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.

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.

Trial registration: ClinicalTrials.gov NCT01173549.

Figures

Figure 1

Mean ± SEM concentration-time profiles from predose to 6 h after the standard meal for plasma glucose (A), insulin (B), oral 14C-glucose tracer (C), and infused 3H-glucose tracer (D); rate of oral glucose appearance (E); and glucose absorption as a function of time after the standard meal (F). CANA, canagliflozin.

Figure 2

Effects of canagliflozin (CANA) treatment on UGE rate (A), EGP rate (B), total Rd (C), and tissue Rd (D) over 6 h after the standard meal and on total glucose turnover from 0 to 2 h (E) and 0 to 6 h (F) postmeal. The calculated mean total amount of oral glucose absorption over 0 to 6 h was 79 g with placebo and 75 g with canagliflozin. The mean value in the placebo group is slightly higher than the 75-g oral glucose load that was ingested, giving a calculated bioavailability of glucose that was slightly >100%. This slight overestimation may be due partly to recycling of the 14C glucose tracer through the Cori cycle that could not be accounted for due to limitations of assay sensitivity not allowing accurate detection of the recycled tracer amounts (see research design and methods). Values shown are mean ± SEM in A–D and mean in E and F.

Figure 3

Mean ± SEM plasma concentration-time profiles of GIP (A), PYY (B), total GLP-1 (C), and active GLP-1 (D). CANA, canagliflozin.