OBJECTIVE: Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is 
also a low-potency SGLT1 inhibitor. This study tested the hypothesis that 
intestinal canagliflozin levels postdose are sufficiently high to transiently 
inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption.
RESEARCH DESIGN AND METHODS: This two-period, crossover study evaluated effects 
of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a 
dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 
600-kcal mixed-meal tolerance test. Plasma glucose, (3)H-glucose, (14)C-glucose, 
and insulin were measured frequently for 6 h to calculate rates of appearance of 
oral glucose (RaO) in plasma, endogenous glucose production, and glucose 
disposal.
RESULTS: Compared with placebo, canagliflozin treatment reduced postprandial 
plasma glucose and insulin excursions (incremental 0- to 2-h area under the 
curve [AUC0-2h] reductions of 35% and 43%, respectively; P < 0.001 for both), 
increased 0- to 6-h urinary glucose excretion (UGE0-6h, 18.2 ± 5.6 vs. <0.2 g; P 
< 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h 
(geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 
vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that 
total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P 
= 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed 
over the first 2 h, but this difference was not sufficient to explain the 
reduction in RaO. Total glucose disposal over 0 to 6 h was similar across 
groups.
CONCLUSIONS: Canagliflozin reduces postprandial plasma glucose and insulin by 
increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to 
intestinal SGLT1 inhibition.