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

<div><p>Introduction</p><p>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.</p><p>Methods</p><p>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.</p><p>Results</p><p>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.</p><p>Conclusions</p><p>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.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00963768" target="_blank">NCT00963768</a></p></div

Baseline Demographic and Metabolic Characteristics.^*

<p>Baseline Demographic and Metabolic Characteristics.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105638#nt102" target="_blank">*</a>}</p

Mean 24-hour urine volume at baseline (Day –1) and after a single dose (Day 1) and after multiple doses (Day 16).

<p>SD, standard deviation; PBO, placebo; CANA, canagliflozin; QD, once daily; BID, twice daily.</p

Study flow diagram.

<p>PBO, placebo; QD, once daily; CANA, canagliflozin; BID, twice daily. *Safety analysis set.</p

Summary of Changes in Safety Parameters.

<p>Summary of Changes in Safety Parameters.</p

Change in RT_G by total daily dose of canagliflozin (Day 16).

<p>* RT_G, renal threshold for glucose; BID, twice daily. *Data are from Western patients only. ^†Canagliflozin 300 mg BID.</p

Mean change in body weight with daily canagliflozin treatment.

<p>PBO, placebo; CANA, canagliflozin; QD, once daily; BID, twice daily.</p

Change in 24-hour UGE and 24-hour Mean RT_G.^*

<p>Change in 24-hour UGE and 24-hour Mean RT_G.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105638#nt107" target="_blank">*</a>}</p

Relationship between baseline 24-hour mean RT_G and 24-hour mean PG.

<p>(A) Distribution of 24-hour mean RT_G values at baseline and (B) correlation between RT_G and 24-hour mean PG prior to canagliflozin treatment. RT_G, renal threshold for glucose; PG, plasma glucose.</p