OBJECTIVE: The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac). METHOD: The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment. RESULTS: The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54–4133 ng/ml, p = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months. CONCLUSION: In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous (80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.
RCT Entities:
OBJECTIVE: The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac). METHOD: The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment. RESULTS: The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54–4133 ng/ml, p = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months. CONCLUSION: In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous (80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.
Authors: M A Daniels; C Kan; D M Willmes; K Ismail; F Pistrosch; D Hopkins; G Mingrone; S R Bornstein; A L Birkenfeld Journal: Pharmacogenomics J Date: 2016-07-19 Impact factor: 3.550
Authors: Mette Marie H Christensen; Kurt Højlund; Ole Hother-Nielsen; Tore B Stage; Per Damkier; Henning Beck-Nielsen; Kim Brøsen Journal: Diabetologia Date: 2015-08-14 Impact factor: 10.122
Authors: L Allyson Checkley; Michael C Rudolph; Elizabeth A Wellberg; Erin D Giles; Reema S Wahdan-Alaswad; Julie A Houck; Susan M Edgerton; Ann D Thor; Pepper Schedin; Steven M Anderson; Paul S MacLean Journal: Cancer Prev Res (Phila) Date: 2017-02-02