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Correlation Between Metformin Therapy and Lack of Vitamin B12 In Patients With T2D

Sep 18, 2021
Editor: Steve Freed, R.PH., CDE

Author: Emmanuella Louissaint, PharmD candidate, LECOM College of Pharmacy

Metformin can bring on vitamin B12 deficiency by lowering vitamin B12 absorption in the gastrointestinal tract.

It’s been reported that 6-30 % of individuals on metformin therapy were deficient in vitamin b12, and that vitamin B12 levels were inversely associated with the duration and dose of metformin therapy. The American Diabetes Association advises monitoring vitamin B12 levels regularly in patients with diabetes on metformin. Homocysteine is an essential constituent in the one-carbon pathway of methionine metabolism, which plays a vital role in DNA methylation and many intracellular vitamin B12 reactions. Therefore, an elevation in homocysteine is often due to vitamin B12 deficiency; multiple studies have placed focus on homocysteine elevation in individuals taking metformin. It is medically advisable that verify that B12 deficiency does not occur under metformin therapy.


Less meat is consumed in Asian countries, suggesting an increased risk of vitamin B12 deficiency. However, not many studies have considered the effect of duration and dose of metformin use in the Asian population. Therefore, this study explored the prevalence of vitamin B12 deficiency in Korean patients with type 2 diabetes on long-term metformin therapy. Furthermore, the study examined whether metformin-induced B12 deficiency in the serum could reveal tissue deficiency by evaluating serum homocysteine levels.

The study protocol abided by the ethical guidelines of the Declaration of Helsinki and received support from the institutional review board at Yongin Severance Hospital. All participants of the study provided written consent. The cross-sectional research considered individuals with type 2 diabetes on metformin therapy for at least six months. Individuals with a medical history of gastrectomy, colectomy, inflammatory bowel disease, or pernicious anemia were not allowed to participate in the study. Individuals who experience acute illnesses such as severe infection, cancer or acute coronary syndrome, significant organ damage within the past 90 days were not allowed to participate in the study. Vegetarian patients, pregnant women, and patients with hematological conditions aside from anemia were also not a part of the study. One thousand one hundred eleven patients 20-85 years of age participated in the study, 645 male patients.

All study participants completed a basic blood exam and questionnaires on neuropathy supplements, drug histories, smoking habits, and alcohol use. Medical researchers carefully examined patients’ medical records. Blood and urine samples were collected in a fasted state to evaluate serum vitamin B12, serum folic acid, serum homocysteine, glucose, insulin, HBA1C, hemoglobin, MCV, AST, ALT, creatine, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and urine albumin creatine ratio. The daily dose of metformin was determined as the average dose taken over the last six months. Competitive binding of immunoenzymatic assays utilizing a Unicel DxI analyzer specified levels of vitamin B12. For the study, a serum B12 level less than 300pg/ml is vitamin B12 deficient.

Less than 1/3 of patients were deficient in vitamin B12, with an average vitamin B12 level of 231.2 ± 44.8 pg/ml. Only one patient had a B12 level less than 100 pg/ml in the participant pool, and sixty patients had B12 levels less than 200pg/ml. Serum homocysteine was much more significant in the B12 deficient group. Serum vitamin B12 levels negatively correlated with metformin dose; however, they were not significantly related to metformin use. As the metformin dose increased, serum vitamin B12 levels lowered considerably. Lastly, serum vitamin B12 levels demonstrated a negative relation with homocysteine levels even after adjustments to multiple confounders such as age, sex, duration of diabetes, alcohol consumption, smoking, anemia, GFR, and multivitamin supplementation. Metformin at ≥ 1500mg/d could be a major cause of vitamin B12 deficiency. Simultaneous supplementation of multivitamins may protect against vitamin B12 deficiency. Serum homocysteine is negatively associated with levels of vitamin B12. Thus, deficiency correlated with metformin use may occur at the tissue level.

Practice Pearls:

  • Long-term use of metformin can lead to vitamin B12 deficiency.
  • Further research is needed to understand the mechanism through which metformin reduces vitamin B12 levels; however, the most likely hypothesis remains that metformin interferes with the calcium-dependent membrane action in charge of vitamin B12 intrinsic factor absorption, which happens in the terminal ileum.
  • Patients on metformin therapy should check their B12 level regularly, potentially annually, to ensure that it is within normal range.


Kim, J., Ahn, C. W., Fang, S., Lee, H. S., & Park, J. S. (2019, November). Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Journal of Medicine.


Emmanuella Louissaint, PharmD candidate, LECOM College of Pharmacy