Anti-NASH agents must be at least neutral with respect to extrahepatic end-organ disease and outcomes. PPARs are promising therapeutic options since:
- PPARs regulate metabolism, inflammation and fibrosis, all of which determine NASH progression.
- Both PPARα-β/δ dual agonism as well as PPARγ agonism have shown beneficial effects on liver histology in phase IIb clinical trials for NASH.
- Single, dual and pan-PPAR agonists are under development for the pharmacological treatment of NASH
In light of current knowledge of the various functions of PPARs, it can be speculated that activation of PPARα, PPARβ/δ and PPARγ may be an effective therapeutic approach to prevent the development and progression of NASH through a combination of metabolic, anti-inflammatory and antifibrotic effects, thereby addressing a large spectrum of parameters involved in the disease along its continuum.
Given the hypoglycaemic, hypocholesterolaemic, antifibrotic, anti-inflammatory and vascular effects of PPARs, the use of agents that activate all three PPAR isoforms, so-called pan-PPAR agonists, is expected to lead to greater improvement in efficacy compared with targeting a single or dual PPAR isoform and may bring an innovative and efficacious therapeutic approach to prevent the development and progression of NASH, providing that side effects such as oedema, weight gain, bone fractures and cardiotoxicity observed with more selective PPAR agonists are absent or limited.
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PPAR agonists currently or previously investigated for the treatment of NASH
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