phage”  from Greek “to eat”) has just metformin, while Glucovance contains a combination of metformin and another drug known as glyburide.  There is another version of Glucophage called Glucophage XR, which is slow-release, so only one dose is needed every 24 hours.

Metformin is very effective in lowering the concentration of blood glucose in diabetics.  It inhibits the release of glucose from the liver and it increases the number of insulin receptors in muscle and fat cells.  These effects make it  possible for patients who have to take insulin injections to lower their doses, and in many cases, to control their blood sugar concentration without needing injections.  Metformin also has been demonstrated in a long-term (10 year) study to very significantly decrease the incidence of both heart attacks and of overall mortality in patients with diabetes.

However, metformin also has the effect of lowering the blood serum vitamin B12 concentration.  The manufacturers do provide this information on the Glucophage package insert.  Specifically it states that in a controlled trial that lasted 29  weeks 7% of the participants developed subnormal levels of vitamin B12.  A vitamin B12 deficiency is variously defined as having a serum concentration of this vitamin of less than 150 pmol/l or 200 pmol/l depending on the source.

A four-year Dutch study published in 2010 obtained similar results in 390 patients who were randomly assigned to receive either 2550 mg/day of metformin in 3 doses of 850 mg, or a placebo (de Jager et al, BMJ 2010;340:c2181).   These patients were all diabetics and on insulin therapy.  During the four years of the study, vitamin B12 deficiencies developed in significantly more of the metformin-treated patients than in those who were administered a placebo, compared to a baseline level determined at the start.  At the end of the study, the risk of developing vitamin B12 deficiency (in this study a deficiency was defined as 150 pmol/l or lower) was 7% higher in the metformin group, and the risk of low vitamin B12 concentration (150-220 pmol/l) was 11% higher in the metformin group than in the placebo-treated group.

Since vitamin B12 treatment is nontoxic, diabetics taking metformin would most likely benefit from supplementation with vitamin B12.  Given the fact that metformin decreases vitamin B12 blood serum concentrations, it would be advantageous to regularly monitor these levels in patients taking metformin.    metformin is thought to act by inhibiting absorption of the vitamin plus intrinsic factor by the cells in the ileum of the small intestine.  A form of the B12 vitamin that bypasses the gastrointestinal tract, like sublingual, transdermal or injected would not be affected by the presence of metformin.