Identification of a genetic risk factor for metformin-induced vitamin B12 deficiency
Authors' conclusion
The observed genetic association suggests that the rs180122 genotype should be considered a significant risk factor for metformin-induced vitamin B12 deficiency. While clinical monitoring of serum vitamin B12 levels in patients on metformin is inconsistently done, this finding highlights the potential clinical utility of targeted monitoring for certain subsets of individuals, including those genetically at high risk.
Study context
- Population
- Metformin users in UK Biobank; replication in a Scottish cohort, Diabetes Prevention Program Outcomes Study (DPPOS) and a Liverpool cohort
- Participants
- 487 vs 6,686
- Comparison
- rs1801222 genotypes: AG and AA vs GG
- Metformin-induced vitamin B12 deficiencyn = 487
- Metformin-tolerant control individualsn = 6,686reference
- Outcome
- Genetic association with metformin-induced vitamin B12 deficiency
Methodological detailscase-control, logistic regression, replication in three cohorts
- Case-control
- Logistic regression
- Replication in three cohorts
Main finding
As reported in the abstract
Metformin-induced vitamin B12 deficiency, CUBN rs1801222/p.S253F
Odds ratio (95% CI)P value
AGvs GG
1.56(1.36–1.79)
adjusted p=1.86×10-10AAvs GG
2.43(1.85–3.20)
adjusted p=1.86×10-10Observational data: associations, not effects.
Further findings
| Outcome | Values |
|---|---|
| Vitamin B12 deficiency with metformin use by genotype | GG 6.02% · GA 7.96% · AA 12.84% |
| Time from metformin initiation to 10% vitamin B12 deficient | AA 11 years · GG 21 years |
Vitamin B12 deficiency in non-metformin-exposed individuals
- Regardless of rs1801222 genotype
- 0.84-1.20%
Vitamin B12 deficiency with metformin use by genotype
- Large interaction with metformin use
Original publication
Identification of a genetic risk factor for metformin-induced vitamin B12 deficiency. Diabetologia. Published 15 January 2026. doi:10.
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