Interaction between variants in the CYP2C9 and POR genes and the risk of sulfonylurea-induced hypoglycaemia: A GoDARTS Study.

Tanja Dujic,Colin N A Palmer,Kaixin Zhou,Ewan R Pearson,Louise A Donnelly,Graham Leese

doi:10.1111/dom.13046

Tanja Dujic, Colin N A Palmer + Show 4 more

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https://doi.org/10.1111/dom.13046

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Abstract

Data on the association of CYP2C9 genetic polymorphisms with sulfonylurea (SU)‐induced hypoglycaemia (SH) are inconsistent. Recent studies showed that variants in the P450 oxidoreductase (POR) gene could affect CYP2C9 activity. In this study, we explored the effects of POR*28 and combined CYP2C9*2 and CYP2C9*3 genotypes on SH and the efficacy of SU treatment in type 2 diabetes. A total of 1770 patients were included in the analysis of SU efficacy, assessed as the combined outcome of the HbA1c reduction and the prescribed SU daily dose. Sixty‐nine patients with severe SH were compared with 311 control patients. The number of CYP2C9 deficient alleles was associated with nearly three‐fold higher odds of hypoglycaemia (OR, 2.81; 95% CI, 1.30‐6.09; P = .009) and better response to SU treatment (β, −0.218; SE, 0.074; P = .003) only in patients carrying the POR*1/*1 genotype. Our results indicate that interaction between CYP2C9 and POR genes may be an important determinant of efficacy and severe adverse effects of SU treatment.

Highlights

Despite development of novel pharmacological agents, sulfonylureas (SUs) continue to be a cornerstone in type 2 diabetes (T2D) treatment
In the analysis stratified by the P450 oxidoreductase (POR) genotypes, the number of CYP2C9 deficient alleles increased the odds of hypoglycaemia nearly 3-fold (OR, 2.81; 95% CI, 1.30-6.09; P = .009) in the POR*1/ *1 genotype group, whereas there was no effect in the POR*28
Earlier studies demonstrated the influence of CYP2C9 genetic polymorphisms on the metabolism and glycaemic response to SUs, data on the association between CYP2C9 genotypes and SUinduced hypoglycaemia are limited and inconsistent.[10]

Summary

Introduction

Despite development of novel pharmacological agents, sulfonylureas (SUs) continue to be a cornerstone in type 2 diabetes (T2D) treatment. SUs are metabolized in the liver primarily by the CYP2C9 enzyme.[5] CYP2C9 is highly polymorphic, with CYP2C9*1 as a major allele. The 2 most common variants, CYP2C9*2 (R144C, rs1799853) and CYP2C9*3 (I359L, rs1057910), have been associated with impaired function and poor metabolism phenotypes[6] (Table S1). The impact of *2 and *3 polymorphisms on the pharmacokinetics of SUs has been demonstrated in studies in healthy subjects.[7] In the largest study to date on the effect of CYP2C9 variants on therapeutic response to SUs, we showed an association of CYP2C9*2 and CYP2C9*3 alleles with greater glycaemic response to SUs and a lower rate of treatment failure,[8] confirming earlier pharmacokinetic data. In the Rotterdam study, patients with T2D carrying the CYP2C9*3 allele required a lower dose of tolbutamide to regulate glycaemia, compared to patients with the wild-type CYP2C9 genotype.[9]

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