The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes

Pharmacogenet Genomics. 2013 Apr;23(4):219-27. doi: 10.1097/FPC.0b013e32835f91fc.

Abstract

Objective: The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPARγ on rosiglitazone's (i) trough steady-state plasma concentration (C(ss,min)), (ii) on glycosylated haemoglobin A1c (HbA1c) and (iii) the risk of developing adverse events, mainly oedema, in patients with type 2 diabetes mellitus (T2D).

Methods: The data used in this study were obtained from the South Danish Diabetes Study including 371 T2D patients with a focus on the 187 patients who were treated with rosiglitazone. The study was a placebo-controlled, partly blinded and multicentre clinical trial. The C(ss,min) of rosiglitazone and HbA1c was determined and the genotype of the patients was identified.

Results: The mean C(ss,min) of rosiglitazone was 21.3 ng/ml (95% confidence interval 18.8; 24.2 ng/ml), with observations ranging from 1 to 296 ng/ml. Carriers of CYP2C8*3 (n=32) (rs10509681 and rs11572080) had a statistically significantly lower mean C(ss,min) than wild types (n=106), and they also had a statistically significantly lower mean absolute difference in HbA1c during rosiglitazone treatment. Finally, the carriers of CYP2C8*3 had a lower odds ratio of developing oedema.

Conclusion: We showed that CYP2C8*3 was associated with lower plasma levels of rosiglitazone and hence a reduced therapeutic response but also a lower risk of developing oedema during treatment with rosiglitazone. Individualized treatment with rosiglitazone on the basis of the CYP2C8 genotype may therefore be possible.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Biomarkers, Pharmacological
  • Cytochrome P-450 CYP2C8
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics*
  • Edema / blood
  • Edema / chemically induced
  • Edema / complications
  • Edema / genetics
  • Female
  • Genetic Association Studies
  • Glycated Hemoglobin A / genetics
  • Glycated Hemoglobin A / metabolism
  • Heat-Shock Proteins / genetics*
  • Humans
  • Male
  • Middle Aged
  • PPAR gamma / genetics*
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Phosphatidate Phosphatase / genetics*
  • Polymorphism, Single Nucleotide
  • Rosiglitazone
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / adverse effects
  • Transcription Factors / genetics*

Substances

  • Biomarkers, Pharmacological
  • Glycated Hemoglobin A
  • Heat-Shock Proteins
  • PPAR gamma
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Thiazolidinediones
  • Transcription Factors
  • hemoglobin A1c protein, human
  • Rosiglitazone
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • LPIN1 protein, human
  • Phosphatidate Phosphatase