Long-Term Metformin Use Linked with Vitamin B12 Deficiency

With commentary by Jill Crandall, MD, professor of clinical medicine, Albert Einstein College of Medicine, New York.

Long-term use of the popular diabetes drug metformin is linked with vitamin B12 deficiency and anemia, according to new research that solidifies some previous research.

vitamin b12

"We have essentially confirmed what many smaller studies have suggested," says Jill Crandall, MD, professor of clinical medicine at the Albert Einstein College of Medicine, the Bronx, who led the new study. "There is a small but significant risk of developing Vitamin B12 deficiency when people take metformin."

The finding, she adds, ''has implications for the consequences of B12 deficiency." These can include cognitive impairment, nerve problems (neuropathy) and anemia (low red blood cell count). B12 is crucial for the proper formation of red blood cells, for neurological functioning and for making DNA.

The link between taking the popular diabetes drug and deficiencies in vitamin B12 has been discussed as long ago as 1969, according to Dr. Crandall. However, few studies have looked at long term use, as her new study has done, tracking people for up to 13 years.

The new study was published online Feb. 22 in the Journal of Clinical Endocrinology & Metabolism.

Overview of the Metformin Study

The researchers evaluated more than 2,000 men and women enrolled in the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study. In these studies, researchers enrolled overweight people who had prediabetes (blood sugar levels higher than normal but not high enough to be termed diabetes) to see if modest weight loss or treatment with metformin could prevent or delay the onset of type 2 diabetes, then followed them to see if the effects endured.

Half of the participants were given 850 milligrams of metformin twice daily and half got placebo pills. At the 5-year mark, more of those in the metformin group than the placebo group had low B12 levels, affecting 4.3% of the metformin group but just 2.3% of the placebo group. However, the gap narrowed at 13 years, with 7.4% of the metformin group and 5.4% of the placebo group having low B12 at that point. The narrowed gap seems counter-intuitive until Dr. Crandall explains what is happening.  "As time goes on, the groups are a little contaminated," Dr. Crandall says, because some in the placebo group, as time went on, developed diabetes and had to begin taking metformin.

Years of use was linked with an increased risk of B12 deficiency, Dr. Crandall found. Those taking metformin were more likely to have anemia, regardless of their B12 status. Those taking metformin with low B12 were more likely to have neuropathy.

The study findings suggest that routine testing of Vitamin B12 should be considered in patients on metformin treatment, Dr. Crandall says. Experts think that metformin affects the way Vitamin B12 is absorbed by the body. "People should be aware of this possibility," Dr. Crandall says of the metformin and low B12 link. Currently, she says, there are no official recommendations for B12 testing of those on metformin. 

Metformin & Vitamin B12: Second Opinion

"I think it lends more support to a practice that is already in place with endocrinologists," says Minisha Sood, MD, director of inpatient diabetes at the Lenox Hill Hospital, New York, of the study findings. She reviewed the research but didn't participate in it.

She screens for Vitamin B12 deficiency in her patients ''at least annually if on metformin."  According to Dr. Sood, many endocrinologists do screen for B12 deficiencies in those on metformin. However, she says, many patients with diabetes who are on metformin are cared for by general practice physicians or internists. These patients should ask their doctor's advice about getting screened for B12 deficiencies, Dr. Sood says. 

B12 Deficiency Symptoms & Treatment 

Symptoms of B12 deficiency may include numbness, tingling in the feet, and memory problems, Dr. Crandall says. Loss of appetite, weight loss and fatigue can occur. The deficiency typically develops slowly over time, so the regular screening could detect it early.

Treatment includes a weekly B12 injection and then switching to oral vitamins. 

The recommended dietary allowance (RDA) for B12 is 2.4 micrograms for those age 14 and older.  Foods high in B12 include cooked clams and beef liver, fortified breakfast cereals and fish such as salmon and trout.

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