title: Impact of clinical factors and CYP2C9 variants for the risk of severe sulfonylurea-induced hypoglycemia.
abstract: OBJECTIVE
  The established risk factors for severe sulfonylurea-induced hypoglycemia (SH) include low hemoglobin (Hb)A(1c), advanced age, long duration of diabetes, multimorbidity, and polypharmacy. As the genetically polymorphic cytochrome P450 (CYP), enzyme CYP2C9 is mainly responsible for the hepatic metabolism of sulfonylureas (SUs), we hypothesized that the slow-metabolizer genotypes *2/*2, *2/*3, and *3/*3 might be overrepresented in type 2 diabetic patients with SH.
  
  
  METHODS
  In a prospective population-based case-control study, CYP2C9 allelic variants of 102 diabetic patients with SH were compared with a matched group of 101 SU-treated patients without a history of SH. The 203 Caucasian patients had been treated with the SUs glimepiride, glibenclamide, or gliquidone. SH was defined as a symptomatic event requiring treatment with intravenously administered glucose and was confirmed by a blood glucose measurement of <50 mg/dl (<2.8 mmol/l). As two control groups, we selected 337 Caucasian diabetic patients receiving antidiabetic drugs per os and 1,988 healthy Caucasian volunteers who had been genotyped earlier.
  
  
  RESULTS
  In the univariate analysis, only a low HbA(1c) value (p = 0.0004) was shown as a risk factor for SH. There was no overrepresentation of the CYP2C9 *2/*2, *2/*3, and *3/*3 variants in the SH group (2%) compared with the control group (5%). However, in the control group, patients with CYP2C9 genotypes, predicting slower metabolism of SU drugs, were treated with significantly lower doses (p = 0.027) than were extensive metabolizers, whereas in the patient group with severe hypoglycemia, the dose was the same for all genotype groups.
  
  
  CONCLUSIONS
  In the present cohort of 102 patients with SH, a low HbA(1c) value was related to the risk for SH. There was no overrepresentation observed of the CYP2C9 slow-metabolizer genotypes in the hypoglycemic patients group, but the drug exposure in the slow-metabolizer genotypes was estimated to be higher in hypoglycemic patients, which might partly have contributed to their risk for SH.
authors.affiliation: First Department of Medicine, Klinikum Lippe-Detmold, Röntgenstr. 18, 32756 Detmold, Germany. Andreas.Holstein@t-online.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Holstein
authors.forename: Michael
authors.initials: M
authors.lastname: Hahn
authors.forename: Olaf
authors.initials: O
authors.lastname: Patzer
authors.forename: Angela
authors.initials: A
authors.lastname: Seeringer
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.forename: Julia
authors.initials: J
authors.lastname: Stingl
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D005260:Female; D056914:Genomic Structural Variation; D005838:Genotype; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D011446:Prospective Studies; D012307:Risk Factors; D013453:Sulfonylurea Compounds / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases