ReseaRch aRticle ISSN 1462-2416 Pharmacogenomics (2009) 10 (11), 1781–1787 10.2217/PGS.09.96 © 2009 Future Medicine Ltd part of 1781 Presence of CYP2C9*3 allele increases risk for hypoglycemia in Type 2 diabetic patients treated with sulfonylureas Hypoglycemia is a common complication of dia- betes therapy and can have a profound impact on patients’ quality of life or may even prove life- threatening [1] . Furthermore, hypoglycemic epi- sodes engender fear or worry about hypoglycemic drugs, which in turn may hinder glycemic goal attainment, thus increasing the risk of diabetic complications [2] . Sulfonylurea oral hypoglycemic agents are commonly used to treat Type 2 dia- betes mellitus (T2DM) patients, as they are relatively cost effective and well tolerated [3] . Hypoglycemia is the most serious adverse effect of sulfonylureas and a major safety concern [4] . The frequency of sulfonylurea-induced hypogly- cemia varies from 1.8–59%, while severe hypo- glycemia due to these agents has been reported from 1.4–10% [5,6] . Interindividual differences in sulfonylurea response can result from age, sex, disease and food interactions, co-morbidity, as well as genetic factors [7] . Impaired metabolism of sulfonylureas due to genetic polymorphisms of the enzymes involved in their metabolic pathway may partially explain the differences in patient dose requirements and frequency of adverse reactions. This is mainly attributed to changed pharmacokinetics, as individuals with impaired sulfonylurea metabolism have higher median total area under the plasma concentration–time curve and prolonged hypoglycemic action [7–13] . Cytochrome P450 (CYP) 2C9 is a major P450 isoform mediating the metabolism of all sulfonylureas [7,14] . Polymorphisms in the CYP2C9 gene seriously affect enzymatic func- tion. Based on phenotype, the population can be divided into extensive, intermediate, and poor metabolizers. The most common CYP2C9 variant alleles, named *2 (rs1799853) and *3 (rs1057910), are responsible for the majority of poor metabolizer phenotypes [7,14] . The frequen- cies of CYP2C9*2 and CYP2C9*3 alleles exhibit signiicant interethnic and inter-racial variation. In Caucasian populations, including Greeks, they range from 8 to 19% for CYP2C9*2 and 3 to 16%, for CYP2C9*3 [15,16] . Aims: Hypoglycemia is a common adverse effect of sulfonylurea oral hypoglycemic agents. Impaired metabolism of sulfonylureas due to gene polymorphisms in the metabolic enzyme CYP2C9 might lead to hypoglycemia. In the present study we explored the association of the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 with the incidence of hypoglycemic events in diabetic patients receiving the sulfonylureas glimepiride and gliclazide. Materials & methods: A total of 92 Type 2 diabetes mellitus (T2DM) patients receiving sulfonylurea and reporting drug-associated hypoglycemia, and 84 T2DM patients receiving sulfonylurea and having never experienced hypoglycemia were included in the study. A sample of 283 nondiabetic controls that had been genotyped earlier served as a second control group. CYP2C9*2 and *3 alleles were detected by use of PCR-RFLP analysis. Results: Frequencies of CYP2C9*1/*3 genotype and CYP2C9*3 allele were signiicantly lower in T2DM patients than nondiabetic controls (p = 0.003 and p = 0.017, respectively). A total of 11 out of 92 subjects (12%) experiencing hypoglycemia carried the CYP2C9*3 allele, as opposed to only 1 out of 84 subjects (1.2%) free of sulfonylurea-induced hypoglycemia. In a model adjusted for age, BMI, mean daily dose of sulfonylurea, duration of T2DM and renal function, CYP2C9*1/*3 genotype increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 1.687; p = 0.011). However, no differences in CYP2C9*2 allele frequency between the two groups were found. Discussion & conclusion: The presence of CYP2C9*3 appears to be protective for development of T2DM. Furthermore, in T2DM patients, CYP2C9*3 increases the risk of hypoglycemia when they are treated with sulfonylureas, possibly due to impaired metabolism of these drugs. CYP2C9 genotyping might thus be a useful tool for predicting adverse effects caused by sulfonylureas and help clinicians in safer prescribing of oral hypoglycemic agents. The potential T2DM protective effect of CYP2C9*3 allele requires further investigation. KEYWORDS: CYP2C9 polymorphism n gliclazide n glimepiride n hypoglycemia n sulfonylurea n Type 2 diabetes mellitus Georgia Ragia 1 , Ioannis Petridis 1,2 , Anna Tavridou 1 , Dimitrios Christakidis 2 & Vangelis G Manolopoulos 1† † Author for correspondence: 1 Laboratory of Pharmacology, Medical School, Democritus University of Thrace, Dragana Campus, 68100 Alexandroupolis, Greece Tel.: +30 255 103 0523 Fax: +30 255 103 0523 emanolop@med.duth.gr 2 Academic General Hospital of Alexandroupolis, Thrace, Greece Author Proof