New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease

Introduction: Novel peroxisome proliferator-activated receptor (PPAR) modulators (selective PPAR modulators [SPPARMs])) and dual PPAR agonists may have an important role in the treatment of cardiometabolic disorders owing to lipid-modifying, insulin-sensitizing and anti-inflammatory effects. Areas covered: This review summarizes the efficacy of new PPAR agonists and SPPARMs that are under development for the treatment of atherogenic dyslipidemia and non-alcoholic fatty liver disease (NAFLD). Expert opinion: ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-alpha with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-gamma with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-alpha/gamma agonists (glitazars) and the SPPARM-delta GW501516 has been abandoned because of safety issues, another SPPARM-delta (MBX-8025) and a dual PPAR-alpha/delta agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.