Introduction: PPARs are nuclear receptors that play key roles in the regulation of metabolism and inflammation. GFT505 is a new dual agonist of the PPARα and PPARδ isoforms, which improves lipid and glucose metabolism in type 2 diabetes mellitus (T2DM) and exerts hepatoprotective effects in mouse models of nonalcoholic fatty liver disease (NAFLD).
Areas covered: This evaluation focuses on the pharmacology and clinical activity of GFT505 in metabolic diseases, including T2DM, dyslipidemia and NAFLD, as well as its promise as a therapeutic option for the treatment of nonalcoholic steatohepatitis. Original publications in English were selected, as well as abstracts of presentations in international congresses. Ongoing clinical trials were identified using the Clinicaltrial.gov database.
Expert opinion: Results from the completed short-term (4 - 8 weeks) Phase IIa studies indicate that GFT505 decreases plasma triglyceride levels and increases high-density lipoprotein-cholesterol, while lowering low-density lipoprotein-cholesterol in prediabetic patients. Hyperinsulinemic-euglycemic clamp studies have also demonstrated an insulin-sensitizing effect of GFT505, with a strong effect on the liver, with a significant lowering effect on plasma liver enzymes. The current safety profile is reassuring, without any signs of PPARγ-related side effects. The combination of its insulin sensitizing and hepatoprotective effects makes GFT505 an excellent drug candidate for NAFLD.
Keywords: PPARα; PPARδ; dyslipidemia; insulin resistance; nonalcoholic steatohepatitis.