Risk Factors of Vitamin B12 Deficiency in Patients Receiving Metformin

Background  Identification of risk factors for metformin-related vitamin B12 deficiency has major potential implications regarding the management of diabetes mellitus.

Methods  We conducted a nested case-control study from a database in which the source population consisted of subjects who had levels of both serum vitamin B12 and hemoglobin A1c checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B12 deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B12 deficiency while taking metformin.

Results  A total of 155 patients with metformin-related vitamin B12 deficiency (mean ± SD serum vitamin B12 concentration, 148.6 ± 40.4 pg/mL [110 ± 30 pmol/L]) were compared with 310 matched controls (466.1 ± 330.4 pg/mL [344 ± 244 pmol/L]). After adjusting for confounders, we found clinically important and statistically significant association of vitamin B12 deficiency with dose and duration of metformin use. Each 1-g/d metformin dose increment conferred an odds ratio of 2.88 (95% confidence interval, 2.15-3.87) for developing vitamin B12 deficiency (P<.001). Among those using metformin for 3 years or more, the adjusted odds ratio was 2.39 (95% confidence interval, 1.46-3.91) (P = .001) compared with those receiving metformin for less than 3 years. After exclusion of 113 subjects with borderline vitamin B12 concentration, dose of metformin remained the strongest independent predictor of vitamin B12 deficiency.

Conclusions  Our results indicate an increased risk of vitamin B12 deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients.