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

Diabetes Obes Metab. 2012 Mar;14(3):271-8. doi: 10.1111/j.1463-1326.2011.01525.x. Epub 2011 Dec 22.

Abstract

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.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Analysis of Variance
  • Benzofurans / pharmacology*
  • Blood Glucose / drug effects*
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Double-Blind Method
  • Fasting / metabolism
  • Female
  • Glucose Tolerance Test
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Japan / epidemiology
  • Male
  • Middle Aged
  • Receptors, G-Protein-Coupled / agonists*
  • Sulfones / pharmacology*
  • Treatment Outcome

Substances

  • Benzofurans
  • Blood Glucose
  • FFAR1 protein, human
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • Receptors, G-Protein-Coupled
  • Sulfones
  • TAK-875