Metformin and B12

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Back in December 2006, Amy Campbell wrote in her blog about the possibility of the popular diabetes drug metformin causing vitamin B12 deficiency. In a follow-up comment, she mentioned that taking calcium supplements might help to remedy this deficiency. The information spurred an outpouring of comments and questions from concerned readers, so those of us on the magazine staff decided to investigate the matter further.

Our Q&A editor, Alwa Cooper, contacted Mariejane Braza, MD, and James F. Hanley, MD, of the UTHSCSA-Regional Academic Health Center in Harlingen, Texas, who had recently conducted some research on the topic of metformin and vitamin B12 deficiency. As published in the November/December 2009 issue of Diabetes Self-Management, here is their answer:

“Metformin is an important and effective medicine for the treatment of Type 2 diabetes; however, with prolonged use, as many as 30% of the people taking it develop a B12 deficiency. It has been our experience that not all physicians are aware of this association.

Detecting B12 deficiency can be difficult, because the early symptoms, such as fatigue or loss of appetite, may be subtle. Other symptoms, such as numbness or tingling in the hands and feet, may be assumed to be complications of diabetes. In a study that we conducted, peripheral neuropathy (nerve damage in the hands, feet, and legs) was more common in subjects with both Type 2 diabetes and B12 deficiency than in those with Type 2 diabetes alone. Prior to our study, it was presumed that these participants’ neuropathy was a complication of their diabetes. We felt, however, that it was not clear whether this was the case or whether B12 deficiency had played a role in or caused the development of the neuropathy.

Testing for B12 deficiency may not always be straightforward. People with a severe B12 deficiency usually have a type of anemia characterized by enlarged red blood cells, a low platelet count, and even a low white blood cell count. However, this type of anemia may not be present in people with a moderate or minimal B12 deficiency. For this reason, direct measurement of B12 levels in the blood (serum B12) is considered the gold standard for diagnosis. However, even this test result may require some expert interpretation, because the level of serum B12 does not always reflect the amount of B12 available to the body’s cells. When the serum B12 level is low, it is overwhelmingly likely that there is a deficiency; however, a low-normal value may also represent a deficiency. In that situation, some experts recommend testing levels of methylmalonic acid and homocysteine; when there is a B12 deficiency, both of these are usually elevated.

Classically, the treatment for B12 deficiency has been intramuscular injection of a common form of B12 called cyanocobalamin, beginning with priming doses (at first daily, then weekly) then monthly doses for life. Another option is oral cyanocobalamin in relatively large doses; in several studies, this approach has been effective in treating the deficiency, no matter what the cause. Oral cyanocobalamin is also inexpensive and rarely causes side effects.

The possible effectiveness of using calcium to reverse or reduce the effects of metformin on B12 deficiency is based on the finding of a 2000 study that demonstrated that people taking metformin had reduced absorption of vitamin B12 that could be reversed with the use of calcium in the form of the over-the-counter antacid Tums. The research suggested that metformin interfered with absorption of vitamin B12 in the small intestine, a process dependent on calcium—thus requiring supplemental calcium to regulate it. But in clinical practice, it is not as clear whether taking extra calcium is enough to avoid a deficiency.

Since our study was done, some of the health-care providers at our center have decided to prescribe oral cyanocobalamin to all of their patients on metformin, making it unnecessary to monitor them for B12 deficiency.”

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