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

• Published in: Diabetes, obesity & metabolism Vol. 17; no. 7; pp. 622 - 629
• Main Authors: Mancini, A. D., Poitout, V.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-07-2015; Wiley Subscription Services, Inc
• Subjects: Agonists; antidiabetic drug; Antidiabetics; Benzofurans - therapeutic use; beta cell; Blood Glucose - drug effects; Clinical trials; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Drug development; Drug therapy; Humans; Hypoglycemic Agents - therapeutic use; Insulin - metabolism; Insulin Secretion; Pharmaceutical industry; pharmacology; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Safety-Based Drug Withdrawals; seven-transmembrane domain receptors; Sulfones - therapeutic use; antidiabetic drug; beta cell; insulin secretion; pharmacology; seven-transmembrane domain receptors
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12442

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.