Abstract

Treatments that lower blood glucose levels and body weight should benefit patients with type 2 diabetes mellitus (T2DM). We developed LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], an orally available small molecule that decreases postprandial glucose excursions by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, we present preclinical studies that explored the ability of LX4211 to improve glycemic control and promote weight loss. We found that 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat, and dog SGLT1 and SGLT2; 2) a single daily LX4211 dose markedly increased UGE for >24 hours in mice, rats, and dogs; and 3) in the KK.Cg-Ay/J heterozygous (KKA^y) mouse model of T2DM, LX4211 lowered A1C and postprandial glucose concentrations while increasing postprandial glucagon-like peptide 1 concentrations. Also, long-term LX4211 treatment 1) decreased oral glucose tolerance test (OGTT) glucose excursions, increased OGTT 30-minute insulin concentrations and increased pancreatic insulin content in KKA^y mice; and 2) decreased weight gain in dogs and rats but not in KKA^y mice while increasing food consumption in dogs, rats, and KKA^y mice; in these KKA^y mice, calories lost through UGE were completely offset by calories gained through hyperphagia. These findings suggest that LX4211 improves glycemic control by dual SGLT1/SGLT2 inhibition in mice as in humans, and that the LX4211-mediated weight loss observed in patients with T2DM may be attenuated by LX4211-mediated hyperphagia in some of these individuals.