Greater dose-ranging effects on A1C levels than on glucosuria with LX4211, a dual inhibitor of SGLT1 and SGLT2, in patients with type 2 diabetes on metformin monotherapy

Diabetes Care. 2015 Mar;38(3):431-8. doi: 10.2337/dc14-0890. Epub 2014 Sep 11.

Abstract

Objective: To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor of sodium-glucose cotransporter (SGLT) 1 and SGLT2, in type 2 diabetes.

Research design and methods: Type 2 diabetic patients inadequately controlled on metformin were randomly assigned to 75 mg once daily, 200 mg once daily, 200 mg twice daily, or 400 mg once daily of LX4211 or placebo. Primary end point was A1C change from baseline to week 12. Secondary end points included changes in blood pressure (BP) and body weight.

Results: Baseline characteristics in 299 patients randomly assigned to LX4211 or placebo in this 12-week dose-ranging study were similar: mean age 55.9 years, A1C 8.1% (65 mmol/mol), BMI 33.1 kg/m(2), and BP 124/79 mmHg. LX4211 significantly reduced A1C to week 12 in a dose-dependent manner by 0.42% (4.6 mmol/mol), 0.52% (5.7 mmol/mol), 0.80% (8.7 mmol/mol), and 0.92% (10.0 mmol/mol), respectively (P < 0.001 each), compared with 0.09% (1.0 mmol/mol) for placebo. Greater A1C reductions were produced by 400 mg once a day than 200 mg once a day LX4211 without higher urinary glucose excretion, suggesting a contribution of SGLT1 inhibition. Significant reductions were seen in body weight (-1.85 kg; P < 0.001) and systolic BP (-5.7 mmHg; P < 0.001), but diastolic BP was unchanged (-1.6; P = 0.164). Adverse events with LX4211 were mild to moderate and similar to placebo, including urinary tract infections and gastrointestinal-related events; genital infections were limited to LX4211 groups (0-5.0%). No hypoglycemia occurred.

Conclusions: Dual inhibition of SGLT1/SGLT2 with LX4211 produced significant dose-ranging improvements in glucose control without dose-increasing glucosuria and was associated with reductions in weight and systolic BP in metformin-treated patients with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT01376557.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Blood Glucose / drug effects
  • Blood Pressure / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Glycated Hemoglobin A / drug effects
  • Glycosides / administration & dosage*
  • Glycosides / adverse effects
  • Glycosuria / chemically induced
  • Humans
  • Hypoglycemia / drug therapy
  • Hypoglycemic Agents / administration & dosage*
  • Hypoglycemic Agents / adverse effects
  • Male
  • Metformin / therapeutic use
  • Middle Aged
  • Sodium-Glucose Transporter 1 / antagonists & inhibitors
  • Sodium-Glucose Transporter 2 Inhibitors
  • Treatment Outcome
  • Weight Loss / drug effects

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Glycosides
  • Hypoglycemic Agents
  • Sodium-Glucose Transporter 1
  • Sodium-Glucose Transporter 2 Inhibitors
  • (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
  • Metformin

Associated data

  • ClinicalTrials.gov/NCT01376557