title: Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: A report from the Cardiac Safety Research Consortium.
abstract: Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy.
authors.affiliation: University of Sheffield, Sheffield, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Heller
authors.affiliation: Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institute, Danderyd's Hospital, Stockholm, Sweden; iCardiac Technologies, Rochester, NY.
authors.forename: Börje
authors.initials: B
authors.lastname: Darpö
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Malcolm I
authors.initials: MI
authors.lastname: Mitchell
authors.affiliation: Eli Lilly and Company, Indianapolis, IN. Electronic address: linnebjerg_helle@lilly.com.
authors.forename: Helle
authors.initials: H
authors.lastname: Linnebjerg
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Leishman
authors.affiliation: US Food and Drug Administration, Silver Spring, MD.
authors.forename: Nitin
authors.initials: N
authors.lastname: Mehrotra
authors.affiliation: US Food and Drug Administration, Silver Spring, MD.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: US Food and Drug Administration, Silver Spring, MD.
authors.forename: John
authors.initials: J
authors.lastname: Koerner
authors.affiliation: US Food and Drug Administration, Silver Spring, MD.
authors.forename: Mónica L
authors.initials: ML
authors.lastname: Fiszman
authors.affiliation: US Food and Drug Administration, Silver Spring, MD.
authors.forename: Suchitra
authors.initials: S
authors.lastname: Balakrishnan
authors.affiliation: US Food and Drug Administration, Silver Spring, MD.
authors.forename: Shen
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Medpace Inc, Cincinnati, OH.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Todaro
authors.affiliation: Eli Lilly and Company, Indianapolis, IN.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hensley
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, Germany.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Guth
authors.affiliation: Thomas Jefferson University, Philadelphia, PA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Michelson
authors.affiliation: Stanford University School of Medicine, Stanford, CA; Cardiac Safety Research Consortium, Durham, NC.
authors.forename: Philip
authors.initials: P
authors.lastname: Sager
mesh_terms: D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects; D004562:Electrocardiography; D000067757:Glucagon-Like Peptide-1 Receptor; D065089:Glycoside Hydrolase Inhibitors; D006329:Heart Conduction System / Q000002:abnormalities*; D006352:Heart Ventricles; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008133:Long QT Syndrome / Q000139:chemically induced*; D018408:Patch-Clamp Techniques; D018027:Receptors, Glucagon / Q000819:agonists; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds / Q000009:adverse effects; D045162:Thiazolidinediones / Q000009:adverse effects; D016276:Ventricular Function
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones