LX4211 Therapy Reduces Postprandial Glucose Levels in Patients With Type 2 Diabetes Mellitus and Renal Impairment Despite Low Urinary Glucose Excretion

• Published in: Clinical therapeutics Vol. 37; no. 1; pp. 71 - 82.e12
• Main Authors: Zambrowicz, Brian, PhD, Lapuerta, Pablo, MD, Strumph, Paul, MD, Banks, Phillip, MS, FRS, Wilson, Alan, PhD, Ogbaa, Ike, MD, Sands, Arthur, MD, PhD, Powell, David, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2015; Elsevier Limited
• Subjects: Aged; Blood Glucose - drug effects; Blood pressure; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Drug dosages; Drug therapy; fasting plasma glucose; Female; Glucagon-Like Peptide 1 - blood; Glucose; Glycosides - pharmacology; Glycosides - therapeutic use; Glycosuria - blood; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin; Internal Medicine; LX4211; Male; Medical Education; Middle Aged; Mortality; pharmacokinetics; postprandial glucose; Postprandial Period - drug effects; renal impairment; Renal Insufficiency - blood; Renal Insufficiency - complications; Renal Insufficiency - physiopathology; SGLT1; SGLT2; Studies; urinary glucose excretion; United States > US; SGLT2; SGLT1; pharmacokinetics; LX4211; fasting plasma glucose; urinary glucose excretion; postprandial glucose; renal impairment
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2014.10.026

Abstract Purpose We sought to assess the efficacy and safety profile of LX4211, a dual inhibitor of sodium-glucose cotransporter1 (SGLT1) and SGLT2, in patients with type 2 diabetes and renal impairment. Methods Thirty-one patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 were randomly assigned to receive 400 mg of LX4211 or placebo for 7 days. The primary end point was the change from baseline to day 7 in postprandial glucose (PPG) levels. Other end points included changes in fasting plasma glucose levels, glucagon-like peptide 1 levels, urinary glucose excretion (UGE), and blood pressure. Findings LX4211 therapy significantly reduced PPG levels relative to placebo in the total population and in patients with an eGFR <45 mL/min/1.73 m2 , with a placebo-adjusted decrease in incremental AUCpredose–4 of 73.5 mg·h/dL ( P = 0.009) and 137.2 mg·h/dL ( P = 0.001) for the total population and the eGFR <45 mL/min/1.73 m2 subgroup, respectively. There was a significant reduction in fasting plasma glucose levels relative to baseline of –27.1 mg/dL ( P < 0.001). Total and active glucagon-like peptide 1 levels were significantly elevated relative to placebo with LX4211 dosing, and UGE was significantly elevated with placebo-subtracted measures of 38.7, 53.5, and 20.4 g/24 h ( P ≤ 0.007 for all 3) in the total population, eGFR 45 to 59 mL/min/1.73 m2 , and eGFR <45 mL/min/1.73 m2 subgroups, respectively. Implications The PPG effects were maintained in patients with an eGFR <45 mL/min/1.73 m2 despite the expected reduction in UGE, suggesting that dual SGLT1 and SGLT2 inhibition with LX4211 could prove useful for the treatment of patients with type 2 diabetes and renal impairment. ClinicalTrials.gov identifier: NCT01555008.