Should Patients Taking Metformin Also Take Vitamin B12?

Gayle Nicholas Scott, PharmD


December 13, 2013


Should I recommend vitamin B12 to patients taking metformin?

Response from Gayle Nicholas Scott, PharmD
Assistant Professor, Eastern Virginia Medical School, Norfolk, Virginia; Clinical Pharmacist, Chesapeake Regional Medical Center, Chesapeake, Virginia

Metformin is a first-line type 2 diabetes treatment that effectively lowers blood glucose and has a good long-term safety record. (It has been available in the United Kingdom since 1958 and the United States since 1995).[1] Metformin also offers the important advantage over most other antihyperglycemic drugs of improved cardiovascular morbidity and mortality risk.[2] Beyond monitoring renal and hepatic function and avoiding concomitant drugs that interfere with renal tubular secretion (eg, cimetidine), metformin use has become rather mundane.

A sometimes forgotten disadvantage of metformin is its effect on vitamin B12 absorption. Although the liability of metformin to lower vitamin B12 levels has been well described,[3] interest in the need for monitoring for vitamin B12 deficiency is more recent.[1,4,5,6]

Vitamin B12 deficiency is estimated to be present in up to 30% of patients with diabetes taking metformin.[1] The risk for vitamin B12 deficiency increases with patient age and the dose and duration of metformin use.[5,7] Concomitant conditions such as suboptimal dietary intake, which is common among vegetarians and alcohol abusers, and malabsorption due to atrophic gastritis, pernicious anemia, chronic pancreatitis, and celiac disease may further increase risk for vitamin B12 deficiency.[5] The combination of metformin with proton pump inhibitors has been reported to have an additive effect on risk for vitamin B12 deficiency.[8]

Vitamin B12 deficiency is associated with megaloblastic anemia and neurologic consequences such as polyneuropathy that may mimic diabetic neuropathy and cognitive decline.[5,9] Patients with diabetes have a greater risk for cognitive impairment than patients without diabetes. Among patients with diabetes, patients who take metformin may be at greater risk for cognitive impairment than patients who do not receive metformin.[1,10]

How vitamin B12 might contribute to neurologic decline is unknown. Vitamin B12 is required for DNA and myelin synthesis and is a cofactor in the production of methionine from homocysteine, which has been linked to cognitive decline. It is also required for the conversion of methylmalonic acid (MMA), an organic acid with potential neurotoxic properties, to succinyl-CoA (an intermediate in the Krebs cycle).[1,9] Both homocysteine and MMA accumulate with vitamin B12 deficiency.[9] Proposed mechanisms for cognitive decline associated with vitamin B12 deficiency include inadequate methylation in the central nervous system, accumulation of homocysteine and/or MMA, and demyelination of white matter.[9]

Suspected vitamin B12 deficiency should be evaluated with MMA levels, homocysteine levels, or both. Measurement of serum vitamin B12 levels often produces both false-negative and false-positive results and is unreliable for diagnosis. Vitamin B12 deficiency can be treated with oral supplements or intramuscular injections depending on type and severity of deficiency.[11]

Screening for vitamin B12 deficiency seems reasonable for all adult patients with diabetes, especially those taking metformin. Consider vitamin B12 supplementation in patients receiving metformin, particularly for older patients and other patients at risk for reduced dietary vitamin B12 absorption, and for patients who have received metformin for several years.


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