Kaku Kohei, Watada Hirotaka, Iwamoto Yasuhiko, Utsunomiya Kazunori, Terauchi Yasuo, Tobe Kazuyuki, Tanizawa Yukio, Araki Eiichi, Ueda Masamichi, Suganami Hideki, Watanabe Daisuke
Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan.
Cardiovasc Diabetol. 2014 Mar 28;13:65. doi: 10.1186/1475-2840-13-65.
In recent years, several oral antidiabetic drugs with new mechanisms of action have become available, expanding the number of treatment options. Sodium/glucose cotransporter-2 (SGLT2) inhibitors are a new class of oral antidiabetic drugs with an insulin-independent mechanism promoting urinary glucose excretion. We report the results of a combined Phase 2 and 3 clinical study (Japic CTI-101349) of the SGLT2 inhibitor tofogliflozin (CSG452, RG7201) in Japanese patients with type 2 diabetes mellitus.
The efficacy and safety of tofogliflozin were assessed in this multicenter, placebo-controlled, randomized, double-blind parallel-group study involving 230 patients with type 2 diabetes mellitus with inadequate glycemic control on diet/exercise therapy. Between 30 October 2010 and 28 February 2012, patients at 33 centers were randomized to either placebo (n = 56) or tofogliflozin (10, 20, or 40 mg; n = 58 each) orally, once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at week 24.
Overall, 229 patients were included in the full analysis set (placebo: n = 56; tofogliflozin 10 mg: n = 57; tofogliflozin 20 and 40 mg: n = 58 each). The least squares (LS) mean change (95% confidence interval) from baseline in HbA1c at week 24 was -0.028% (-0.192 to 0.137) in the placebo group, compared with -0.797% (-0.960 to -0.634) in the tofogliflozin 10 mg group, -1.017% (-1.178 to -0.856) in the tofogliflozin 20 mg group, and -0.870% (-1.031 to -0.709) in the tofogliflozin 40 mg group (p < 0.0001 for the LS mean differences in all tofogliflozin groups vs placebo). There were also prominent decreases in fasting blood glucose, 2-h postprandial glucose, and body weight in all tofogliflozin groups compared with the placebo group. The main adverse events were hyperketonemia, ketonuria, and pollakiuria. The incidence of hypoglycemia was low. Furthermore, most adverse events were classified as mild or moderate in severity.
Tofogliflozin 10, 20, or 40 mg administered once daily as monotherapy significantly decreased HbA1c and body weight, and was generally well tolerated in Japanese patients with type 2 diabetes mellitus. Phase 3 studies were recently completed and support the findings of this combined Phase 2 and 3 study.
This study was registered in the JAPIC clinical trials registry (ID: Japic CTI-101349).
近年来，几种具有新作用机制的口服抗糖尿病药物问世，增加了治疗选择。钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂是一类新型口服抗糖尿病药物，其作用机制不依赖胰岛素，可促进尿糖排泄。我们报告了SGLT2抑制剂托格列净（CSG452，RG7201）在日本2型糖尿病患者中进行的2期和3期联合临床研究（Japic CTI-101349）的结果。
在这项多中心、安慰剂对照、随机、双盲平行组研究中，评估了托格列净的疗效和安全性，该研究纳入了230例接受饮食/运动治疗但血糖控制不佳的2型糖尿病患者。在2010年10月30日至2012年2月28日期间，33个中心的患者被随机分为安慰剂组（n = 56）或托格列净组（10、20或40 mg；每组n = 58），口服给药，每日一次，共24周。主要疗效终点是第24周时糖化血红蛋白（HbA1c）相对于基线的变化。
总体而言，229例患者纳入全分析集（安慰剂组：n = 56；托格列净10 mg组：n = 57；托格列净20 mg组和40 mg组：每组n = 58）。第24周时，安慰剂组HbA1c相对于基线的最小二乘（LS）均值变化（及其95%置信区间）为-0.028%（-0.192至0.137），托格列净10 mg组为-0.797%（-0.960至-0.634），托格列净20 mg组为-1.017%（-1.178至-0.856），托格列净40 mg组为-0.870%（-1.031至-0.709）（所有托格列净组与安慰剂组的LS均值差异p < 0.0001）。与安慰剂组相比，所有托格列净组的空腹血糖、餐后2小时血糖和体重也均显著降低。主要不良事件为高酮血症、酮尿症和尿频。低血糖发生率较低。此外，大多数不良事件的严重程度为轻度或中度。
托格列净10、20或40 mg每日一次单药治疗可显著降低HbA1c和体重，在日本2型糖尿病患者中总体耐受性良好。3期研究最近已完成，支持了这项2期和3期联合研究的结果。
本研究已在日本药品和医疗器械综合机构（PMDA）临床试验注册中心注册（注册号：Japic CTI-101349）。
