Sotagliflozin Decreases Postprandial Glucose and Insulin Concentrations by Delaying Intestinal Glucose Absorption

Abstract

Context: The effect of sotagliflozin (a dual sodium-glucose cotransporter [SGLT] 2 and SGLT1 inhibitor) on intestinal glucose absorption has not been investigated in humans.

Objective: To measure rate of appearance of oral glucose (RaO) using a dual glucose tracer method following standardized mixed meals taken after single sotagliflozin or canagliflozin doses.

Setting: Clinical research organization.

Design and participants: In a double-blind, 3-period crossover study (NCT01916863), 24 healthy participants were randomized to 2 cohorts of 12 participants. Within each cohort, participants were randomly assigned single oral doses of either sotagliflozin 400 mg, canagliflozin 300 mg, or placebo on each of test days 1, 8, and 15. On test days, Cohort 1 had breakfast containing [6,6-2H2] glucose 0.25 hours postdose and lunch containing [1-2H1] glucose 5.25 hours postdose; Cohort 2 had breakfast containing no labeled glucose 0.25 hours postdose and lunch containing [6,6-2H2] glucose 4.25 hours postdose. All participants received a 10- to 15-hour continuous [U-13C6] glucose infusion starting 5 hours before their first [6,6-2H2] glucose-containing meal.

Main outcome: RaO, postprandial glucose (PPG), and postprandial insulin.

Results: Sotagliflozin and canagliflozin decreased area under the curve (AUC)0-1 hour and/or AUC0-2 hours for RaO, PPG, and insulin after breakfast and/or the 4.25-hour postdose lunch (P < .05 versus placebo). After the 5.25-hour postdose lunch, sotagliflozin lowered RaO AUC0-1 hour and PPG AUC0-5 hours versus both placebo and canagliflozin (P < .05).

Conclusions: Sotagliflozin delayed and blunted intestinal glucose absorption after meals, resulting in lower PPG and insulin levels, likely due to prolonged local inhibition of intestinal SGLT1 that persisted for ≥5 hours after dosing.

Keywords: SGLT1 inhibitor; SGLT2 inhibitor; Sotagliflozin; intestinal glucose absorption; postprandial glucose; type 2 diabetes.

Figure 1.

Schematic of (A) overall study design and (B) stable isotope, blood collection and meal protocol design for Cohort 1 (top panel) and Cohort 2 (bottom panel).

Figure 2.

Effect of single doses of sotagliflozin or canagliflozin on the rate of appearance of oral glucose (R_aO) in blood during the mixed meal tolerance tests (MMTTs). All data points are mean ± standard error of the mean.

Figure 3.

Individual subject data for the effect of single doses of sotagliflozin or canagliflozin on R_aO AUC_{0–1 hour} and R_aO AUC_{0–2 hours} during the MMTTs. Data are presented as mean ± SD.

Figure 4.

Effect of single doses of sotagliflozin or canagliflozin on postprandial glucose (PPG) concentrations during the MMTTs. All data points are mean ± standard error of the mean.

Figure 5.

Effect of single doses of sotagliflozin or canagliflozin on (A,C) insulin concentrations and (B,D) C-peptide concentrations during the mixed meal tolerance tests. All data points are mean ± standard error of the mean.

Figure 6.

Effect of single doses of sotagliflozin or canagliflozin on (A,B) endogenous glucose production, (C,D) glucagon concentrations and (E,F) RdT during the mixed meal tolerance tests. All data points are mean ± standard error of the mean.

Figure 7.

Effect of single doses of sotagliflozin and canagliflozin on intestinal peptides at the indicated times during the Cohort 1 breakfast mixed meal tolerance test: (A) tGLP1; (B) aGLP1; (C) total PYY; and (D) total gastric inhibitory polypeptide. All data points are mean ± standard error of the mean.