Question

Metformin is the most widely used oral hypoglycemic agent and studies have shown that serum vitamin B12 levels are inversely associated with the dose and duration of Metformin use. Discuss the pathogenic mechanisms of vitamin B12 deficiency in Metformin treatment. Provide support literature for your response and be sure to cite your sources.

Answer 1

Metformin is a popular diabetic or hypoglycemic drug. It is believed that long term use of Metformin linked with Vitamin B12 deficiency. Metformin works as an insulin sanitizer to reduce your production of glucose and is commonly prescribed to individuals with type 2 diabetes. It is believed and studies shows that Metformin can affect the absorption of vitamin B12 in the ileum of small intestine. It is also believed that those patients taking Metformin were more likely to have anemia and also neuropathy because deficiency of Vitamin B12 causes severe nerve damage.

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.

Long-term use of metformin can, however, lead to vitamin B12 (cobalamin) deficiency. Vitamin B12 plays a vital role in several chemical reactions inside the human body that are critical for DNA synthesis and amino (part of protein) and fatty acid (part of cholesterol) metabolism. A study from France reported that in about one in 20 cases of vitamin B12 deficiency, metformin is the main cause. Up to one-third of patients treated with metformin can experience decreased vitamin B12 absorption from the gut, which, with time, can result in lowering of the blood level of this vitamin. This problem is more likely with prolonged use of metformin, higher doses taken and in older individuals.

A small, but detectable, decrease in the blood level of vitamin B12 happens early during treatment with metformin ( three to four months after initiation), but it usually takes much longer (5 to 10 years) for the level to drop below the normal value and result in symptoms. This is because our bodies store a large amount of vitamin B12 in the liver (around 2,500 micrograms), while we only use 1 to 2 micrograms per day. The main natural source of vitamin B12 is from what we eat, mainly animal products such as meat, fish, eggs, and dairy (vitamin B12-fortified foods include cereals, yeasts, or tofu), and most people eating a general diet get enough of vitamin B12 in their food to meet the recommended daily adult allowance of 2.4 – 2.8 micrograms in their food.

Calcium supplementation seems to reduce this effect of metformin – in some patients, it may prevent the problem from getting worse, but it will not restore the level of vitamin B12 to normal.

Vitamin B12 deficiency can lead to many hematological (blood) and neurological problems. It could also result in bowel irregularities, weaken the immune system, and lower bone mineral density (osteoporosis). Often, only one symptom may be present. The classic blood finding is a condition called megaloblastic anemia (with a complete blood count – CBC – showing a low hemoglobin, the protein in red blood cells that carries oxygen throughout the body, and a large red cell size). Sometimes, patients will have other blood abnormalities such as abnormal white blood cell appearance (described as hypersegmented neutrophils), or pancytopenia (a combination of low hemoglobin, low white blood cells and low platelets). The neurological symptoms include mild numbness and tingling in the feet (peripheral neuropathy), muscle weakness, decreased vision, balance problems, loss of bowel or urine-holding control, chronic fatigue, psychiatric symptoms (depression, psychosis), or memory problems. The symptoms of peripheral neuropathy due to vitamin B12 deficiency can mimic those of diabetesassociated nerve damage.

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