Introduction: The transporter OCT1 is involved in the influx of metformin into the liver and the transporter MATE1 is involved in the efflux of metformin out of the liver. Recently, we identified that the polymorphism rs622342 in the gene coding for OCT1, and the polymorphism rs2289669 in the gene coding for MATE1, are associated with the degree of glucose-lowering effect by metformin. In this study, we analysed the existence of interaction between these two polymorphisms. Design and methods: We identified all incident metformin users in the Rotterdam Study, a population-based cohort study. Interaction between these two polymorphisms and change in HbA1c levels was analyzed. Results: In incident metformin users with the OCT1 rs622342 AA genotype, no association was found between the MATE1 rs2289669 genotype and the HbA1c-lowering effect (p = 0.39). In users with the OCT1 rs622342 AC genotype a non-significant tendency was found between the MATE1 rs2289669 genotype and the HbA1c-lowering effect (p = 0.070), and in users with the OCT1 rs622342 CC genotype a significant association was found between the MATE1 rs2289669 genotype and the glucose-lowering effect of metformin (p = 0.005). Conclusion: The effect of the MATE1 rs2289669 genotype on the glucose-lowering effect of metformin is stronger in incident users with the rs622342 CC genotype than in incident users with the rs622342 AA genotype. In most patients, metformin will lower HbA1c levels sufficiently, except in patients with a reduced function of the OCT1 transporter and a normal function of the MATE1 transporter.</p
