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Rose Zhao-Wei Ting, MBBS; Cheuk Chun Szeto, MD, FRCP; Michael Ho-Ming Chan, FRCPA, FHKCPath; Kwok Kuen Ma, MBBS; Kai Ming Chow, MRCP

Arch Intern Med. 2006;166:1975-1979.

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 A_1c 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.

Author Affiliations: Departments of Medicine and Therapeutics (Drs Ting, Szeto, and Chow) and Chemical Pathology (Dr Chan), Prince of Wales Hospital, The Chinese University of Hong Kong, Sha Tin; and Department of Surgery, Queen Mary Hospital (Dr Ma), Hong Kong, China.

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