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

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 mUmin/1.73 m(2) 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 mUmin/1.73 m(2), with a placebo-adjusted decrease in incremental AUC(predose-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 m(2) 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 mIlmin/1.73 m(2), and eGFR <45 mt./min/1.73 m(2) subgroups, respectively. Implications: The PPG effects were maintained in patients with an eGFR <45 mL/min/1.73 m(2) 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. (C) 2015 Elsevier HS Journals, Inc. All rights reserved.