int-131 and Non-alcoholic-Fatty-Liver-Disease

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease and important unmet medical need. Current guidelines recommend, under specific restrictions, pioglitazone or vitamin E in patients with NASH and significant fibrosis, but the use of both remains off-label. We summarize evidence on medications for the treatment of nonalcoholic steatohepatitis (NASH), since NASH has been mainly associated with higher morbidity and mortality. Some of these medications are currently in phase 3 clinical trials, including obeticholic acid (a farnesoid X receptor agonist), elafibranor (a peroxisome proliferator activated receptor [PPAR]-α/δ dual agonist), cenicriviroc (a CC chemokine receptor antagonist), MSDC-0602 K (a PPAR sparing modulator), selonsertib (an apoptosis signal-regulating kinase-1 inhibitor) and resmetirom (a thyroid hormone receptor agonist). A significant research effort is also targeting PPARs and selective PPAR modulators, including INT131 and pemafibrate, with the expectation that novel drugs may have beneficial effects similar to those of pioglitazone, but without the associated adverse effects. Whether these and other medications could offer tangible therapeutic benefits, alone or in combination, apparently on a background of lifestyle modification, i.e. exercise and a healthy dietary pattern (e.g. Mediterranean diet) remain to be proven. In conclusion, major advances are expected for the treatment of NASH.

Topics: Animals; Clinical Trials, Phase III as Topic; Humans; Non-alcoholic Fatty Liver Disease; PPAR alpha; Quinolines; Sulfonamides

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.. 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).. 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.

Topics: Acetates; Animals; Atherosclerosis; Chalcones; Cholesterol, HDL; Dyslipidemias; Fatty Liver; Fenofibrate; Humans; Insulin Resistance; Lipoproteins, HDL; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Propionates; Quinolines; Sulfonamides; Thiazoles; Triazoles; Triglycerides

Topics: Animals; Biomedical Research; Humans; Hyperlipidemias; Hypoglycemic Agents; Ligands; Lipotropic Agents; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Pioglitazone; PPAR gamma; Quinolines; Sulfonamides; Thiazolidinediones