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Abstract
AimsMetformin 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 (OCT1) variants and severe intolerance to metformin in people with Type 2 diabetes. The aim of this study was to explore the association of OCT1 reduced‐function polymorphisms with common metformin‐induced gastrointestinal side effects in Type 2 diabetes.MethodsThis 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 OCT1 gene (SLC22A1): R61C (rs12208357) and M420del (rs72552763). The association of OCT1 reduced‐function alleles with gastrointestinal side effects was analysed using logistic regression.ResultsForty‐three patients (47%) experienced gastrointestinal adverse effects in the first 6 months of metformin treatment. Interestingly, the number of OCT1 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).ConclusionsIn conclusion, we showed for the first time the association between OCT1 variants and common metformin‐induced gastrointestinal side effects. These results confirm recent findings related to the role of OCT1 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.
Highlights
Metformin is the first-line drug for treatment of Type 2 diabetes [1], and the most widely used oral anti-diabetes agent
In conclusion, we showed for the first time the association between organic cation transporter 1 (OCT1) variants and common metformin-induced gastrointestinal side effects
These results confirm recent findings related to the role of OCT1 in severe metformin intolerance, and suggest that high inter-individual variability in mild/moderate and severe gastrointestinal intolerance share a common underlying mechanism
Summary
Metformin is the first-line drug for treatment of Type 2 diabetes [1], and the most widely used oral anti-diabetes agent. It has considerable advantages over other Type 2 diabetes therapies, including low risk of hypoglycaemia, weight neutrality, low cost and possible cardiovascular benefits [1]. We recently reported the first study of the genetic and phenotypic determinants of severe intolerance to metformin in a large cohort of people with Type 2 diabetes [3]. In the reported research, a proxy phenotype for metformin gastrointestinal intolerance was established based upon prescribing patterns, namely the discontinuation of metformin and switching to another oral hypoglycaemic agent in the first months of metformin treatment. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK
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