Metformin and vitamin B12: why do levels fall, and which symptoms should you watch for?

Yes, on average. Controlled trials have measured lower blood vitamin B12 levels on metformin than on placebo. The fall is usually moderate, but more people in the treated group drop below the deficiency threshold.

The most robust trial on the question, the Dutch HOME trial, followed 390 people with type 2 diabetes who were already on insulin. Half received 850 mg of metformin three times a day and the other half a placebo, for 4.3 years. Compared with placebo, metformin was associated with an average fall of 19% in vitamin B12 (95% confidence interval: 14 to 24%)¹. By the end of the study, the proportion of people with frank deficiency (below 150 pmol/l) was 7.2 points higher in the metformin group, and that of low levels (150 to 220 pmol/l) 11.2 points higher.

The authors express these differences as a "number needed to harm" of 13.8 over 4.3 years: on average, one additional deficiency appeared for roughly every 14 people treated¹. They also found higher homocysteine in people with deficiency (23.7 µmol/l on average, against 14.9 µmol/l when B12 was normal). This marker rises when cells are genuinely short of the vitamin, which indicates that the fall measured in the blood is not a mere laboratory artefact.

The best-described mechanism concerns absorption of the vitamin in the last section of the small intestine, the ileum. This step depends on calcium, and metformin appears to disrupt it.

In the digestive tract, vitamin B12 from food binds to a protein called intrinsic factor. The resulting complex is then taken up by receptors on the surface of ileal cells, and this uptake requires calcium to take place. In 2000, a New York team proposed that metformin interferes with this process by acting on cell membranes. It followed 14 patients switched from a sulphonylurea to metformin: their total B12 and their holotranscobalamin, the fraction of B12 actually available to tissues, fell in parallel. After three months, oral calcium corrected the fall in holotranscobalamin².

This study is small and has not been replicated on a large scale. It suggests a plausible mechanism without providing grounds for recommending calcium. It does, however, shed light on a useful point: vitamin B12 is indeed present on the plate, but part of it may be less well absorbed. If this mechanism is confirmed, a diet rich in animal products is not enough to prevent the fall.

The risk increases with the daily dose and with years of treatment, with no clear threshold. The American Diabetes Association (ADA) cites as reference points a dose of 1,500 mg a day or more and a duration of 4 to 5 years³.

A case-control study in Hong Kong of 155 patients with deficiency and 310 controls quantified the effect of dose: each additional daily gram of metformin was associated with a 2.88-fold higher risk of deficiency. From 3 years of treatment onwards, this risk was 2.39 times higher than with a shorter duration⁴. In the US DPPOS cohort, each year of metformin was associated with a 13% increase in the risk of deficiency (odds ratio 1.13)⁵.

Meta-analyses point the same way. The one by Chapman and colleagues, covering four trials, estimates the average fall at 57 pmol/l after 6 weeks to 3 months of treatment⁶. The one by Yang and colleagues, covering 31 studies, reports a 2.09-fold higher risk of deficiency in people taking metformin, with an effect that depends on dose and duration. However, it finds no significant association with anaemia or neuropathy⁷.

The DPPOS study shows that a fall in B12 appears from 5 years of treatment and persists at 13 years, even in people who did not yet have diabetes at the outset.

The Diabetes Prevention Program (DPP) randomised more than 2,000 overweight adults with prediabetes to metformin (850 mg twice a day) or placebo for 3.2 years. The metformin group then continued treatment open-label for 9 years⁵. At 5 years, a low level (203 pg/ml or less) affected 4.3% of the metformin group against 2.3% of the placebo group. At 13 years, the difference (7.4% against 5.4%) was no longer statistically significant.

When borderline levels (298 pg/ml or less) were included, the difference remained clear: 19.1% against 9.5% at 5 years, then 20.3% against 15.6% at 13 years⁵. Anaemia was more common on metformin, with no link to B12 status. Peripheral neuropathy, on the other hand, was more common in people on metformin whose B12 was low.

Vitamin B12 deficiency shows up mainly as anaemia, tiredness and nerve problems: tingling, numbness or loss of sensation in the feet and hands. These signs resemble those of diabetes, which often delays diagnosis.

Vitamin B12 is involved in making red blood cells and in maintaining the sheath that protects the nerves. When it is lacking, a person may develop⁸ :

• so-called megaloblastic anaemia, with red blood cells that are too large and too few;
• tiredness, breathlessness on exertion, pallor;
• tingling, numbness or loss of sensation, starting in the feet;
• problems with balance, memory or mood in more advanced forms.

The difficulty lies in the overlap with the complications of diabetes. Diabetic neuropathy also affects the feet first, and tiredness often accompanies imperfect blood sugar control. A further analysis of the HOME trial showed that metformin progressively raised methylmalonic acid, a marker of tissue B12 deficiency, and that this rise was accompanied by a worsening neuropathy score⁹. In the same trial, the beneficial effect of metformin on blood sugar offset this unfavourable effect, so that the net balance on neuropathy was not significant.

Authorities recommend testing as soon as deficiency is suspected, and periodic monitoring in people at risk. The exact frequency varies from country to country.

In 2022, following a European assessment, lower vitamin B12 levels were classified as a common side effect of metformin, likely to affect up to one person in ten. The UK medicines regulator (MHRA) cites as risk factors a high dose, long duration, a low baseline level, digestive disease or stomach surgery, a vegan diet, older age and the use of proton pump inhibitors or colchicine¹⁰. The product information for medicines containing metformin now states that if deficiency is suspected, for example in the presence of anaemia or neuropathy, B12 levels should be checked, and that periodic monitoring may be needed in people at risk¹¹.

The ADA goes a little further. Its recommendation 3.10 suggests considering periodic testing in anyone on long-term metformin, particularly in the presence of anaemia or neuropathy, and its text advises annual testing after more than 4 years of treatment³. Blood testing and, where appropriate, adding vitamin B12 are decided with your doctor or pharmacist. Metformin itself should not be stopped or changed without medical advice: the product information states that it should be continued as long as it is tolerated, with the deficiency corrected if necessary¹¹.

Yes, vitamin B12 and metformin can be taken together, and correcting a confirmed deficiency is precisely a matter of providing B12. The metformin product information describes no interaction between the two and provides for treatment to continue while a deficiency is corrected¹¹.

In adults with deficiency, a review by the American Academy of Family Physicians states that high-dose oral B12, 1 to 2 mg a day, corrects anaemia and neurological symptoms as well as injections do. Injections act faster and remain preferred in severe deficiency⁸.

However, no trial has yet shown that routinely giving B12 to everyone on metformin prevents neuropathy. Vitamin B12 contributes to the normal functioning of the nervous system and to normal energy-yielding metabolism, but this general effect says nothing in advance about what a supplement brings to a given person. Testing remains the best way to know where you stand.