New Peroxisome Proliferator-Activated Receptor Agonists: Potential Treatments for Atherogenic Dyslipidemia and Non-Alcoholic Fatty Liver Disease

Expert Opin Pharmacother. 2014 Mar;15(4):493-503. doi: 10.1517/14656566.2014.876992. Epub 2014 Jan 16.

Abstract

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-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ 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.

Publication types

  • Review

MeSH terms

  • Acetates / therapeutic use
  • Animals
  • Atherosclerosis / prevention & control*
  • Chalcones / therapeutic use
  • Cholesterol, HDL / blood
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / metabolism
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Fenofibrate / analogs & derivatives
  • Fenofibrate / therapeutic use
  • Humans
  • Insulin Resistance
  • Lipoproteins, HDL / blood
  • Non-alcoholic Fatty Liver Disease
  • Peroxisome Proliferator-Activated Receptors / agonists*
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Propionates / therapeutic use
  • Quinolines / therapeutic use
  • Sulfonamides / therapeutic use
  • Thiazoles / therapeutic use
  • Triazoles / therapeutic use
  • Triglycerides / blood

Substances

  • (2-methyl-4-(5-methyl-2-(4-trifluoromethyl-phenyl)-2H-(1,2,3)triazol-4-ylmethylsulfanyl)phenoxy)acetic acid
  • 2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid
  • 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoic acid
  • Acetates
  • Chalcones
  • Cholesterol, HDL
  • GW 501516
  • INT 131
  • Lipoproteins, HDL
  • Peroxisome Proliferator-Activated Receptors
  • Propionates
  • Quinolines
  • Sulfonamides
  • Thiazoles
  • Triazoles
  • Triglycerides
  • Fenofibrate