Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan.
Diabetes Obes Metab. 2012 Mar;14(3):271-8. doi: 10.1111/j.1463-1326.2011.01525.x. Epub 2011 Dec 22.
Free fatty acids act as signalling molecules for modulating insulin secretion, and their insulinotropic effects are glucose-dependent and mediated through G protein-coupled receptor 40 (GPR40). This mechanism is a potential target for new treatments for managing diabetes. In this study, we present the first clinical data for TAK-875, a novel highly selective, orally bioavailable GPR40 agonist, in Japanese patients with type 2 diabetes insufficiently controlled by diet or exercise therapy.
This was an exploratory phase II, multicentre, randomized, double-blind, parallel group study comparing the efficacy and tolerability of TAK-875 100 and 400 mg, and placebo, all administered once daily for 2 weeks.
After 2 weeks of treatment, TAK-875 produced marked glucose lowering effects in a 75 g oral glucose tolerance test (OGTT) as evidenced by mean ± SE intergroup differences in plasma glucose AUC(0-3 h) of -12.98 ± 1.48 (p < 0.0001) and -8.12 ± 1.49 mmol·h/l (p < 0.0001), for TAK-875 400 mg vs. placebo and TAK-875 100 mg vs. placebo, respectively, and 2 h plasma glucose [-4.95 ± 0.71 (p < 0.0001) and -3.21 ± 0.71 mmol/l (p < 0.0001), respectively]. This was accompanied by a significant increase in insulin AUC(0-3 h) [34.68 ± 12.16 (p < 0.01) and 31.49 ± 12.20 (p < 0 · 05) µIU·h/ml, respectively]. Improvement in glycaemic profile was mirrored by a significant change in fasting plasma glucose [-2.37 ± 0·27 (p < 0.0001) and -1.88 ± 0.27 mmol/l (p < 0.0001), respectively]. No cases of hypoglycaemia were observed despite the significant reduction in plasma glucose.
These exploratory findings provide evidence of the glucose-dependent insulinotropic potential of the GPR40 agonist TAK-875, and the promising clinical changes support future longer term clinical investigation.
游离脂肪酸可作为调节胰岛素分泌的信号分子，其胰岛素促分泌作用依赖于葡萄糖，并通过 G 蛋白偶联受体 40（GPR40）介导。该机制是管理糖尿病的新型治疗方法的潜在靶点。在这项研究中，我们报告了新型高度选择性、口服生物利用的 GPR40 激动剂 TAK-875 在日本 2 型糖尿病患者中的首个临床数据，这些患者通过饮食或运动疗法治疗血糖控制不佳。
这是一项探索性的 II 期、多中心、随机、双盲、平行组研究，比较了 TAK-875 100mg 和 400mg 与安慰剂每日一次给药 2 周的疗效和耐受性。
经过 2 周的治疗，TAK-875 在 75g 口服葡萄糖耐量试验（OGTT）中产生了显著的降糖作用，TAK-875 400mg 与安慰剂相比，血浆葡萄糖 AUC（0-3h）的组间差异平均值± SE 为-12.98±1.48mmol·l（p＜0.0001），TAK-875 100mg 与安慰剂相比为-8.12±1.49mmol·l（p＜0.0001），并且 2h 时的血浆葡萄糖浓度分别为-4.95±0.71mmol·l（p＜0.0001）和-3.21±0.71mmol·l（p＜0.0001）。这伴随着胰岛素 AUC（0-3h）的显著增加[34.68±12.16μIU·h/ml（p＜0.01）和 31.49±12.20μIU·h/ml（p＜0.05）]。血糖谱的改善与空腹血浆葡萄糖的显著变化相一致[-2.37±0.27mmol·l（p＜0.0001）和-1.88±0.27mmol·l（p＜0.0001）]。尽管血糖显著降低，但未观察到低血糖病例。
这些探索性发现提供了 GPR40 激动剂 TAK-875 具有葡萄糖依赖性胰岛素促分泌作用的证据，并且有希望的临床变化支持未来更长期的临床研究。
