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J Diabetes. 2019 Jan 7. doi: 10.1111/1753-0407.12900. [Epub ahead of print]

Associations between metformin use and vitamin B12 level, anemia and neuropathy in patients with diabetes: a meta-analysis.

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Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
Eisai China Inc, Shanghai, China.



Metformin is the first line therapy for patients with diabetes. However, it may lower vitamin B12 (B12) level which could have hematological or neurological implications. The current study aimed to perform meta-analyses of all available studies on associations between metformin use and B12 level, anemia and neuropathy in diabetic patients.


The PubMed, Web of Knowledge, Cochrane Library and Embase were searched to identify all relevant studies published in English prior to March 2018. Cochrane Review Manager 5.3 was used to calculate the pooled risk ratios (RRs) and 95% confidence intervals (CIs) for dichotomous outcomes and the pooled mean differences (MDs) and 95% CIs for continuous outcomes.


31 studies were included in the meta-analyses. Compared to diabetic patients not taking metformin, patients taking metformin had significantly higher risk of B12 deficiency (RR=2.09; 95% CI [1.49, 2.93]; P<0.0001; I2 =64%) and significantly lower serum B12 concentration (MD=-63.70; 95% CI [-74.35, -53.05] pmol/l; P<0.00001; I2 =87%) in a duration and dose dependent manner. Metformin use was also associated with significantly greater % decrease in serum B12 concentration from baseline in diabetic patients (MD=-14.68; 95% CI [-17.98, -11.39]%; P<0.00001; I2 =33%). Analyses revealed no significant association between metformin use and prevalence of anemia or neuropathy.


Metformin use led to significantly lowered B12 level and significantly higher risk of B12 deficiency in diabetic patients. More quality studies are needed to explore the associations between metformin use and anemia and neuropathy in these patients. Annual B12 assessment in diabetic patients taking metformin was recommended.


anemia; diabetes; metformin; neuropathy; vitamin B12 deficiency


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