title: GPR40-induced insulin secretion by the novel agonist TAK-875: first clinical findings in patients with type 2 diabetes.
abstract: OBJECTIVE
  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.
authors: Pharmaceutical Development Division, Takeda Pharmaceutical Company Limited, Osaka, Japan. takahiro.araki@tgrd.com
authors: T
authors: T
authors: Araki
authors: M
authors: M
authors: Hirayama
authors: S
authors: S
authors: Hiroi
authors: K
authors: K
authors: Kaku
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001572:Benzofurans / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology; D004311:Double-Blind Method; D005215:Fasting / Q000378:metabolism; D005260:Female; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013450:Sulfones / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D001572:Benzofurans; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C473034:FFAR1 protein, human; C557331:TAK-875