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Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes

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. METHODS: Patients (N = 116) discont...

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Autores principales: Sha, Sue, Devineni, Damayanthi, Ghosh, Atalanta, Polidori, David, Hompesch, Marcus, Arnolds, Sabine, Morrow, Linda, Spitzer, Heike, Demarest, Keith, Rothenberg, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148334/
https://www.ncbi.nlm.nih.gov/pubmed/25166023
http://dx.doi.org/10.1371/journal.pone.0105638
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author Sha, Sue
Devineni, Damayanthi
Ghosh, Atalanta
Polidori, David
Hompesch, Marcus
Arnolds, Sabine
Morrow, Linda
Spitzer, Heike
Demarest, Keith
Rothenberg, Paul
author_facet Sha, Sue
Devineni, Damayanthi
Ghosh, Atalanta
Polidori, David
Hompesch, Marcus
Arnolds, Sabine
Morrow, Linda
Spitzer, Heike
Demarest, Keith
Rothenberg, Paul
author_sort Sha, Sue
collection PubMed
description 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. METHODS: Patients (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 (RT(G)) 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. RESULTS: Canagliflozin 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 RT(G), 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 RT(G) 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. CONCLUSIONS: Canagliflozin increased UGE and decreased RT(G), leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00963768
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spelling pubmed-41483342014-08-29 Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes Sha, Sue Devineni, Damayanthi Ghosh, Atalanta Polidori, David Hompesch, Marcus Arnolds, Sabine Morrow, Linda Spitzer, Heike Demarest, Keith Rothenberg, Paul PLoS One Research Article 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. METHODS: Patients (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 (RT(G)) 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. RESULTS: Canagliflozin 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 RT(G), 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 RT(G) 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. CONCLUSIONS: Canagliflozin increased UGE and decreased RT(G), leading to reductions in PG, insulin, and body weight, and was generally well tolerated in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00963768 Public Library of Science 2014-08-28 /pmc/articles/PMC4148334/ /pubmed/25166023 http://dx.doi.org/10.1371/journal.pone.0105638 Text en © 2014 Sha et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sha, Sue
Devineni, Damayanthi
Ghosh, Atalanta
Polidori, David
Hompesch, Marcus
Arnolds, Sabine
Morrow, Linda
Spitzer, Heike
Demarest, Keith
Rothenberg, Paul
Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes
title Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes
title_full Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes
title_fullStr Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes
title_full_unstemmed Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes
title_short Pharmacodynamic Effects of Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, from a Randomized Study in Patients with Type 2 Diabetes
title_sort pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148334/
https://www.ncbi.nlm.nih.gov/pubmed/25166023
http://dx.doi.org/10.1371/journal.pone.0105638
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