Risk factors of vitamin B12 deficiency in patients receiving metformin

Background: Identification of risk factors for metforminrelated vitamin B-12 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 B-12 and hemoglobin A(1c) checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B-12 deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B-12 deficiency while taking metformin. Results: A total of 155 patients with metformin-related vitamin B-12 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 B-12 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 B-12 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 B-12 concentration, dose of metformin remained the strongest independent predictor of vitamin B-12 deficiency. Conclusions: Our results indicate an increased risk of vitamin B-12 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.