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

From the Guidelines

Metformin causes vitamin B12 deficiency through its interference with B12 absorption in the digestive system, and long-term use increases the risk of deficiency, particularly in patients taking larger doses or with risk factors such as advanced age. The primary mechanism involves metformin altering calcium-dependent membrane function in the ileum, which disrupts the absorption of the vitamin B12-intrinsic factor complex, as suggested by recent guidelines 1. Additionally, metformin may decrease intrinsic factor secretion and change intestinal motility or bacterial flora, further compromising B12 absorption. This effect is dose-dependent and increases with longer duration of metformin use, typically becoming clinically significant after 5-10 years of treatment, with a significantly higher risk for vitamin B12 deficiency noted at 4.3 years in the HOME study and at 5 years in the DPP 1.

The risk of B12 deficiency is higher in patients taking larger doses (greater than 1,000 mg daily) and in elderly patients. B12 deficiency can lead to megaloblastic anemia, peripheral neuropathy, and cognitive impairment. For patients on long-term metformin therapy, regular monitoring of vitamin B12 levels is recommended, particularly in those with risk factors such as advanced age, vegetarian diet, or gastrointestinal disorders 1. Supplementation with oral or injectable B12 can effectively prevent or treat deficiency while continuing metformin therapy for diabetes management. It has been suggested that a person who has been on metformin for more than 4 years or is at risk for vitamin B12 deficiency should be monitored for vitamin B12 deficiency annually 1.

Key points to consider:

• Metformin interferes with B12 absorption, increasing the risk of deficiency with long-term use
• Risk factors for B12 deficiency include advanced age, larger doses, and gastrointestinal disorders
• Regular monitoring of vitamin B12 levels is recommended for patients on long-term metformin therapy
• Supplementation with oral or injectable B12 can prevent or treat deficiency while continuing metformin therapy.

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

• Metformin may interfere with vitamin B12 absorption
• Approximately 7% of patients in clinical trials developed subnormal vitamin B12 levels
• Certain individuals with inadequate vitamin B12 or calcium intake or absorption are predisposed to developing subnormal vitamin B12 levels
• Vitamin B12 deficiency may be associated with anemia
• Discontinuation of metformin or vitamin B12 supplementation can reverse the decrease in vitamin B12 levels 2 2.

From the Research

Mechanism of Metformin-Induced Vitamin B12 Deficiency

• Metformin interferes with the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to the cubam receptor in the terminal ileum, leading to impaired vitamin B12 absorption 3.
• The exact mechanism of metformin-induced vitamin B12 deficiency is not fully established, but it is thought to be related to the absorption process 3.

Risk Factors for Vitamin B12 Deficiency in Metformin-Treated Patients

• Higher doses and longer durations of metformin treatment increase the risk of vitamin B12 deficiency 4, 3.
• Male patients are more likely to develop vitamin B12 deficiency than female patients 3.
• Black race has a lower prevalence of vitamin B12 deficiency in metformin-treated patients 3.
• Chronic diseases such as type 2 diabetes, hyperlipidemia, coronary artery disease, polycystic ovary disease, and obesity are associated with an increased risk of vitamin B12 deficiency 3.

Clinical Consequences of Vitamin B12 Deficiency

• Vitamin B12 deficiency can lead to hematologic abnormalities, such as megaloblastic anemia and formation of hypersegmented neutrophils 5.
• Vitamin B12 deficiency can cause or worsen distal symmetrical, autonomic, and cardiac neuropathy in patients with diabetes 6.
• Vitamin B12 deficiency can lead to progressive axonal demyelination and peripheral neuropathy 5.

Screening and Prevention of Vitamin B12 Deficiency

• Routine monitoring of vitamin B12 levels is recommended in all patients who use metformin, particularly if metformin has been used for over 5 years 6.
• Factors that accelerate the loss of hepatic vitamin B12 stores, such as proton pump inhibitors, bariatric surgery, being elderly, and having an increased turnover of red blood cells, should be considered when monitoring vitamin B12 levels 6.
• Therapies for vitamin B12 deficiency include prophylactic calcium and vitamin B12 supplements, metformin withdrawal, replenishing vitamin B12 stores with intramuscular or oral vitamin B12 therapy, and regular monitoring of vitamin B12 levels and vitamin B12 supplements if metformin continues to be used 6.