Activity Faculty
Niyaz Gosmanov, MD, CDE
Associate Professor of Medicine/Endocrinology
Section of Endocrinology and Diabetes
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma

Article
Polidori D, Sha S, Mudaliar S, et al. 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. Diabetes Care. 2013;36:2154-2161.

Background
The sodium glucose cotransporter (SGLT) 2 is the major transporter responsible for reabsorption of glucose filtered through the renal glomerulus. The related SGLT1 is expressed in the distal segment of the proximal tubule, in the intestinal mucosa of the small intestine, and in other tissues to a lesser extent. Although SGLT1 plays a smaller role in renal glucose absorption than SGLT2, SGLT1 is the primary pathway involved in intestinal glucose and galactose absorption. Canagliflozin and dapagliflozin are FDA approved SGLT2 inhibitors. Canagliflozin is also a low-potency SGLT1 inhibitor. Doses of canagliflozin higher than 200 mg reduce postprandial plasma glucose and insulin concentrations but this effect is short-lived compared to the enhancement of urinary glucose excretion. These findings led to the hypothesis that after dosing and during drug absorption, canagliflozin concentrations in the lumen of the intestinal tract could be sufficiently high to provide transient inhibition of intestinal SGLT1-mediated glucose absorption, thereby lowering postprandial plasma glucose and insulin concentrations.

Research Designs 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 ± 5.6 vs. < 0.2 g; P < 0.001)
  • Delayed RaO
  • Reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001)
  • Reduced AUC RaO by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002)
  • Increased RaO in the period from 2 to 6 h such that total AUC RaO over 0 to 6 h was < 6% lower versus placebo (960 vs. 1018 mg/kg; P = 0.003)

Expert Opinion
The authors analyzed postprandial glucose metabolism with highly sophisticated methods. The results are consistent with a second mechanism of action of canagliflozin: in addition to increasing urinary glucose excretion, canagliflozin decreases the rate of oral glucose appearance in the blood. Although there is a slight delay in gastric emptying, glucose and gut peptide analyses suggest delayed glucose absorption. The findings are consistent with intestinal inhibition of SGLT1 by high lumen concentrations of the drug after oral administration.

Reduction of postprandial insulin concentrations in the canagliflozin group is likely due to decreased plasma glucose; the authors state that the relationship between plasma glucose and the insulin secretion rate was unchanged by canagliflozin treatment. The clinical impact of this mechanism depends on high concentrations of canagliflozin in the intestine. It is interesting to note that in the 0-2 hour period when glucose absorption is inhibited, glucose disposal by the tissues is also diminished from 73 g to 53 g. This may be attributable to lower plasma glucose and insulin levels.

This article increases our understanding of the new class of SGLT2 inhibitors for treatment of type 2 diabetes and also suggests that targeting glucose absorption in the gut (as with the α-glucosidase inhibitors such as acarbose) could be of therapeutic interest.

Abstract Link

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