CYP2C8 and SLCO1B1 variants and therapeutic response to thiazolidinediones in patients with type 2 diabetes.

Adem Y. Dawed, Louise Donnelly, Roger Tavendale, Fiona Carr, Graham Leese, Colin N.A. Palmer, Ewan Pearson, Kaixin Zhou (Lead / Corresponding author)

Research output: Contribution to journalArticle

28 Citations (Scopus)
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Abstract

Objective: Thiazolidinediones (TZDs) are putatively transported into the liver by OATP1B1 (encoded by SLCO1B1) and metabolized by CYP450 2C8 enzyme (encoded by CYP2C8). Whilst CYP2C8*3 has been shown to alter TZD pharmacokinetics, it has not been shown to alter efficacy.
Design: We genotyped 833 Scottish Type 2 diabetes patients treated with pioglitazone or rosiglitazone and jointly investigated association of variants in these two genes with therapeutic outcome.
Result: The CYP2C8*3 variant was associated with reduced glycaemic response to rosiglitazone (P = 0.01) and less weight gain (P = 0.02). The SLCO1B1 521T>C variant was associated with enhanced glycaemic response to rosiglitazone (P = 0.04). The super responders defined by combined genotypes at CYP2C8 and SLCO1B1 had a 0.39% (4 mmol/mol) greater HbA1c reduction (P = 0.006) than the poor responders. Neither of the variants had a significant impact on pioglitazone response.
Conclusion: These results show that variants in CYP2C8 and SLCO1B1 have a large clinical impact on the therapeutic response to rosiglitazone, and highlight the importance of studying transporter and metabolising genes together in pharmacogenetics.
Original languageEnglish
Pages (from-to)1902-1908
Number of pages7
JournalDiabetes Care
Volume39
Issue number11
Early online date6 Jun 2016
DOIs
Publication statusPublished - Nov 2016

Keywords

  • CYP2C8
  • SLCO1B1
  • Thiazolidinediones
  • Rosiglitazone

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