Diabetes Obes Metab. 2011 Nov 3. doi: 10.1111/j.1463-1326.2011.01525.x. [Epub ahead of print]
GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes.
Araki T, Hirayama M, Hiroi S, Kaku K.
Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Kawasaki Medical School, Okayama, Japan.
Aim: 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. Methods: 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. Results: After 2 weeks of treatment, TAK-875 produced marked glucose lowering effects in a 75 g oral glucose tolerance test as evidenced by mean±SE intergroup differences in plasma glucose AUC(0-3h) 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 2h 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(0-3h) (34.68±12.16 [p<0.001] and 31.49±12.20 µIU·h/ml [p<0·05], 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. Conclusions: 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. |
