Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: Results of a randomized, placebo-controlled study

Abstract

OBJECTIVE-Canagliflozin, a sodiumglucose cotransporter (SGLT) 2 inhibitor, is also a lowpotency 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, 3H-glucose, 14C-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±65.6 vs. <0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31%over 0 to 1 h (geometricmeans, 264 vs. 381 mg/kg; <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. © 2013 by the American Diabetes Association.