How does metformin (biguanide oral hypoglycemic agent) cause vitamin B12 deficiency?

From the Guidelines

Metformin causes vitamin B12 deficiency through its long-term use, which interferes with B12 absorption in the digestive tract, and patients taking metformin, especially at doses above 1000 mg daily or for extended periods, should have their B12 levels monitored regularly, typically annually. The primary mechanism involves metformin altering calcium-dependent membrane action in the ileum, which disrupts the absorption of the vitamin B12-intrinsic factor complex 1. Additionally, metformin may change intestinal motility, bacterial flora, and increase bacterial consumption of B12. The risk of B12 deficiency increases with higher metformin doses and longer duration of treatment, typically becoming clinically significant after 5-10 years of use.

Some key points to consider:

• Metformin may be used safely in individuals with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², but monitoring for vitamin B12 deficiency should be considered for those taking metformin long term 1.
• The lowering effect of metformin on vitamin B12 increases with time, with a significantly higher risk for vitamin B12 deficiency noted at 4.3 years in the HOME study and significantly greater risk of low B12 levels at 5 years in the DPP 1.
• Supplementation with vitamin B12 (1000 mcg daily orally or 1000 mcg monthly by injection) can effectively prevent or treat this deficiency.
• Early detection is important as B12 deficiency can cause neurological damage, anemia, and other health problems if left untreated.

It is essential to monitor B12 levels in patients taking metformin, especially those with anemia or peripheral neuropathy, as recommended by the American Diabetes Association standards of medical care in diabetes 1. Regular monitoring and supplementation can help prevent or treat vitamin B12 deficiency, reducing the risk of associated health problems.

From the FDA Drug Label

In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients Such decrease, possibly due to interference with B 12 absorption from the B 12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B 12 supplementation Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels.

Metformin may cause B12 deficiency by interfering with B12 absorption from the B12-intrinsic factor complex. This decrease in B12 levels may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation 2. Key points:

• Metformin may interfere with B12 absorption
• Decrease in B12 levels may be associated with anemia
• Reversible with discontinuation of metformin or vitamin B12 supplementation Predisposed individuals:
• Those with inadequate vitamin B12 or calcium intake or absorption 2

From the Research

Mechanism of Metformin-Induced B12 Deficiency

• Metformin blocks the absorption of vitamin B12, although the exact mechanism is not established 3
• It is suggested that metformin interferes with the calcium-dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum 3

Risk Factors for Metformin-Induced B12 Deficiency

• Higher doses of metformin increase the risk of vitamin B12 deficiency 4
• Longer durations of metformin treatment increase the risk of vitamin B12 deficiency 4
• Patient age and ethnicity may also be risk factors for metformin-induced B12 deficiency 4
• Years of metformin use are associated with increased risk of B12 deficiency, with an odds ratio of 1.13 per year of metformin use 5

Clinical Consequences of Metformin-Induced B12 Deficiency

• Vitamin B12 deficiency can lead to hematologic abnormalities, such as megaloblastic anemia and formation of hypersegmented neutrophils 6
• Vitamin B12 deficiency can also cause progressive axonal demyelination and peripheral neuropathy 6
• Metformin-induced vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic, and cardiac neuropathy in patients with diabetes 3

Screening and Management of Metformin-Induced B12 Deficiency

• Routine testing of vitamin B12 levels in metformin-treated patients should be considered, particularly if metformin has been used for over 5 years 5, 3
• Periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin 3
• Therapies for metformin-induced B12 deficiency include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, and replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy 3