LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00962065 NCT01188863.

Figures

Figure 1

Effect of LX4211 on glycemic parameters and UGE. (a) Chemical structure of LX4211, (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol. (b) FPG. This schematic representation of the study design depicts mean changes in FPG levels from baseline (day −1) values throughout the study. (c) HbA1c. Change in HbA1c levels after 28 days of treatment with LX4211 or placebo. (d) OGTT glucose AUCs. AUCs for glucose obtained from OGTTs performed on days −2, 2, 13, and 27. (e) OGTT glucose excursions above fasting (hour 0) values. OGTT glucose excursions were plotted after correcting for differences in FPG by adjusting hour 0 glucose values to 0 mg/dl. Left, data from day −2; right, data from day 27. (f) UGE. UGE was estimated by measuring the total amount of glucose in 24-h urine samples collected on days −1, 1, 14, and 28; the data shown represent the mean change from baseline (day −1) values. The color key identifying each group in b–f is at the bottom of the figure. For d and e, AUC values for each LX4211 treatment group on each day were compared with the AUC values of the placebo group on that day. For b,d,f: different from placebo, ***P < 0.001, **P < 0.01; different from 150 mg dose group, ••P < 0.01, •P < 0.05. ♦, n = 11 for the placebo group on days 27 and 28. For e, AUC values on day 27 were significantly lower for each LX4211 treatment group as compared with placebo, P < 0.001. Error bars in c represent 1 SD. All the data are presented as arithmetic means except in c, in which the data are presented as differences in least squares means. AUC, area under the curve for glucose concentration; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; OGTT, oral glucose tolerance test; UGE, urinary glucose excretion.

Figure 2

Effects of single doses of liquid or solid forms of oral LX4211 on UGE and on circulating levels of GLP-1, PYY, and LX4211. (a) Study design. This schematic representation depicts the treatment sequence; each of three groups of patients (n = 4 per group) received each of three LX4211 formulations on days 1, 6, and 11. Metformin was washed out before day 1, and LX4211 formulations administered on days 1 and 6 were washed out over the 5 days following each of the doses. The levels of UGE, GLP-1, PYY, and LX4211 measured on the day when the LX4211 formulation was administered to 12 patients with type 2 diabetes mellitus (T2DM) were compared with those on day −1 (baseline control levels) measured in the same 12 patients. (b) UGE. UGE was estimated by measuring the total amount of glucose present in 24-h urine samples collected at baseline (day −1) and on the days when each LX4211 formulation was administered; the data shown represent mean changes from baseline values. (c–e) Circulating GLP-1 and PYY. These were measured at the same time points on day −1 and on the days when each LX4211 formulation was administered. In c–e, arrows show the time points at which meals were provided, and P values are presented at the bottom of each of these panels. (c) Total GLP-1. (d) Active GLP-1. (e) Total PYY. (f) Time course of plasma LX4211 levels after oral administration of liquid or tablet LX4211 forms. The color key identifying each group in b–f is at the bottom of the figure. Error bars in b represent 1 SD. All data are presented as arithmetic means. AUC, area under the curve; D/C, discontinue; GLP-1, glucagon-like peptide-1; PK, pharmacokinetic analysis; PYY, peptide YY; UGE, urinary glucose excretion.