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

摘要

OBJECTIVE: The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPAR?? on rosiglitazone's (i) trough steady-state plasma concentration (Css,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 Css,min of rosiglitazone and HbA1c was determined and the genotype of the patients was identified. RESULTS: The mean Css,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 Css,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. ? 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.