Abstract

SGLT2 is the target of several investigational compounds that aim to treat type 2 diabetes mellitus (T2DM). LX4211 is a potent systemic inhibitor of SGLT2 that also inhibits SGLT1 locally in the gastrointestinal (GI) tract. In prior clinical studies, dual inhibition by LX4211 provided glycemic control and metabolic benefits without triggering clinically significant GI side effects. In this study we explored the impact of timing of the dosing regimen on a variety of pharmacodynamic (PD) parameters including postprandial glucose (PPG), fasting plasma glucose (FPG), and insulin. 12 healthy subjects were enrolled, sequestered, and randomly assigned to LX4211 (n=10) or placebo (n=2). Subjects received LX4211 two (2) hours prior to breakfast for 7 days to establish a steady state, followed by dosing at 5 different times relative to meal, in a Latin square design balanced for first order carryover effects, on Days 8-12. PD parameters, including PPG, FPG, and insulin were assessed. Safety and tolerability were also evaluated throughout the study. All 12 subjects completed the study. Results across dosing times were comparable. All adverse events (AEs) were mild and infrequent; no events were deemed to be related to the administration of LX4211. LX4211 produced marked suppression of PPG excursion and hyperinsulinemia after breakfast with either morning or split dose, without producing hypoglycemia or diarrhea in healthy subjects.