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GPR40‐induced insulin secretion by the novel agonist TAK‐875: first clinical findings in patients with type 2 diabetes
Author(s) -
Araki T.,
Hirayama M.,
Hiroi S.,
Kaku K.
Publication year - 2012
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2011.01525.x
Subject(s) - free fatty acid receptor 1 , medicine , endocrinology , type 2 diabetes , placebo , tolerability , insulin , agonist , diabetes mellitus , area under the curve , glucose tolerance test , receptor , insulin resistance , adverse effect , alternative medicine , pathology
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.