Why does metformin (biguanide oral hypoglycemic agent) lead to vitamin B12 deficiency?

From the Guidelines

Metformin leads to vitamin B12 deficiency primarily through interference with vitamin B12 absorption in the gastrointestinal tract, and patients on long-term metformin therapy should have their vitamin B12 levels monitored periodically, especially those with anemia, peripheral neuropathy, or cognitive changes, as recommended by the 2023 standards of care in diabetes 1. This occurs through several mechanisms, including:

• Altering calcium-dependent membrane function in the ileum, where B12 absorption takes place, reducing the availability of calcium necessary for B12 absorption.
• Causing changes in intestinal motility and bacterial flora, further compromising B12 absorption.
• Possibly directly inhibiting the intrinsic factor-B12 complex, essential for B12 absorption. 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 1. Some key points to consider include:
• The Diabetes Prevention Program Outcomes Study found that long-term users of metformin may develop vitamin B12 deficiency, and periodic testing of vitamin B12 levels should be considered in metformin users, especially those with anemia or peripheral neuropathy 1.
• Elderly patients are particularly vulnerable to this side effect due to their already reduced B12 absorption capacity.
• Supplementation with oral vitamin B12 (1000-2000 mcg daily) or monthly injections may be necessary for patients with documented deficiency or those at high risk 1. It is essential to monitor vitamin B12 levels in patients taking metformin, especially in those with anemia or peripheral neuropathy, to prevent irreversible neurological damage and other complications associated with vitamin B12 deficiency 1.

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

Metformin may lead to vitamin B12 deficiency due to interference with B12 absorption from the B12-intrinsic factor complex. This decrease in vitamin B12 levels may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation 2.

• Key points:
  • Decrease in vitamin B12 levels observed in approximately 7% of patients
  • Interference with B12 absorption from the B12-intrinsic factor complex is the possible cause
  • Associated with anemia
  • Rapidly reversible with discontinuation of metformin or vitamin B12 supplementation

From the Research

Mechanism of Metformin-Induced Vitamin B12 Deficiency

• Metformin blocks the absorption of vitamin B12 through a mechanism that has not been established, but could be due to interference with the calcium-dependent binding of the intrinsic factor vitamin B12 complex to the cubam receptor in the terminal ileum 3.
• The subsequent deficiency of vitamin B12 may cause or accelerate distal symmetrical and autonomic neuropathy in patients with diabetes.

Association between Metformin Use and Vitamin B12 Deficiency

• Several observational studies and meta-analyses have reported a significant association between metformin utilization and vitamin B12 deficiency 4, 5, 6.
• Prospective studies have shown that not only do metformin utilizers have lower vitamin B12 levels, but they also have higher frequencies of distal symmetrical polyneuropathy and autonomic neuropathy 3.
• Metformin use was also associated with significantly greater percentage decrease in serum vitamin B12 concentrations from baseline in diabetic patients 6.

Risk Factors for Vitamin B12 Deficiency in Metformin Users

• High-dose metformin therapy (≥2000 mg/day) is a major factor related to vitamin B12 deficiency 5, 7.
• Long-term metformin therapy (≥5 years) can deplete hepatic stores of vitamin B12 3.
• Other factors that accelerate the loss of hepatic vitamin B12 stores include proton pump inhibitors, bariatric surgery, being elderly, and having an increased turnover of red blood cells 3.

Monitoring and Prevention of Vitamin B12 Deficiency

• Periodic monitoring of vitamin B12 is recommended in all patients who utilize metformin, particularly if metformin has been used for over 5 years 3.
• Annual vitamin B12 assessment in diabetic patients taking metformin is recommended 6.
• Concurrent supplementation of multivitamins may potentially protect against vitamin B12 deficiency 5.