As per the New Advisory, vitamin B12 insufficiency is now considered a typical adverse effect in metformin-treated individuals. This article discusses the co-relation between metformin and vitamin B12 deficiency and guides physicians with some valuable advice on how to manage such patients.

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The drug metformin is approved for the treatment of type 2 diabetes mellitus and PCOS. In addition to immediate-release and extended-release tablets, metformin is now available as an oral solution.

Sources of Vitamin B12

Vitamin B12 (cobalamin) is an essential component for maintaining healthy neurons and blood cells. It is present in animal-based foods such as milk, cheese, yoghurt, and eggs. Additionally, it is added to some fortified meals, such as morning cereals.

Causes of Vitamin B12 deficiency

Infections, malabsorption, medical diseases (Crohn's disease, pernicious anaemia), gastric resection, and low food intake are common causes of vitamin B12 insufficiency.

Symptoms:

Patients with a vitamin B12 deficiency may exhibit no symptoms, megaloblastic anaemia symptoms, neuropathy symptoms, or both. Low vitamin B12 levels may also cause mental disorders (depression, irritability, cognitive impairment), glossitis (swelling and inflammation of the tongue), mouth ulcers, and visual and motor difficulties.

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Metformin and vitamin B12 deficiency

Several studies have demonstrated a link between long-term metformin usage and vitamin B12 deficiency. Among the most important was a secondary analysis from the Diabetes Prevention Program (DPP)/DDP Outcomes Study (DDPOS), one of the biggest and longest studies ever undertaken on metformin usage.

The study, which was published in the April 2016 edition of the Journal of Clinical Endocrinology and Metabolism, indicated that for each year of total metformin usage, the risk of vitamin B12 insufficiency rose by 13 per cent in more than 1,000 participants who had taken metformin for about 12 years.

Another research revealed that persons with type 2 diabetes who used metformin at dosages of more than one thousand milligrams (mg) for at least four years were at increased risk for vitamin B12 insufficiency. Each 100 mg step in metformin dose increased by 8% the odds of having vitamin B12 deficiency.

Currently, it is believed that the cause is multifaceted, including altered intestinal motility, bacterial overgrowth, and decreased vitamin B12 absorption in the small intestine (or a combination of these factors).

Can the B12 absorption be harmed by metformin?

Metformin may cause vitamin B12 deficiency through one or more of the following mechanisms:

1. Interference with the calcium-dependent binding of the intrinsic factor (IF)-vitamin B12 complex to the cubilin receptor on enterocytes at the ileum level and/or interaction with the cubilin endocytic receptor; leads to decreased vitamin B12 absorption in the ileum, which could be due to the effects of metformin on calcium-dependent membrane action.
2. Alteration in bile acid metabolism and reabsorption, resulting in the impaired enterohepatic circulation of vitamin B1 and Reduced IF secretion by gastric parietal cells.
3. Increased liver accumulation of vitamin B12, resulting in altered tissue distribution and metabolism of vitamin B12; and
4. Alteration in small intestine motility results in small intestinal bacterial overgrowth and subsequent inhibition of IF-vitamin B12 complex absorption in the distal ileum.

At what dosage of metformin is vitamin B12 insufficiency possible?

A daily dose of 1,500 mg or higher of metformin is related to an increased risk of vitamin B12 insufficiency, according to 2019 research.

What vitamin B12 dietary supplement is the best?

Look for methylcobalamin-labelled supplements of vitamin B12. Methylcobalamin is better absorbed by the body than other forms of vitamin B12. In addition, sublingual (under-the-tongue) formulations are more absorbed than pills or even injections.

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Factors predisposing to vitamin B12 deficiency

There are several risk factors for vitamin B12 insufficiency.

1. Basal vitamin B12 concentrations in the lower end of the normal range
2. Diseases linked with decreased vitamin B12 absorption (such as ageing and gastrointestinal problems such as whole or partial gastrectomy, Crohn's disease, and other bowel inflammatory disorders, or autoimmune disorders)
3. Diets with diminished vitamin B12 sources (such as strict vegan and some vegetarian diets)
4. Co-administered drugs known to limit vitamin B12 absorption (including proton pump inhibitors or colchicine)

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How to prevent low blood vitamin B12 levels?

1. An annual assessment of your vitamin B12 status while taking metformin might alert the doctor to any drops in your levels that could be early indicators of a deficit. One method for determining vitamin B12 status is a blood test that detects B12 levels directly. A more sensitive test that measures methylmalonic acid (MMA) levels in the blood may be able to identify low B12 levels early.
2. Including lots of vitamin B12-rich foods in your diet, such as eggs, beef, salmon, chicken, and nutritional yeast; and/or taking B12 supplements may avoid a deficit (particularly if you're vegetarian, vegan, or mostly plant-based since B12 is most typically found in animal products).
3. The body absorbs methylcobalamin vitamin B12 sublingually (a drink kept under the mouth for 30 seconds) most efficiently.

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Disclaimer- The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

About the author of this article: Dr Monish Raut is a practising super specialist from New Delhi.