Metformin and reduced vitamin B12 levels: new advice for monitoring patients at risk

Decreased vitamin B12 levels, or vitamin B12 deficiency, is now considered to be a common side effect in patients on metformin treatment, especially in those receiving a higher dose or longer treatment duration and in those with existing risk factors. We are therefore advising checking vitamin B12 serum levels in patients being treated with metformin who have symptoms suggestive of vitamin B12 deficiency. We also advise that periodic monitoring for patients with risk factors for vitamin B12 deficiency should be considered.

From:
Medicines and Healthcare products Regulatory Agency
Published
20 June 2022
Therapeutic area:
Dispensing GP practices, Endocrinology, diabetology and metabolism

Advice for healthcare professionals:

  • metformin can commonly reduce vitamin B12 levels in patients, which may lead to vitamin B12 deficiency
  • the risk of low vitamin B12 levels increases with higher metformin dose, longer treatment duration, and in patients with risk factors for vitamin B12 deficiency
  • test vitamin B12 serum levels if deficiency is suspected (for example, in patients presenting with megaloblastic anaemia or new-onset neuropathy) and follow current clinical guidelines on investigation and management of vitamin B12 deficiency (for example, see Clinical Knowledge Summary from NICE)
  • consider periodic vitamin B12 monitoring in patients with risk factors for vitamin B12 deficiency (see list of risk factors in article)
  • administer corrective treatment for vitamin B12 deficiency in line with current clinical guidelines; continue metformin therapy for as long as it is tolerated and not contraindicated
  • report suspected adverse drug reactions associated with metformin on a Yellow Card

Advice for healthcare professionals to give to patients and carers:

  • if you are taking metformin, seek medical advice if you develop new or worsening symptoms of extreme tiredness, a sore and red tongue, pins and needles, or pale or yellow skin – these can be signs of low vitamin B12 levels
  • you may need blood tests to find out the cause of your symptoms; these symptoms can also be caused by diabetes or other unrelated health issues
  • you can keep taking metformin while vitamin B12 levels are being corrected
  • do not stop your treatment without first discussing this with your doctor

About metformin and vitamin B12 deficiency

Metformin is a medicine authorised to treat type 2 diabetes mellitus and to help prevent type 2 diabetes in patients at high risk of developing it. Metformin is available as immediate and modified-release tablets, as well as an oral solution.

Vitamin B12 (cobalamin) is a nutrient that helps to keep the body’s nerve and blood cells healthy. It is found in foods of animal origin including milk, cheese, yoghurt, and eggs. It is also added to some fortified foods such as breakfast cereals. Common causes of vitamin B12 deficiency include infections, malabsorption, medical conditions (Crohn’s disease, pernicious anaemia), gastric resection, and inadequate dietary intake.

Patients with a vitamin B12 deficiency can be asymptomatic or they can present with symptoms of megaloblastic anaemia or neuropathy or both. Other symptoms of low vitamin B12 levels may include mental disturbance (depression, irritability, cognitive impairment), glossitis (swollen and inflamed tongue), mouth ulcers, and visual and motor disturbances. It is important for patients with anaemia or neuropathy caused by vitamin B12 deficiency to be diagnosed and treated as soon as possible to avoid the development of permanent symptoms.

Decreased vitamin B12 levels are a known consequence of long-term treatment with metformin. The mechanism is currently thought to be multifactorial, comprising altered intestinal motility, bacterial overgrowth, and reduced uptake of vitamin B12 within the small intestine (or a combination of these factors).

Product information update

The known adverse drug reaction of vitamin B12 deficiency was recently reviewed for the brand leader Glucophage (metformin) within Europe with input from the MHRA. After this review, we have agreed that the product information for medicines containing metformin should be updated.

The current literature suggest that the frequency of this adverse drug reaction is higher than previously thought.[footnote 1] The Glucophage product information for healthcare professionals and patients has now been updated to state that vitamin B12 deficiency is a common adverse drug reaction, and may affect up to 1 in 10 people who take it.

The product information has also been updated to note that the risk of this adverse reaction occurring increases with increasing metformin dose and treatment duration and in patients with risk factors known to cause vitamin B12 deficiency.[footnote 1] [footnote 2] [footnote 3] [footnote 4]

The updated product information also includes new advice to healthcare professionals to test vitamin B12 levels in those presenting with anaemia or neuropathy and that periodic vitamin B12 monitoring should be considered in patients with risk factors for vitamin B12 deficiency. The product information for other medicines containing metformin will also be updated including fixed-dose combination products containing metformin.

Risk factors for vitamin B12 deficiency

Risk factors for vitamin B12 deficiency are wide ranging. They include:

  • baseline vitamin B12 levels at the lower end of the normal range
  • conditions associated with reduced vitamin B12 absorption (such as elderly people and those with gastrointestinal disorders such as total or partial gastrectomy, Crohn’s disease and other bowel inflammatory disorders, or autoimmune conditions)
  • diets with reduced sources of vitamin B12 (such as strict vegan and some vegetarian diets)
  • concomitant medication known to impair vitamin B12 absorption (including proton pump inhibitors or colchicine)
  • genetic predisposition to vitamin B12 deficiency, such as intrinsic factor receptor deficiency (Imerslund-Gräsbeck syndrome) and transcobalamin II deficiency

Report suspected drug reactions on a Yellow Card

Please continue to report suspected adverse drug reactions to the Yellow Card scheme.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset timing, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines, medical device and test kit incidents used in coronavirus (COVID-19) testing and treatment using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

If you have been forwarded this article, subscribe directly to Drug Safety Update via our website.

Article citation: Drug Safety Update volume 15, issue 11: June 2022: 1.

  1. Aroda VR and others. Long-term metformin use and vitamin b12 deficiency in the diabetes prevention program outcomes study. Journal of Clinical Endocrinology and Metabolism 2016; volume 101: pages 1754 to 61 (viewed on 24 April 2022). ↩ ↩2

  2. Beulens JW and others. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetologica 2015; volume 52: pages 47 to 53 (viewed on 24 April 2022). ↩

  3. de Jager J and others. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. British Medical Journal 2010; volume 340: c2181 (viewed on 24 April 2022). ↩

  4. Miller JW. Proton Pump Inhibitors, H2-Receptor Antagonists, Metformin, and Vitamin B-12 Deficiency: Clinical Implications. Advances in Nutrition 2018; volume 9: pages 511S to 518S (viewed on 24 April 2022). ↩

Published 20 June 2022
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