Aims: Metformin uptake is transporter-dependent. Observational data indicates that reduced-function variants in organic cation transporter 1 (OCT1) and OCT1-inhibiting drugs increase risk of metformin intolerance. The ImpOCT study investigated impact of OCT1 genotype and use of omeprazole (an OCT1-inhibiting drug) on an individual’s metformin tolerance.
Methods: This recruit-by-genotype, double-blind, randomised, placebo-controlled, crossover study recruited 61 nondiabetic individuals with homozygous reduced-function (null) or wild type (WT) OCT1 genotype. During two 4-week treatment periods, participants received metformin and concurrent omeprazole or placebo. Metformin was titrated weekly according to tolerance, assessed by interview and symptom severity scoring. The primary outcome was maximum tolerated dose of metformin (MTD) in each treatment period. Results were analysed using mixed effects modelling, assessing effect of genotype, treatment and gene x drug interaction on MTD.
Results: Participants were well matched for age and gender. Median BMI was higher in OCT1 null (26.3 [IQR 24.1 - 28.1] vs. 29 [IQR 26.5 - 31.8], p<0.001), though these OCT1 variants are not associated with obesity. Frequency of tolerance was comparable (WT 60% vs. null 64.5%, p=0.7). We identified a significant gene x drug interaction (p=0.04) - OCT1 WT individuals have improved MTD whilst taking omeprazole, compared to placebo, p=0.008, whereas OCT1 null individuals show no improvement in MTD with omeprazole compared to placebo, p=0.87. BMI was not significant in the model of MTD, p=0.27.
Conclusions: Reduced function SNPs in OCT1 are relatively common and can affect transporter efficacy. This study identified a gene x drug interaction, between OCT1, metformin and omeprazole. Our data indicates that OCT1 WT individuals may benefit from PPI treatment to improve symptoms of metformin intolerance - this benefit is lost in those with reduced OCT1 function.
L.J. McCreight: None. S.M. Hapca: None. E. Pearson: None.
UK Wellcome Trust (to E.P.)