Vitamin B12 deficiency in those taking metformin has been known about since at least 1969; however, it has recently been identified to be more common than previously thought, prompting reviews of the existing literature and exploration of the most appropriate management options.
In this systematic review, Pratama and colleagues highlight the paucity of studies specifically in those with metformin-induced B12 deficiency and the lack of guidance on best approaches to supplementation for treatment or prevention. The article provides a helpful review of key papers exploring the mechanisms and timeframes of metformin-induced B12 deficiency, which can help us in the implementation of the MHRA guidance issued in June 2022.
Metformin may decrease intrinsic factor secretion from parietal cells, interfere with the calcium-dependent binding of the resulting intrinsic factor and B12 complex to receptors on the ileal lining, and change small intestinal motility, resulting in decreased B12 absorption. Metformin may also increase liver accumulation of B12, meaning it is less available, and it may alter reabsorption of bile acids, disrupting the enterohepatic circulation of B12. As well as causing B12 deficiency, an increase in methylmalonic acid occurs, which is thought to result in loss of myelin in the peripheral nerves and, consequently, neuropathy, which may be symptomatic as early as 2 years into metformin treatment.
There is around a 2.5-fold increase in B12 deficiency incidence in those treated with metformin, and this may occur as early as 3 months, although hepatic stores of vitamin B12 may take 5 years or more to deplete (Bell, 2022). In a previous randomised, placebo-controlled trial, de Jager et al (2010) added metformin 850 mg three times daily to insulin therapy (a higher metformin dose than is usually now used) and demonstrated a number needed to harm of just under 14 for development of B12 deficiency over the 4.3 years of the trial. Other studies have also confirmed that B12 deficiency increases with long-term use and is dose-dependent.
The authors express concern that there is not yet clear guidance on supplementation route and methods, and they discuss studies exploring this. A 1 mg intramuscular injection of hydroxocobalamin every 3 months is the commonest option in both studies and practice, and is recommended by NICE (2022a) in its guidance on management of B12 deficiency. Methylcobalamin is an active form of B12 which can be taken orally or sublingually, is retained longer in the body and has been studied for treatment of peripheral neuropathy. If oral therapy is trialled, check B12 levels at 8–12 weeks. Studies in this systematic review support B12 supplementation for the treatment or prevention of metformin-induced deficiency and neuropathy, demonstrating increased levels of B12 and decreased serum homocysteine with supplementation.
Metformin remains the first-line treatment option for most people with type 2 diabetes, including in the recently published ADA/EASD Consensus Report (Davies et al, 2022) and in the NICE (2022b) NG28 advice on type 2 diabetes management.
The MHRA (2022) recently issued guidance on the increased risk of vitamin B12 deficiency in people treated with metformin, highlighting increased risks with higher metformin doses, longer treatment duration and in patients with risk factors for B12 deficiency, including the following:
- Existing low B12 levels.
- People at risk of decreased absorption (elderly, inflammatory bowel disease, gastric resection or autoimmune conditions).
- Strict vegan and some vegetarian diets.
- Medications known to decrease B12 absorption (proton pump inhibitors, colchicine).
Clinicians are encouraged to test B12 levels in those presenting with anaemia or neuropathy, and to consider testing periodically in those with risk factors for deficiency. Those with low B12 may be asymptomatic, have symptoms of anaemia or neuropathy, or have glossitis, mouth ulcers, mental disturbances (depression, irritability, cognitive impairment). It is recommended that metformin treatment should continue while the B12 deficiency is corrected, in view of the drug’s known benefits in type 2 diabetes and its central role in treatment guidelines.