Are you at risk of a deficiency?

By Angela Grassi, MS, RDN, LDN 

 Medically reviewed by Elizabeth Barnes, RDN

People who take metformin to treat insulin resistance caused by type 2 diabetes or polycystic ovary syndrome (PCOS) may be at risk of developing a vitamin B12 deficiency, research has shown.12

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Low levels of vitamin B12 can cause serious and sometimes permanent neurological damage, as well as bone marrow production issues with subsequent anemia. This is why levels of this nutrient must be monitored in anyone taking metformin. This drug is available as a generic product as well as under the brand names Glucophage, Glucophage XR, Glumetza, Fortamet, and Riomet.

If you're on this drug, and particularly if you've been taking it for a while, it's important to be aware of the association between long-term use of metformin and vitamin B12 deficiency. This will allow you to have informed discussions about your treatment with your healthcare provider and empower you to play a vital role in your care.

May 28, 2020: The Food and Drug Administration (FDA) requested manufacturers of certain formulations of metformin voluntarily withdraw the product from the market after the agency identified unacceptable levels of N-Nitrosodimethylamine (NDMA). Patients should continue taking their metformin as prescribed until their healthcare provider can prescribe an alternative treatment, if applicable. Stopping metformin without a replacement can pose serious health risks to patients with type 2 diabetes.

The Importance of Vitamin B12

Vitamin B12 is a water-soluble vitamin that's essential for nerve conduction, mental functioning, DNA synthesis, and red blood cell formation. It's readily available in animal products, including fish, meat, poultry, eggs, and milk and other dairy foods. The recommended daily amount of vitamin B12 for most adults is 2.4 micrograms (mcg).3

A deficiency of vitamin B12 can affect mood and energy and even result in permanent and irreversible neuropathy (nerve damage). Symptoms of B12 deficiency include certain types of anemia, neuropathy, chronic fatigue, memory loss, confusion, mood changes, and eventually, even dementia.3

Metformin and Vitamin B12 Deficiency

A number of studies have found an association between long-term use of metformin and depleted vitamin B12 levels. Among the most significant of these, for example, was a secondary analysis from the Diabetes Prevention Program (DPP)/DDP Outcomes Study (DDPOS), one of the largest and lengthiest studies of metformin use ever conducted.1

Published in the April 2016 issue of the Journal of Clinical Endocrinology and Metabolism, it found that more than 1,000 subjects who took metformin for approximately 12 years had a 13% increased risk of vitamin B12 deficiency for each year of total metformin use.

Another study found that people with type 2 diabetes who took metformin at doses of more than 1,000 milligrams (mg) for four or more years were especially at risk of vitamin B12 deficiency.4

Preventing Vitamin B12 Deficiency

If you take metformin, a yearly check of your vitamin B12 status can alert your healthcare provider to any dips in your levels that may be early signs of a deficiency. One way to determine vitamin B12 status is with a test that directly measures levels of B12 in a blood sample. A more sensitive test looking at levels of a metabolite in the blood called methylmalonic acid (MMA) may be able to detect low B12 levels earlier.

Meanwhile, including plenty of foods rich in vitamin B12 in your diet, such as eggs, beef, salmon, chicken, and nutritional yeast; and/or taking supplemental B12 may help to prevent a deficiency (especially if you're vegetarian, vegan, or predominantly plant-based, as B12 is most commonly found in animal products).

The methylcobalamin form of vitamin B12 in a sublingual format (a liquid held under the tongue for 30 seconds) is best absorbed by the body, but you should consult your healthcare provider about the ideal supplement and correct dosage for you.

Sources

Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab. 2016;101(4):1754-1761. doi:10.1210/jc.2015-3754

Greibe E, Trolle B, Bor MV, et al. Metformin lowers serum cobalamin without changing other markers of cobalamin status: a study on women with polycystic ovary syndrome. Nutrients. 2013 Jul 5;5(7):2475-82. doi:10.3390/nu5072475

National Institutes of Health. Office of Dietary Supplements. Vitamin B12 fact sheet for health professionals.

Ko SH, Ko SH, Ahn YB, et al. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci. 2014;29(7):965-972. doi:10.3346/jkms.2014.29.7.965

Kim J, Ahn CW, Fang S, Lee HS, Park JS. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore). 2019;98(46):e17918. doi:10.1097/MD.0000000000017918

Additional Reading

Ho M, Halim JH, Gow ML, et al. Vitamin B12 in obese adolescents with clinical features of insulin resistance. Nutrients. 2014 Dec 4;6(12):5611-8. doi:10.3390/nu6125611

Ingole JR, Patel RD, Ingole SJ, Pandave HT. Opportunistic screening of vitamin B12 deficiency in it professionals presenting for routine health check-up. J Clin Diagn Res. 2015 Dec;9(12): OC01-OC02. doi:10.7860/JCDR/2015/16191.6866

Liu Q, Li S, Quan H, et al. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014 Jun 24;9(6):e100379. doi:10.1371/journal.pone.0100379

Niafar M, Hai F, Porhomayon J, et al. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015 Feb;10(1):93-102. doi:10.1007/s11739-014-1157-5

By Angela Grassi, MS, RDN, LDN
 Angela Grassi, MS, RDN, LDN, is the founder of the PCOS Nutrition Center.