Should Metformin Be Paired with a Vitamin B12 Prescription?

Karolina Machnica, MD

By Karolina Machnica, MD

Metformin is one of the oldest and most commonly prescribed blood sugar-lowering drugs used in the treatment of diabetes mellitus. Approximately 120 million diabetes patients worldwide are treated with this drug. The active ingredient in metformin (a derivative of a substance called guanidine), extracted from the French lilac plant (Galega officinalis), had been used for centuries by European medical practitioners to treat diabetes along with multiple other conditions such as plague, worms, bites, chorea, or urinary infections.

Metformin is usually the first medication started (along with lifestyle interventions) after a diagnosis of type 2 diabetes, the diabetes that occurs when insulin does not work as well as it should, and includes a progressive loss of insulin production and release from the pancreas over time. Most patients tolerate metformin well, with the most common side effects relating to the gastrointestinal system (bloating, nausea and diarrhea). These possible side-effects are usually mild and often resolve with time or a simple dose adjustment.

Metformin also is known to reduce possible cardiovascular complications of diabetes such as heart attacks or strokes, the number-one killer of patients with type 2 diabetes.

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.

Checking for vitamin B12 deficiency starts with a simple blood test. Deficiency is unlikely when the level is above 300 picograms per liter (pg/mL). In some laboratories, this will be equivalent to above 221 picomoles per liter (pmol/L), but is possible when the level is borderline, between 200 and 300 pg/mL (148 – 221 pmol/L), and is confirmed when the level is below 200 pg/mL (below 148 pmol/L). Additional blood tests can be done for those with borderline results and those with neurological symptoms that are difficult to explain, as these individuals may be experiencing vitamin B12 deficiency on the cellular level and will benefit from treatment, but their blood vitamin B12 remains relatively “normal.” These additional tests include homocysteine and methylmalonic acid. Both values will be elevated in vitamin B12 deficiency.

This evaluation should be accompanied by a review of medical conditions, medications and personal habits in order to exclude other causes for these elevated values. Patients taking metformin who test positive for vitamin B12 deficiency also need to be evaluated for other common causes of low vitamin B12: pernicious anemia, food-cobalamin malabsorption syndrome (the most common cause), very strict vegetable-based diets, stomach/small bowel/pancreatic abnormalities, certain medications (some antibiotics, acid reducers, colchicine) and parasites.

While discontinuing metformin may be advised in severe cases of metformin-induced vitamin B12 deficiency, metformin can be continued in most patients who are receiving adequate vitamin B12 replacement. Typically, vitamin B12 replacement is given in the form of an injection (either intramuscular or deep subcutaneous, i.e., under the skin) of 1,000 micrograms of cyanocobalamin (a form of vitamin B12) initially daily for a week, followed by weekly for a month, and sometimes continued monthly for life. There are many protocols available, and some clinics may use different doses and schedules.

In mild cases of vitamin B12 deficiency, or in patients who cannot tolerate shots, oral vitamin B12 replacement (with cyanocobalamin) can be used. Very high doses are usually given, typically 1,000 to 2,000 micrograms a day. Many patients will start with the injectable form, and, after their vitamin B12 level is back to normal, will convert to the oral form. A nasal spray and sublingual (under the tongue) tablets of cyanocobalamin are also available and approved for treatment. Other formulations containing different forms of vitamin B12 (methylcobalamin, hydroxocobalamin, adenosylcobalamin) are not officially approved for treatment of vitamin B12 deficiency.

Vitamin B12 replacement will reverse hematological abnormalities within days to weeks, will stop – but not completely reverse – further progression of nerve damage, and improve neurological and psychiatric symptoms within several months. Vitamin B12, homocysteine, methylmalonic acid and hematological studies (CBC) should be monitored during and after treatment.

Many experts recommend evaluating patients for vitamin B12 deficiency at the time metformin is begun, followed by every one to 2 years while on metformin therapy. Others even suggest a once-yearly injection of 1,000 micrograms of vitamin B12 as an alternative to testing. All patients should also be screened for distal neuropathy beginning at the time of diagnosis of type 2 diabetes, followed by at least yearly re-evaluation – this can not only diagnose diabetic neuropathy, but will identify other polyneuropathies, including that of metformin-induced vitamin B12 deficiency.