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.