New Metformin Warning: Mandatory Supplementation with Vitamin B12
The most common medication used in women with PCOS is the insulin-sensitizer metformin. Research is strongly showing that long-term use of metformin and at high doses (1.5mg or higher daily) can deplete levels of vitamin B12. A deficiency of vitamin B12 can cause permanent neurological and nerve damage as well as mood changes and decreased energy. Here’s what you need to know to avoid a vitamin B12 deficiency if you take metformin.
Metformin is a medication that became available in the U.S. in 1995 for the treatment of type 2 diabetes. Metformin is the most widely used medication used to lower insulin levels in those with polycystic ovary syndrome. Other names for metformin include glucophage, glucophage XR, glumetza, and fortamet.
Metformin lowers blood glucose levels in three ways:
- It suppresses the liver’s production of glucose.
- It increases the sensitivity of your liver, muscle, fat, and cells to the insulin your body makes.
- It slows the absorption of carbohydrates you consume
Metformin use may affect the absorption of vitamin B12 possibly through alterations in intestinal mobility, increased bacterial overgrowth, or alterations of the vitamin B12-intrinsic factor complex. Metformin can cause a malabsorption in B12 due to digestive changes, which leads to the binding of B12-intrinsic factor complex (intrinsic factor is needed to absorb B12 in the gut) and a reduction of B12 absorption.
Vitamin B12 Deficiency in Metformin Users
The largest study thus far to examine the link between metformin and vitamin B12 is the Diabetes Prevention Program Outcomes Study (DDPOS). This study looked at B12 levels of individuals with prediabetes who took 850 mg Metformin 2x/day and compared them to those taking a placebo. At 5 years, 4.3% of the metformin users had low levels of B12 (<203 pg/ml) vs 2.3% of placebo takers and 19% of metformin users had borderline low B12 levels (204 –298 pg/ml) compared with 9.5% of placebo.
Vitamin B12 levels decreased over the years among individuals who took metformin. At 13 years, 7.4% of metformin users had low B12 levels and 20.3% had borderline low levels.
One study published in the Journal of Clinical and Diagnostic Research found that 33% of individuals who took metformin were deficient in Vitamin B12
A 2015 systematic review and meta analysis which looked at a large number of studies, concluded that metformin treatment is significantly associated with an increase in incidence of B12 deficiency and reduced serum VB12 levels.
Nearly a third of obese adolescents with clinical insulin resistance had a low or borderline serum B12 status in a study published in Nutrients.
The prevalence of vitamin B12 deficiency in metformin-treated type 2 diabetes patients in Korea was 9.5%. Vitamin B12 deficient patients had longer duration of metformin use and higher daily metformin dose.Vitamin B12 deficiency was defined as vitamin B12 ≤ 300 pg/mL without folate deficiency (folate > 4 ng/mL).
B12 Deficiency Among Metformin Users With PCOS
Studies done investigating metformin use in women with PCOS are severely lacking. There is much more data on people with diabetes who take metformin with the majority of the evidence showing metformin decreases B12 levels. As for studies done in women with PCOS, here is what the evidence shows:
A 2014 Systematic review and meta-analysis looked at individuals with type 2 diabetes and women with PCOS who took metformin. The higher the metformin dose, the more deficient people were in vitamin B12. The effect of metformin on vitamin B12 levels was nearly the same in patients with type 2 diabetes and PCOS. Moreover, metformin reduced vitamin B12 concentration in both long (≥3 years) and short (<3 years) term.
One study in Nutrients found serum B12 levels declined and reached significant lower levels after just six months of treatment in women with PCOS taking 1.5-2.5 grams of metformin daily.
In 2009, Kaya et al. found that vitamin B12 concentrations were significantly lower in obese PCOS women in comparison with obese control women.
Women with PCOS tend to take higher amounts of metformin (average dose is 1,500-2,000 mg daily) than those with diabetes to help manage insulin resistance. Both long-term use and high dosage intake as seen in the PCOS population, are risk factors for vitamin B12 deficiency.
About Vitamin B12
Vitamin B12 is a water-soluble vitamin that is required for proper red blood cell formation, neurological function, and DNA synthesis. There’s some evidence that vitamin B12 may help prevent heart disease and possibly even Alzheimer disease. This vitamin is found primarily in animal foods, such as beef, seafood, eggs, and dairy products, which is why some vegans are at risk for a B12 deficiency (click here for a list of food sources of B12). Elderly people are often at risk for deficiency as well, due to problems with absorption from the gastrointestinal tract.
Symptoms of B12 deficiency include certain types of anemia, neuropathy (nerve damage), chronic fatigue, memory loss, confusion, mood changes and even dementia. Pernicious anemia, a severe form of long-term vitamin B12 deficiency is an autoimmune disease that affects the stomach. If you experience any of these symptoms, see your doctor immediately.
Supplementing with Vitamin B12
Individuals who take metformin get B12 levels checked annually. A simple blood test can assess vitamin B12 status. Normal lab reference ranges may vary by lab. Values below approximately 170–250 pg/mL (120–180 picomol/L) for adults indicate a vitamin B12 deficiency. Elevated serum homocysteine and methylmalonic acid levels may also indicate a B12 deficiency.
Authors of the book, Could It Be B12, say levels to indicate a vitamin 12 deficiency are too low and that people with levels under 400 pg/mL could very well be deficient with B12 and have effects.
All individuals age 14 or higher need 2.4 mcg B12 daily whether they take metformin or not. Women who are pregnant or nursing will need slightly more. Mandatory supplementation with B12 has now been proposed for those taking metformin. Taking a daily multivitamin containing 100% of the daily value (DV) for vitamin B12 may do the trick although many of our patients who take a mulitivitamin with B12 and are on high doses of metformin are still deficient in vitamin B12, requiring extra supplementation.
The best absorbable form of Vitamin B12 is methlycobalimum. Taking vitamin B12 sublingual (under the tongue) is recommended for over the counter B12 supplements.
We recommend all our patients who take metformin, have their vitamin B12 levels checked annually. Many women with PCOS also take oral contraceptives which also may interfere with B12 absorption and should also have B12 levels checked. The amount of B12 to take should be individualized and discussed with your doctor or registered dietitian nutritionist.
Have you had your levels of Vitamin B12 checked? Share with us by leaving a comment below.
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