Vitamin B12 Insufficiency Resulting from Long-Term Metformin Therapy

Metformin (Glucophage^®) is a biguanide antihyperglycemic agent that is widely used in the management of non-insulin dependent diabetes mellitus, metabolic syndrome and polycystic ovary syndrome. Metformin improves insulin sensitivity by increasing peripheral glucose uptake while reducing hepatic glucose output. Concurrent with the rise in metabolic disorders, the prevalence of metformin use has doubled since 2004, with over 92 million prescriptions written in 2020 and over 20 million Americans currently receiving this medication.¹

In 1969, Berchtold and colleagues reported vitamin B₁₂ (cobalamin) malabsorption in patients receiving metformin as early as 3 months after initiation of therapy.² In a pre-market clinical trial, vitamin B₁₂ levels fell significantly in up to 7% of patients over a 29-week evaluation period.³ Other studies and case reports found that 10-30% of patients exhibit signs of reduced cobalamin absorption, with clinically significant insufficiency evident in about 30% of individuals.^4,5

In the longest, largest prospective placebo-controlled randomized trial to date, standard metformin therapy reduced vitamin B₁₂ levels by 19% over 4.3 years. Serum homocysteine, a surrogate marker of folate, vitamin B₆ and vitamin B₁₂ status, rose by 5%. Metformin use was associated with an 11-fold increased risk for low serum cobalamin levels compared to placebo.⁶ The short duration of this trial likely underestimates risk, as metformin-associated B₁₂ malabsorption may not be detectable until 5-10 years after initiation of treatment.^7-9

The mechanisms underlying interference with vitamin B₁₂ absorption involve alterations in intestinal bacteria and/or direct interactions with the intrinsic factor-cobalamin complex, which mediates absorption of this nutrient in the small intestine.^4,8,10

Progression to fulminant deficiency, i.e. anemia, is rare, but the hematologic abnormalities and peripheral neuropathies of vitamin B₁₂ insufficiency are not uncommon in clinical investigations using standard metformin regimens.⁸ Signs and symptoms are reversible with metformin discontinuation or cobalamin supplementation.^3,4,7,8

Routine measurement of serum B₁₂ levels is advised every 2-3 years by the manufacturer, but more frequent (annual) monitoring is prudent in patients with low dietary intakes or other pre-existing risk factors, such as malabsorption syndromes.^3,7

Intramuscular cobalamin injections or discontinuation of the medication are seldom required to replete vitamin B₁₂. One study found that calcium supplementation decreases metformin-induced B₁₂ malabsorption, but does not reliably restore serum levels.^7,11 Oral supplementation with vitamin B₁₂ is a simple, effective and inexpensive method of restoring and maintaining normal vitamin B₁₂ status in individuals with suspected malabsorption resulting from prolonged use of metformin. ^3,4,7

Author: Kelly Heim, Ph.D.

Kelly Heim, Ph.D. is a pharmacologist specializing in integrative therapies and interactions. He serves as Senior Scientific Director, Pharmacology & Genomics for the health care professional brands of Atrium Innovations, and offers complimentary courses, lectures and learning resources on current topics in basic and clinical pharmacology at integrativepharmacology.com.  

References

1. Statista. Number of metformin prescriptions in the U.S. from 2004 to 2020.            https://www.statista.com/statistics/780332/metformin-hydrochloride-prescriptions-number-in-the-us/ Accessed Mar 25, 2023.
2. Berchtold P, Bolli P, Arbenz U, Keiser G. Disturbance of intestinal absorption following metformin therapy (observations on the mode of action of biguanides). Diabetologia. 1969;5:405–412
3. Glucophage. Package insert. Bristol-Myers Squibb Company, 2017.
4. Buvat DR. Use of Metformin Is a Cause of Vitamin B12 Deficiency. Am Fam Physician. 2004;69(2):264-266
5. 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 Apr;101(4):1754-61.
6. de Jager J, Kooy A, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181.
7. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67:979-86.
8. Andres E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency. Arch Intern Med. 2002;162:2251-2.
9. Stowers JM, Smith OA. Vitamin B12 and metformin. Br Med J. 1971;3:246-7.
10. Gilligan MA. Metformin and vitamin B12 deficiency. Arch Intern Med. 2002;162:484-5.
11. Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000 Sep;23(9):1227-31.