Sha Sue, Devineni Damayanthi, Ghosh Atalanta, Polidori David, Hompesch Marcus, Arnolds Sabine, Morrow Linda, Spitzer Heike, Demarest Keith, Rothenberg Paul
PLoS One. 2014 Sep 30;9(9):e110069. doi: 10.1371/journal.pone.0110069. eCollection 2014.
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.
本随机、双盲、安慰剂对照的单剂量和多剂量递增研究评估了钠-葡萄糖协同转运蛋白2抑制剂卡格列净在2型糖尿病患者中的药效学作用以及安全性/耐受性。
患者（N = 116）在随机分组前2周停用抗高血糖药物。患者在美国和德国的2个研究中心接受每日一次30、100、200或400 mg卡格列净或每日两次300 mg卡格列净，或安慰剂治疗，或在韩国的1个研究中心接受每日一次30 mg卡格列净或安慰剂治疗，同时维持等热量饮食2周。在第-1天、第1天和第16天，测量尿葡萄糖排泄量（UGE）、血浆葡萄糖（PG）、空腹血糖（FPG）和胰岛素水平。根据UGE、PG和估算肾小球滤过率计算葡萄糖肾阈值（RTG）。基于不良事件（AE）报告、生命体征、心电图、临床实验室检查和体格检查评估安全性。
卡格列净使UGE呈剂量依赖性增加（卡格列净剂量≥100 mg时，增加量为80 - 120 g/天），且在14天给药期内各剂量下均维持增加。卡格列净使RTG呈剂量依赖性降低，最大降幅至4 - 5 mM（72 - 90 mg/dL）。卡格列净还降低了FPG和24小时平均PG；在第1天即出现血糖降低，并在2周内维持。卡格列净使血浆胰岛素降低与观察到的PG降低一致。卡格列净还减轻了体重。不良事件为一过性，强度为轻至中度，且各治疗组间均衡；1例接受卡格列净治疗的女性报告发生一次阴道念珠菌病。卡格列净未引起低血糖，这与RTG值保持在低血糖阈值以上一致。在第16天，尿量、尿电解质排泄、肾功能或常规实验室检查值无具有临床意义的变化。
卡格列净增加UGE并降低RTG，导致PG、胰岛素和体重降低，在2型糖尿病患者中总体耐受性良好。
ClinicalTrials.gov NCT00963768。
