title: 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 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.
  
  
  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.
authors: Janssen Research & Development, LLC, San Diego, California, USA. dpolido1@its.jnj.com
authors: David
authors: D
authors: Polidori
authors: Sue
authors: S
authors: Sha
authors: Sunder
authors: S
authors: Mudaliar
authors: Theodore P
authors: TP
authors: Ciaraldi
authors: Atalanta
authors: A
authors: Ghosh
authors: Nicole
authors: N
authors: Vaccaro
authors: Kristin
authors: K
authors: Farrell
authors: Paul
authors: P
authors: Rothenberg
authors: Robert R
authors: RR
authors: Henry
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics; D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D000068896:Canagliflozin; D018592:Cross-Over Studies; D003864:Depression, Chemical; D005746:Gastric Emptying / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005960:Glucosides / Q000627:therapeutic use*; D006029:Glycosuria / Q000139:chemically induced*; D006801:Humans; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D010919:Placebos; D019518:Postprandial Period; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D005960:Glucosides; D007328:Insulin; D010919:Placebos; C495674:SLC5A1 protein, human; C089180:SLC5A2 protein, human; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin; D000082:Acetaminophen; D005947:Glucose