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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.
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 language | English |
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Pages (from-to) | 1902-1908 |
Number of pages | 7 |
Journal | Diabetes Care |
Volume | 39 |
Issue number | 11 |
Early online date | 6 Jun 2016 |
DOIs | |
Publication status | Published - Nov 2016 |
Keywords
- CYP2C8
- SLCO1B1
- Thiazolidinediones
- Rosiglitazone
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- 1 Finished
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Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)
Pearson, E. (Investigator)
16/02/15 → 15/08/21
Project: Research