ObjectiveCanagliflozin is a sodium glucose co-transporter 2 inhibitor approved for treating patients with type 2 diabetes. This study evaluated renal and non-renal effects of canagliflozin on postprandial plasma glucose (PG) excursion in patients with type 2 diabetes inadequately controlled with metformin. Materials/MethodsPatients (N=37) were randomized to a four-period crossover study with 3-day inpatient stays in each period and 2-week wash-outs between periods. Patients received Treatments (A) placebo/placebo, (B) canagliflozin 300mg/placebo, (C) canagliflozin 300mg/canagliflozin 300mg, or (D) canagliflozin 300mg/canagliflozin 150mg on Day 2/Day 3 in one of four treatment sequences (similar urinary glucose excretion [UGE] expected for Treatments B–D). A mixed-meal tolerance test (MMTT) was given 20minutes post-dose on Day 3 of each period. ResultsA single dose of canagliflozin 300mg reduced both fasting and postprandial PG compared with placebo, with generally similar effects on fasting PG and UGE observed for Treatments B–D. An additional dose of canagliflozin 300mg (Treatment C), but not 150mg (Treatment D), prior to the MMTT on Day 3 provided greater postprandial PG reduction versus placebo (difference in incremental glucose AUC0–2h, −7.5% for B vs A; −18.5% for C vs A; −12.0% [P=0.012] for C vs B), leading to modestly greater reductions in total glucose AUC0–2h with Treatment C versus Treatment B or D. Canagliflozin was generally well tolerated. ConclusionsThese findings suggest that a non-renal mechanism (ie, beyond UGE) contributes to glucose lowering for canagliflozin 300mg, but not 150mg.