The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c

Pharmacogenet Genomics. 2011 Dec;21(12):837-50. doi: 10.1097/FPC.0b013e32834c0010.

Abstract

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Double-Blind Method
  • Glycated Hemoglobin A / metabolism*
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / blood*
  • Metformin / administration & dosage
  • Metformin / blood*
  • Middle Aged
  • Multicenter Studies as Topic
  • Organic Cation Transport Proteins / genetics
  • Organic Cation Transporter 1 / genetics
  • Organic Cation Transporter 2
  • Prospective Studies

Substances

  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • MATE1 protein, human
  • MATE2-K protein, human
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 1
  • Organic Cation Transporter 2
  • SLC22A2 protein, human
  • Metformin