GPR40 agonists for the treatment of type 2 diabetes: life after 'TAKing' a hit

Diabetes Obes Metab. 2015 Jul;17(7):622-9. doi: 10.1111/dom.12442. Epub 2015 Feb 24.


The free fatty acid receptor GPR40 has been proposed as a potential target for type 2 diabetes (T2D) pharmacotherapy. This idea has been validated in both preclinical and clinical studies, in which activation of GPR40 was shown to improve glycaemic control by stimulating glucose-dependent insulin secretion; however, the recent termination of phase III clinical trials using the GPR40 agonist TAK-875 (fasiglifam) has raised important questions regarding the long-term safety and viability of targeting GPR40 and, more specifically, about our understanding of this receptor's basic biology. In the present review, we provide a summary of established and novel concepts related to GPR40's pharmacobiology and discuss the current status and future outlook for GPR40-based drug development for the treatment of T2D.

Keywords: antidiabetic drug; beta cell; insulin secretion; pharmacology; seven-transmembrane domain receptors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Benzofurans / therapeutic use*
  • Blood Glucose / drug effects
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / metabolism
  • Insulin Secretion
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Safety-Based Drug Withdrawals
  • Sulfones / therapeutic use*


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