Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes.

Sue Sha,Marcus Hompesch,Heike Spitzer,Atalanta Ghosh,Keith Demarest,Sabine Arnolds,Paul Rothenberg,David Polidori,Linda Morrow,Damayanthi Devineni,Noel Christopher Barengo

doi:10.1371/journal.pone.0105638

Abstract

IntroductionThis randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes.MethodsPatients (N = 116) discontinued their antihyperglycemic medications 2 weeks before randomization. Patients received canagliflozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily, or placebo at 2 study centers in the United States and Germany, or canagliflozin 30 mg once daily or placebo at 1 study center in Korea, while maintaining an isocaloric diet for 2 weeks. On Days –1, 1, and 16, urinary glucose excretion (UGE), plasma glucose (PG), fasting PG (FPG), and insulin were measured. The renal threshold for glucose (RTG) was calculated from UGE, PG, and estimated glomerular filtration rate. Safety was evaluated based on adverse event (AE) reports, vital signs, electrocardiograms, clinical laboratory tests, and physical examinations.ResultsCanagliflozin increased UGE dose-dependently (∼80–120 g/day with canagliflozin ≥100 mg), with increases maintained over the 14-day dosing period with each dose. Canagliflozin dose-dependently decreased RTG, with maximal reductions to ∼4–5 mM (72–90 mg/dL). Canagliflozin also reduced FPG and 24-hour mean PG; glucose reductions were seen on Day 1 and maintained over 2 weeks. Plasma insulin reductions with canagliflozin were consistent with observed PG reductions. Canagliflozin also reduced body weight. AEs were transient, mild to moderate in intensity, and balanced across groups; 1 canagliflozin-treated female reported an episode of vaginal candidiasis. Canagliflozin did not cause hypoglycemia, consistent with the RTG values remaining above the hypoglycemia threshold. At Day 16, there were no clinically meaningful changes in urine volume, urine electrolyte excretion, renal function, or routine laboratory test values.ConclusionsCanagliflozin increased UGE and decreased RTG, leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes.Trial RegistrationClinicalTrials.gov NCT00963768

Highlights

This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes
The majority of renal glucose reabsorption is mediated by the sodium glucose co-transporter 2 (SGLT2), which is a highcapacity, low-affinity glucose co-transporter expressed in the S1 segment of the proximal tubule [2,3]
The SGLT1 and SGLT2 transporters are able to reabsorb virtually all filtered glucose until the filtered load exceeds the capacity of the transporters; the plasma glucose (PG) concentration at which this occurs is designated as the renal threshold for glucose (RTG) [2,4,5]

Summary

Introduction

This randomized, double-blind, placebo-controlled, single and multiple ascending-dose study evaluated the pharmacodynamic effects and safety/tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes. The majority of renal glucose reabsorption is mediated by the sodium glucose co-transporter 2 (SGLT2), which is a highcapacity, low-affinity glucose co-transporter expressed in the S1 segment of the proximal tubule [2,3]. SGLT1, a low-capacity, high-affinity glucose co-transporter expressed in the S2 and S3 segments of the proximal tubule, is involved in renal glucose reabsorption, but to a lesser extent than SGLT2 [2,3]. Reducing renal glucose reabsorption via SGLT2 inhibition is a new approach to treating patients with type 2 diabetes [6]. Canagliflozin lowers PG by lowering RTG and reducing renal glucose reabsorption, leading to increased urinary glucose excretion (UGE) [17,18,19]. The increased UGE with SGLT2 inhibition is associated with a mild osmotic diuresis and a loss of calories leading to body weight reduction

Objectives

Methods

Results

Conclusion