Abstract

LX4211, a dual inhibitor of SGLT1 and SGLT2, has repeatedly improved glycemic control with a favorable gastrointestinal (GI) safety profile. Therapeutic LX4211 effects may be mediated, in part, by modulation of glucose absorption/incretin stimulation in the GI tract; it is important to explore the effect of dosing relative to meals on these parameters. 12 healthy subjects were sequestered and randomly assigned (2 placebo:10 LX4211). LX4211 was dosed for 7 days, to a steady state, then administered at 5 different times with respect to meals, using a Latin square design balanced for first order carryover effects. Pharmacodynamic (PD) parameters sensitive to SGLT-1 inhibition, including glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), (GI hormones associated with glycemic control and satiety), were measured, as was urinary glucose excretion (UGE), a PD parameter sensitive to SGLT2 inhibition. Safety was evaluated throughout the study. Results across dosing times relative to Day -1 are presented. All regimens produced significant elevations of GLP-1 relative to Day -1. There were significant differences in GLP-1 between dosing 1-hour and just prior to breakfast, favoring the latter. All adverse events (AE) were mild and infrequent; no AEs were drug-related. No hypoglycemia or diarrhea occurred. (See RESULTS) The effect of LX4211 on UGE, an SGLT2-associated PD parameter, remained consistent across all dosing times; increases in the SGLT1-associated PD parameter GLP-1 (total and active) was greatest when dosing occurred just prior to the breakfast.