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 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.

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.