Reduced function SLC22A1 polymorphisms encoding Organic Cation Transporter 1 (OCT1) and glycaemic response to metformin: A Go-DARTS study

Abstract

Objective. Metformin is actively transported into the liver by the organic cation transporter OCT1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss of function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes.

Research Design and Methods. The DARTS database includes prescribing, biochemistry and clinical phenotype of all patients with diabetes within Tayside, Scotland from 1992 onwards. R69C and 420del variants of SLC22A1 were genotyped in 3450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modelling the maximum HbA1c reduction in the 18 months after starting metformin and whether a treatment target of HbA1c <7% was achieved. Sustained metformin effect on HbA1c between 6 and 42 months was also assessed, as was the time to metformin monotherapy failure. Covariates were SLC22A1 genotype, BMI, average drug dose, adherence and creatinine clearance.

Results. 1531 patients were identified with definable metformin response. R61C and 420del variants did not affect the initial HbA1c reduction (p=;0.47; p=0.92 respectively), the chance of achieving a treatment target (p=0.83; p=0.36), the average HbA1c on monotherapy up to 42 months (p=0.44; p=0.75), or the hazard of monotherapy failure (p=0.85; p=0.56).

Conclusions. The SLC22A1 loss of function variants, R61C and 420del, do not attenuate the HbA1c reduction achieved by metformin in patients with type 2 diabetes.