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Aims  Metformin is the most widely used oral anti‐diabetes agent and has considerable benefits over other therapies, yet 20–30% of people develop gastrointestinal side effects, and 5% are unable to tolerate metformin due to the severity of these side effects. The mechanism for gastrointestinal side effects and their considerable inter‐individual variability is unclear. We have recently shown the association between organic cation transporter 1 ( OCT 1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of  OCT 1 reduced‐function polymorphisms with common metformin‐induced gastrointestinal side effects in Type 2 diabetes.    Methods  This prospective observational cohort study included 92 patients with newly diagnosed Type 2 diabetes, incident users of metformin. Patients were genotyped for two common loss‐of‐function variants in the  OCT 1 gene (  SLC 22A1 ): R61C (rs12208357) and M420del (rs72552763). The association of  OCT 1 reduced‐function alleles with gastrointestinal side effects was analysed using logistic regression.    Results  Forty‐three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of  OCT 1 reduced‐function alleles was significantly associated with over two‐fold higher odds of the common metformin‐induced gastrointestinal side effects (odds ratio = 2.31, 95% confidence interval 1.07–5.01,  P  = 0.034).    Conclusions  In conclusion, we showed for the first time the association between  OCT 1 variants and common metformin‐induced gastrointestinal side effects. These results confirm recent findings related to the role of  OCT 1 in severe metformin intolerance, and suggest that high inter‐individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism. These data could contribute to more personalized and safer metformin treatment.

Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with Type 2 diabetes