Canagliflozin, a potent, selective sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes, lowers plasma glucose (PG) by lowering the renal threshold for glucose (RT(G) ) and increasing urinary glucose excretion (UGE). An ascending single oral-dose phase 1 study investigated safety, tolerability and pharmacodynamics of canagliflozin in healthy men (N = 63) randomized to receive canagliflozin (n = 48) or placebo (n = 15). Canagliflozin (10, 30, 100, 200, 400, 600 or 800 mg q.d. or 400 mg b.i.d.) was administered to eight cohorts (six subjects/cohort: canagliflozin; two subjects/cohort: placebo). Dose dependently, canagliflozin decreased calculated 24-h mean RT(G) with maximal reduction to approximately 60 mg/dl, and increased mean 24-h UGE. At doses >200 mg administered before breakfast, canagliflozin reduced postprandial PG and serum insulin excursions at that meal. Canagliflozin was generally well tolerated; most adverse events were mild and no hypoglycaemia was reported. These results support further study of canagliflozin.

OBJECTIVECanagliflozin, 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 METHODSThis 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.RESULTSCompared 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.CONCLUSIONSCanagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition.

Aim: To evaluate the impact of the sodium glucose co-transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. Materials and methods:In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% AE 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/ adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. Results: Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: −0.71% [−1.08; −0.33]) and body weight (−3.4% [−5.4; −1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (−4.6% [−6.4; −2.7]) versus placebo (−2.4% [−4.2; −0.6]; P = 0.09). In patients withnon-alcoholic fatty liver disease (n = 37), the decrease in IHTG was −6.9% (−9.5; −4.2) versus −3.8% (−6.3; −1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05).Conclusions: Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin. K E Y W O R D Sfatty, liver, canagliflozin, insulin resistance, insulin secretion, liver, randomized trial

Context:The stepwise hyperglycemic clamp procedure (SHCP) is the gold standard for measuring the renal threshold for glucose excretion (RTG), but its use is limited to small studies in specialized laboratories.Objective:The objective of the study was to validate a new method for determining RTG using data obtained during a mixed-meal tolerance test (MMTT) in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus (T2DM).Design:This was an open-label study with 2 sequential parts.Setting:The study was performed at a single center in Germany.Patients:Twenty-eight subjects with T2DM were studied.Interventions:No treatment intervention was given in part 1. In part 2, subjects were treated with canagliflozin 100 mg/d for 8 days. In each part, subjects underwent an MMTT and a 5-step SHCP on consecutive days.Main Outcome Measures:For both methods, RTG was estimated using measured blood glucose (BG) and urinary glucose excretion (UGE); estimated glomerular filtration rates were also used to determine RTG during the MMTT. The methods were compared using the concordance correlation coefficient and geometric mean ratios.Results:In untreated and canagliflozin-treated subjects, the relationship between UGE rate and BG was well described by a threshold relationship. Good agreement was obtained between the MMTT-based and SHCP-derived RTG values. The concordance correlation coefficient (for all subjects) was 0.94; geometric mean ratios (90% confidence intervals) for RTG values (MMTT/SHCP) were 0.93 (0.89–0.96) in untreated subjects and 1.03 (0.78–1.37) in canagliflozin-treated subjects. Study procedures and treatments were generally well tolerated in untreated and canagliflozin-treated subjects.Conclusions:In both untreated and canagliflozin-treated subjects with T2DM, RTG can be accurately estimated from measured BG, UGE, and estimated glomerular filtration rates using an MMTT-based method.

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