Background
 TAK-875, a selective G-protein-coupled receptor 40 (GPR40) agonist, improves glucose tolerance hyperglycemia. However, TAK-875 was withdrawn from phase 3 clinical trials due to drug-induced liver injury (DILI). They asuured the cause of DILI by TAK-875 was to change the homeostasis of bile acid. 
AIM
 We should consider whether DILI by TAK-875 is assosiated with GPR40. The hepatotoxicity of TAK-875 is not a class effect of the GPR40 agonist, and HD-6277 is safety.
Material and methods
 In this study, HD-6277 (a novel selective GPR40 agonist) was evaluated DILI with TAK-875 in vitro/vivo study. HD-6277 was assessed phospholipidosis in HepG2 cell. We examined the inhibitory effects on hepatobiliary transporters to explore the mechanisms underlying its hepatotoxicity. To evaluate the potential liver toxicity of HD-6277 and TAK-875 administered to Beagle dogs once daily orally by capsule in Beagle Dogs for a period of 2-weeks. And ALT levels were investigated in diet-induced obesity rats induced by ethanol-induced liver injury, following each drug’s administration for 2 weeks. 
Results
 HD-6277 was not induced phospholipidosis in HepG2 cell by 100 uM, but TAK-875 was. In hepatobiliary transporter inhibitory assay, HD-6277 showed safer value in influx and efflux transporters (NTCP; Na+/taurocholate cotransporting polypeptide, OATPs; organic anion transporter polypeptides, BSEP; human bile salt export pump, MRP2; multidrug resistance-associated protein 2) than TAK-875. TAK-875 induced liver changes consisting of multifocal bile duct proliferation(hyperplasia/hypertrophy). Moreover, in alcoholic fatty liver model, TAK-875 enhanced ALT level. 
Conclusion
 These findings suggest that HD-6277 and TAK-875 showed different inhibitory effects on hepatobiliary transporters. Probably, HD-6277 may be less effects to DILI than TAK-875. It was reported that TAK-875 induced liver toxicity may not related to a class effect of the GPR40 agonist.

HD-6277 is a selective GPR40 agonist with no drug-induced liver injury compare with Fasiglifam