Dataset Information

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

ABSTRACT:

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 (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.

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 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.

Conclusions

Canagliflozin 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 registration

ClinicalTrials.gov NCT00963768.

SUBMITTER: Sha S

PROVIDER: S-EPMC4148334 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

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

Sha Sue S Devineni Damayanthi D Ghosh Atalanta A Polidori David D Hompesch Marcus M Arnolds Sabine S Morrow Linda L Spitzer Heike H Demarest Keith K Rothenberg Paul P

PloS one 20140828 8

<h4>Introduction</h4>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.<h4>Methods</h4>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 cen ...[more]

PMID: 25166023

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Project description: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.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 (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.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 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.Canagliflozin 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.ClinicalTrials.gov NCT00963768.

Project description:BackgroundPhysiologic determinants, such as pulse pressure [difference between systolic blood pressure (SBP) and diastolic BP (DBP)], mean arterial pressure (2/3 DBP + 1/3 SBP), and double product [beats per minute (bpm) × SBP], are linked to cardiovascular outcomes. The effects of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on pulse pressure, mean arterial pressure, and double product were assessed in patients with type 2 diabetes mellitus (T2DM).MethodsThis post hoc analysis was based on pooled data from four 26-week, randomized, double-blind, placebo-controlled studies evaluating canagliflozin in patients with T2DM (N = 2313) and a 6-week, randomized, double-blind, placebo-controlled, ambulatory BP monitoring (ABPM) study evaluating canagliflozin in patients with T2DM and hypertension (N = 169). Changes from baseline in SBP, DBP, pulse pressure, mean arterial pressure, and double product were assessed using seated BP measurements (pooled studies) or averaged 24-h BP assessments (ABPM study). Safety was assessed based on adverse event reports.ResultsIn the pooled studies, canagliflozin 100 and 300 mg reduced SBP (-4.3 and -5.0 vs -0.3 mmHg) and DBP (-2.5 and -2.4 vs -0.6 mmHg) versus placebo at week 26. Reductions in pulse pressure (-1.8 and -2.6 vs 0.2 mmHg), mean arterial pressure (-3.1 and -3.3 vs -0.5 mmHg), and double product (-381 and -416 vs -30 bpm × mmHg) were also seen with canagliflozin 100 and 300 mg versus placebo. In the ABPM study, canagliflozin 100 and 300 mg reduced mean 24-h SBP (-4.5 and -6.2 vs -1.2 mmHg) and DBP (-2.2 and -3.2 vs -0.3 mmHg) versus placebo at week 6. Canagliflozin 300 mg provided reductions in pulse pressure (-3.3 vs -0.8 mmHg) and mean arterial pressure (-4.2 vs -0.6 mmHg) compared with placebo, while canagliflozin 100 mg had more modest effects on these parameters. Canagliflozin was generally well tolerated in both study populations.ConclusionsCanagliflozin improved all three cardiovascular physiologic markers, consistent with the hypothesis that canagliflozin may have beneficial effects on some cardiovascular outcomes in patients with T2DM. Trial registration ClinicalTrials.gov Identifier: NCT01081834 (registered March 2010); NCT01106677 (registered April 2010); NCT01106625 (registered April 2010); NCT01106690 (registered April 2010); NCT01939496 (registered September 2013).

Dataset Information

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

Introduction

Methods

Results

Conclusions

Trial registration

Publications

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

Similar Datasets

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