GPR119 激动剂 DS-8500a 在日本 2 型糖尿病患者中的疗效和安全性：一项随机、双盲、安慰剂对照、12 周研究。
Efficacy and Safety of GPR119 Agonist DS-8500a in Japanese Patients with Type 2 Diabetes: a Randomized, Double-Blind, Placebo-Controlled, 12-Week Study.
机构信息
Department of Endocrinology, Diabetes and Geriatric Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
出版信息
Adv Ther. 2018 Mar;35(3):367-381. doi: 10.1007/s12325-018-0668-2. Epub 2018 Feb 27.
INTRODUCTION
G protein-coupled receptor 119 (GPR119) is a promising target for the treatment of type 2 diabetes mellitus (T2DM), as both insulin and glucagon-like peptide-1 secretion can be promoted with a single drug. We compared the efficacy and safety of the GPR119 agonist DS-8500a with placebo and sitagliptin 50 mg in Japanese patients with T2DM.
METHODS
This randomized, double-blind, parallel-group comparison study was conducted in Japan (trial registration NCT02628392, JapicCTI-153068). Eligible patients aged ≥ 20 years with T2DM and hemoglobin A1c (HbA1c) ≥ 7.0% and < 10.0% were randomized to receive placebo, DS-8500a (25, 50, or 75 mg), or sitagliptin 50 mg once daily for 12 weeks. The primary efficacy endpoint was change in HbA1c from baseline to week 12. Secondary endpoints included change in fasting plasma glucose (FPG), glucose AUC during a meal tolerance test, 2-hour postprandial glucose (2hr-PPG), and changes in lipid parameters (total, low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) cholesterol, and triglycerides) at week 12. Safety endpoints included adverse events, hypoglycemia, and clinical/laboratory variables.
RESULTS
DS-8500a demonstrated dose-dependent HbA1c lowering compared with placebo at week 12: change from baseline - 0.23% (p = 0.0173), - 0.37% (p = 0.0001), and - 0.44% (p < 0.0001) in the 25-mg, 50-mg, and 75-mg groups, respectively. At 50- and 75-mg doses, DS-8500a significantly lowered FPG, glucose AUC, and 2hr-PPG compared with placebo. The glucose-lowering effect was maintained up to 12 weeks. DS-8500a did not lower any of the above parameters to a greater extent than sitagliptin. Compared with placebo and sitagliptin, DS-8500a 50 and 75 mg significantly reduced total cholesterol, LDL-cholesterol, and triglycerides, and significantly increased HDL-cholesterol. All DS-8500a doses were well tolerated. Two cases of clinically relevant drug-related hypoglycemia occurred in the DS-8500a 50-mg group.
CONCLUSION
DS-8500a was well tolerated and demonstrated significant glucose-lowering effects and favorable changes in lipid profiles up to 12 weeks in Japanese patients with T2DM.
FUNDING
Daiichi Sankyo Co. Ltd.
简介
G 蛋白偶联受体 119（GPR119）是治疗 2 型糖尿病（T2DM）的有前途的靶点，因为单一药物可以促进胰岛素和胰高血糖素样肽-1 的分泌。我们比较了 GPR119 激动剂 DS-8500a 与安慰剂和西他列汀 50mg 在日本 T2DM 患者中的疗效和安全性。
方法
这是一项在日本进行的随机、双盲、平行组比较研究（试验注册 NCT02628392，JapicCTI-153068）。年龄≥20 岁、糖化血红蛋白（HbA1c）≥7.0%且<10.0%的 T2DM 患者符合入组标准，随机接受安慰剂、DS-8500a（25、50 或 75mg）或西他列汀 50mg 每日 1 次治疗 12 周。主要疗效终点为治疗 12 周时 HbA1c 自基线的变化。次要终点包括空腹血糖（FPG）、餐耐量试验期间血糖 AUC、餐后 2 小时血糖（2hr-PPG）以及治疗 12 周时血脂参数（总胆固醇、低密度脂蛋白（LDL-）和高密度脂蛋白（HDL-）胆固醇以及甘油三酯）的变化。安全性终点包括不良事件、低血糖和临床/实验室变量。
结果
与安慰剂相比，DS-8500a 在第 12 周时表现出剂量依赖性的 HbA1c 降低：25mg、50mg 和 75mg 组分别降低-0.23%（p=0.0173）、-0.37%（p=0.0001）和-0.44%（p<0.0001）。在 50mg 和 75mg 剂量下，DS-8500a 可显著降低 FPG、血糖 AUC 和 2hr-PPG，与安慰剂相比。降糖作用持续至 12 周。与安慰剂和西他列汀相比，DS-8500a 50mg 和 75mg 并未使任何上述参数的降低程度大于西他列汀。与安慰剂和西他列汀相比，DS-8500a 50mg 和 75mg 可显著降低总胆固醇、LDL-胆固醇和甘油三酯，显著升高 HDL-胆固醇。所有 DS-8500a 剂量均具有良好的耐受性。DS-8500a 50mg 组有两例与药物相关的临床相关低血糖事件。
结论
DS-8500a 在日本 T2DM 患者中耐受性良好，可显著降低血糖，并在 12 周内改善血脂谱。
资金来源
第一三共株式会社。
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