B12 deficiency linked to long-term metformin use

Abstract

For many years, vitamin B12 deficiency has been a recognized complication from metformin use. Now, results from one of the largest studies on this subject show a direct link between long-term use of metformin and B12 deficiency.The Diabetes Prevention Program (DPP)/Diabetes Prevention Program Outcomes Study (DPPOS) presented investigators—who represented more than 20 institutions—with the opportunity to examine blood samples from study participants taking either metformin or placebo.“We were aware of the potential of B12 deficiency when we started the study over 15 years ago, and we monitored study participants by screening for anemia,” Jill Crandall, MD, professor of clinical medicine at Albert Einstein College of Medicine in New York City, told Pharmacy Today. A B12 deficiency can lead to anemia.When the study began in 1996, it included more than 3,000 people aged 25 years and older with impaired glucose tolerance. Fifty participants were excluded from the analysis after having weight loss surgery.Vitamin B12 and homocysteine levels were assessed in metformin- and placebo-assigned participants at 5 years and 13 years. Researchers found that at year 5, 20% of the metformin cohort had low or borderline low B12 levels, compared with 10% of patients in the placebo group. At year 13, B12 deficiency was more common in both the metformin and placebo groups.According to Crandall, who was also lead author of the study, about 30% of the placebo group participants were taking metformin by year 13 because they had developed diabetes and received treatment from their physician.After controlling for age, sex, baseline body mass index, prescription acid suppression therapy, diabetes status, and weight change, there was a 13% increased risk of B12 deficiency per year of metformin use since randomization, according to the results.Crandall said the analysis also found B12 deficiency present even in the absence of symptoms such as anemia.Although the findings suggest metformin–associated B12 deficiency may increase the risk of neuropathy, Crandall said this needs to be confirmed in a larger study.Takeaway for clinical practiceDespite the accumulating evidence linking metformin use and B12 deficiency, assessment of B12 levels in patients treated with metformin has not been incorporated into clinical practice guidelines.“Health care providers should be aware of the association of metformin with B12 deficiency and consider periodic testing of their patients taking metformin,” said Crandall. In addition, she said the absence of anemia is not sufficient to exclude a low vitamin B12 level.Eva Vivian, PharmD, professor at University of Wisconsin–Madison School of Pharmacy, said health care providers should screen patients treated with metformin therapy for B12 deficiency annually. In addition, she said anyone already diagnosed with peripheral neuropathy who uses metformin should be screened for B12 deficiency.Symptoms of B12 deficiency could include weakness, numbness or tingling, problems walking, and vision loss.The scoop on vitamin B12Humans get vitamin B12 from animal-based foods or supplements because the body does not produce it naturally. Certain medical conditions can also cause B12 deficiency. “Patients on chronic metformin therapy should be encouraged to consume meats and dairy products that are high in vitamin B12,” said Vivian. “Some people, such as strict vegetarians or the elderly, may need to take supplements or receive injections on a regular basis.”Because vitamin B12 is normally stored in the body, it can take a long time to deplete those stores and develop the deficiency. Crandall said that’s a concern because most people who take metformin for treatment of diabetes take it for many years, often decades. For many years, vitamin B12 deficiency has been a recognized complication from metformin use. Now, results from one of the largest studies on this subject show a direct link between long-term use of metformin and B12 deficiency. The Diabetes Prevention Program (DPP)/Diabetes Prevention Program Outcomes Study (DPPOS) presented investigators—who represented more than 20 institutions—with the opportunity to examine blood samples from study participants taking either metformin or placebo. “We were aware of the potential of B12 deficiency when we started the study over 15 years ago, and we monitored study participants by screening for anemia,” Jill Crandall, MD, professor of clinical medicine at Albert Einstein College of Medicine in New York City, told Pharmacy Today. A B12 deficiency can lead to anemia. When the study began in 1996, it included more than 3,000 people aged 25 years and older with impaired glucose tolerance. Fifty participants were excluded from the analysis after having weight loss surgery. Vitamin B12 and homocysteine levels were assessed in metformin- and placebo-assigned participants at 5 years and 13 years. Researchers found that at year 5, 20% of the metformin cohort had low or borderline low B12 levels, compared with 10% of patients in the placebo group. At year 13, B12 deficiency was more common in both the metformin and placebo groups. According to Crandall, who was also lead author of the study, about 30% of the placebo group participants were taking metformin by year 13 because they had developed diabetes and received treatment from their physician. After controlling for age, sex, baseline body mass index, prescription acid suppression therapy, diabetes status, and weight change, there was a 13% increased risk of B12 deficiency per year of metformin use since randomization, according to the results. Crandall said the analysis also found B12 deficiency present even in the absence of symptoms such as anemia. Although the findings suggest metformin–associated B12 deficiency may increase the risk of neuropathy, Crandall said this needs to be confirmed in a larger study. Takeaway for clinical practiceDespite the accumulating evidence linking metformin use and B12 deficiency, assessment of B12 levels in patients treated with metformin has not been incorporated into clinical practice guidelines.“Health care providers should be aware of the association of metformin with B12 deficiency and consider periodic testing of their patients taking metformin,” said Crandall. In addition, she said the absence of anemia is not sufficient to exclude a low vitamin B12 level.Eva Vivian, PharmD, professor at University of Wisconsin–Madison School of Pharmacy, said health care providers should screen patients treated with metformin therapy for B12 deficiency annually. In addition, she said anyone already diagnosed with peripheral neuropathy who uses metformin should be screened for B12 deficiency.Symptoms of B12 deficiency could include weakness, numbness or tingling, problems walking, and vision loss. Despite the accumulating evidence linking metformin use and B12 deficiency, assessment of B12 levels in patients treated with metformin has not been incorporated into clinical practice guidelines. “Health care providers should be aware of the association of metformin with B12 deficiency and consider periodic testing of their patients taking metformin,” said Crandall. In addition, she said the absence of anemia is not sufficient to exclude a low vitamin B12 level. Eva Vivian, PharmD, professor at University of Wisconsin–Madison School of Pharmacy, said health care providers should screen patients treated with metformin therapy for B12 deficiency annually. In addition, she said anyone already diagnosed with peripheral neuropathy who uses metformin should be screened for B12 deficiency. Symptoms of B12 deficiency could include weakness, numbness or tingling, problems walking, and vision loss. The scoop on vitamin B12Humans get vitamin B12 from animal-based foods or supplements because the body does not produce it naturally. Certain medical conditions can also cause B12 deficiency. “Patients on chronic metformin therapy should be encouraged to consume meats and dairy products that are high in vitamin B12,” said Vivian. “Some people, such as strict vegetarians or the elderly, may need to take supplements or receive injections on a regular basis.”Because vitamin B12 is normally stored in the body, it can take a long time to deplete those stores and develop the deficiency. Crandall said that’s a concern because most people who take metformin for treatment of diabetes take it for many years, often decades. Humans get vitamin B12 from animal-based foods or supplements because the body does not produce it naturally. Certain medical conditions can also cause B12 deficiency. “Patients on chronic metformin therapy should be encouraged to consume meats and dairy products that are high in vitamin B12,” said Vivian. “Some people, such as strict vegetarians or the elderly, may need to take supplements or receive injections on a regular basis.” Because vitamin B12 is normally stored in the body, it can take a long time to deplete those stores and develop the deficiency. Crandall said that’s a concern because most people who take metformin for treatment of diabetes take it for many years, often decades.