title: Influence of common polymorphisms in the SLC5A2 gene on metabolic traits in subjects at increased risk of diabetes and on response to empagliflozin treatment in patients with diabetes.
abstract: Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes.
  
  
  
  Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies ≥5%) present in the SLC5A2 gene locus.
  
  
  
  In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA1c, plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P≥0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA1c, fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study.
  
  
  
  Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin.
authors.affiliation: aBoehringer Ingelheim Pharma GmbH & Co. KG, Biberach bGerman Center for Diabetes Research (DZD) cInstitute for Diabetes Research and Metabolic Diseases, Helmholtz Centre Munich dDepartment of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology, and Clinical Chemistry eInterfaculty Centre for Pharmacogenomics and Pharma Research, University of Tuebingen fInstitute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry, Eberhard Karls University Tuebingen, Tuebingen gInstitute of Experimental Genetics, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg hBoehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany iEli Lilly and Company, Indianapolis, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Zimdahl
authors.forename: Axel
authors.initials: A
authors.lastname: Haupt
authors.forename: Michael
authors.initials: M
authors.lastname: Brendel
authors.forename: Louis
authors.initials: L
authors.lastname: Bour
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Afshin
authors.initials: A
authors.lastname: Salsali
authors.forename: Uli C
authors.initials: UC
authors.lastname: Broedl
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
mesh_terms: D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure; D001835:Body Weight; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005960:Glucosides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics*
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; C570240:empagliflozin