title: Study design and rationale of a dose-ranging trial of LX4211, a dual inhibitor of SGLT1 and SGLT2, in type 2 diabetes inadequately controlled on metformin monotherapy.
abstract: Sodium-glucose cotransporters 1 (SGLT1) and 2 (SGLT2) are the major cellular transporters responsible for gastrointestinal (GI) glucose absorption and renal glucose reabsorption, respectively. LX4211, a dual inhibitor of SGLT1 and SGLT2, reduces glucose absorption from the GI tract and enhances urinary glucose excretion. Although several SGLT2-selective inhibitors have been tested in large phase 2 studies, dual inhibition of SGLT1 and SGLT2 is novel at this stage of drug development, and it has implications for clinical-trial design. In this article, we describe the design and rationale of a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel group study to evaluate the safety and efficacy of LX4211 in subjects with type 2 diabetes mellitus who have inadequate glycemic control on metformin monotherapy. The primary endpoint is the change in glycated hemoglobin A1c from baseline to week 12. Secondary endpoints include the proportion of subjects achieving a glycated hemoglobin A1c value of <7%, change from baseline in fasting plasma glucose and postprandial glucose (as part of an oral glucose tolerance test), body weight, and blood pressure. Safety is evaluated with particular focus on hypoglycemia, GI symptoms, and incidence of genitourinary tract infections.
authors: Department of Clinical Development, Lexicon Pharmaceuticals, Inc., 350 Carter Road, Princeton, NJ 08540, USA. plapuerta@lxrx.com
authors: Pablo
authors: P
authors: Lapuerta
authors: Julio
authors: J
authors: Rosenstock
authors: Brian
authors: B
authors: Zambrowicz
authors: David R
authors: DR
authors: Powell
authors: Ike
authors: I
authors: Ogbaa
authors: Joel
authors: J
authors: Freiman
authors: William T
authors: WT
authors: Cefalu
authors: Phillip
authors: P
authors: Banks
authors: Kenny
authors: K
authors: Frazier
authors: Mike
authors: M
authors: Kelly
authors: Arthur
authors: A
authors: Sands
mesh_terms: D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D002985:Clinical Protocols; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006442:Glycated Hemoglobin / Q000378:metabolism; D006027:Glycosides / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D012107:Research Design; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors; D017211:Treatment Failure; D014481:United States; D014552:Urinary Tract Infections / Q000139:chemically induced
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D006027:Glycosides; D007004:Hypoglycemic Agents; D008687:Metformin; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; C517652:hemoglobin A1c protein, human; C575681:(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
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