Introduction: In addition to inhibiting sodium-glucose cotransporter 2 (SGLT2), canagliflozin is also an inhibitor of SGLT1, which plays a role in intestinal glucose absorption. This study was designed to investigate the effects of a single dose of canagliflozin on intestinal glucose absorption.
Methods: This crossover study compared the effects of placebo and canagliflozin 300 mg given 20 min before a mean (600-kcal mixed-meal tolerance test) in 20 healthy subjects. Glucose and insulin levels were measured over 6 hours to determine the rates of oral glucose appearance in plasma, endogenous glucose production, and glucose disposal.
Results: Postprandial plasma glucose and insulin excursions (incremental 0- to 2-hour area under the curve from baseline to 2 hours) were reduced by 35% and 43% with canagliflozin, respectively (P<0.001 for both versus placebo). Canagliflozin also increased the urinary glucose excretion from baseline to 6 hours (18.2 g vs <0.2 g with placebo; P<0.001). While canagliflozin delayed the rate of oral glucose appearance in plasma, the rate at 6 hours was only approximately 6% lower with canagliflozin vs placebo (P=0.003).
Conclusion: Canagliflozin reduced postprandial plasma glucose excursions via two mechanisms: 1) increased urinary glucose excretion due to renal SGLT2 inhibition; and 2) delayed absorption of ingested glucose, likely due to intestinal SGLT1 inhibition. Canagliflozin conferred a minimal (<6%) decrease in oral glucose appearance in plasma compared with placebo, suggesting that the effects of canagliflozin do not result from glucose malabsorption.
Commentary by J. Michael Gonzalez-Campoy MD, PhD, FACE
The predominant effect of SGLT2 inhibitors is on the proximal renal tubules. Inhibition of SGLT2 prevents glucose reabsorption from the tubular lumen and results in the excretion of filtered glucose into the urine. This mechanism of action leads to a drop in plasma glucose concentrations that is sustained over time.
Canagliflozin is also a weak inhibitor of SGLT1. In other tissues that contribute to glucose homeostasis, including the small intestine, the action of SGLT1 is predominant. Therefore, establishing the intestinal effects of canagliflozin on glucose homeostasis is an important contribution to our knowledge of this medication.
In this study, Polidori et al document that the rate of appearance of radio-labeled glucose into the circulation is significantly decreased in the immediate postprandial period by oral canagliflozin, compared to placebo. Although modest in nature compared to the renal effect, this effect of canagliflozin on the gut (ie, blunting post-prandial glucose peaks) adds to its therapeutic effect for people with diabetes.
In this study, plasma concentrations of gut peptides—including glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY)—were measured to help assess the gut’s handling of glucose. Two-hour postprandial GIP was reduced by 50%, total GLP-1 increased 35%, and PYY increased 60%, with canagliflozin as compared to placebo. These gut peptide concentration changes are consistent with delayed intestinal glucose absorption.
Canagliflozin was well tolerated and no patients discontinued the medication due to adverse events. In addition, no subjects reported symptoms suggestive of glucose malabsorption or gastrointestinal adverse effects.
Thus, the benefits of canagliflozin extend from just a renal action to a broader enterohormonal effect.