Thirty‐six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once‐daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2‐mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA_1c; and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon‐like peptide‐1 levels. In a follow‐up single‐dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon‐like peptide‐1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1‐mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211‐mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.

Clinical Pharmacology & Therapeutics (2012); 92 2, 158–169. doi:10.1038/clpt.2012.58