LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial

Clin Pharmacol Ther. 2012 Aug;92(2):158-69. doi: 10.1038/clpt.2012.58. Epub 2012 Jul 4.

Abstract

Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once-daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon-like peptide-1 levels. In a follow-up single-dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon-like peptide-1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1-mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211-mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

Trial registration: ClinicalTrials.gov NCT00962065 NCT01188863.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Blood Glucose / drug effects*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Female
  • Glucagon-Like Peptide 1 / blood
  • Glucose Tolerance Test
  • Glycated Hemoglobin A / drug effects
  • Glycated Hemoglobin A / metabolism
  • Glycosides / administration & dosage
  • Glycosides / therapeutic use*
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / therapeutic use*
  • Intestinal Absorption
  • Male
  • Middle Aged
  • Peptide YY / blood
  • Sodium-Glucose Transporter 1 / antagonists & inhibitors*
  • Sodium-Glucose Transporter 2 Inhibitors*
  • Triglycerides / blood

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Glycosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 1
  • Sodium-Glucose Transporter 2 Inhibitors
  • Triglycerides
  • hemoglobin A1c protein, human
  • Peptide YY
  • (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
  • Glucagon-Like Peptide 1

Associated data

  • ClinicalTrials.gov/NCT00962065
  • ClinicalTrials.gov/NCT01188863