GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes

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 (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 AUC0-3 h [34.68 +/- 12.16 (p < 0.01) and 31.49 +/- 12.20 (p < 0.05) mu vertical bar U.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. 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.