OR22-5 Sotagliflozin Decreases Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption

Sotagliflozin (Sota) inhibits sodium glucose cotransporter 2 (SGLT2; IC(50)=1.8 nM) and SGLT1 (IC(50)=36 nM). In humans, Sota improves glycemic control in part by increasing urinary glucose excretion via renal SGLT2 inhibition. Sota also lowers postprandial glucose (PPG), likely by inhibiting intestinal SGLT1 to delay the rate of appearance of oral glucose (R(a)O). To test the hypothesis that Sota delays SGLT1-mediated R(a)O, we performed a randomized, 3-period crossover study comparing effects of single doses of placebo (Pbo), Sota (400 mg) and canagliflozin (Cana, 300 mg), an SGLT2 inhibitor (IC(50)=4.2 nM) that inhibits SGLT1 (IC(50)=663 nM) with lower potency than Sota, on R(a)O using a dual-glucose tracer method in two cohorts of 12 healthy subjects each; plasma glucose, insulin and additional pharmacodynamic parameters were also evaluated. All subjects received a continuous [U-(13)C(6)] glucose infusion starting 5 hr before their first mixed meal (MM) test. Cohort 1 subjects had a MM breakfast containing [6,6-(2)H(2)] glucose starting 0.25 hr postdose and a MM lunch containing [1-(2)H(1)] glucose starting 5.25 hr postdose. Cohort 2 subjects had a MM breakfast containing no labeled glucose starting 0.25 hr postdose and a MM lunch containing [6,6-(2)H(2)] glucose starting 4.25 hr postdose. Plasma glucose, and labeled glucose as a fraction of plasma glucose, were measured frequently for 5 hr after any MM containing labeled glucose, while plasma levels of insulin, intestinal hormones and other analytes were measured frequently after any MM containing [6,6-(2)H(2)] glucose. For the Cohort 1 MM breakfast, Sota and Cana: 1) lowered R(a)O AUC[0-1 hr] and R(a)O AUC[0-2 hr], and also lowered AUC[0-4hr] for insulin, c-peptide and gastric inhibitory peptide (GIP), all p<0.05 vs Pbo; 2) showed trends toward lowering PPG AUC[0-4hr] vs Pbo; 3) increased AUC[0-4hr] for total glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), both p<0.05 vs Pbo; and 4) did not alter glucagon AUC[0-4hr] or the AUC[0-5hr] for R(a)O or endogenous glucose production (EGP). Results were similar for the Cohort 2 MM lunch starting 4.25 hr postdose, except: 1) R(a)O, insulin and c-peptide AUC[0-1hr] decreased more for Sota vs Cana, all p<0.05; and 2) Sota and Cana increased glucagon AUC[0-4hr] and EGP AUC[0-5hr], both p<0.05 vs Pbo. For the Cohort 1 MM lunch starting 5.25 hr postdose: 1) Sota lowered R(a)O AUC[0-1hr] vs Cana and Pbo, and lowered PPG AUC[0-5hr] vs Cana and Pbo, both p<0.05; and 2) Cana did not lower R(a)O AUC[0-1hr] or PPG AUC[0-5hr] vs Pbo. We conclude that Sota delayed R(a)O, resulting in lower postprandial levels of glucose and insulin. The mechanism was likely a prolonged local inhibition of intestinal SGLT1 that persisted, despite feeding, during at least the first 5 hours after oral Sota dosing. The Sota-mediated decrease in GIP levels and increases in GLP-1 and PYY levels after oral glucose challenge are consistent with local inhibition of intestinal SGLT1.