Safety issues and prospects for future generations of PPAR modulators

Area of Science:

• Pharmacology and Drug Development
• Metabolic Disorders Research
• Molecular Biology

Background:

• Peroxisome proliferator-activated receptors (PPARs) regulate glucose, lipid, and inflammation pathways, making them attractive targets for metabolic diseases like diabetes and atherosclerosis.
• Existing PPAR agonists, such as fibrates (PPARα) and thiazolidinediones (PPARγ), demonstrate clinical benefits but have limitations.
• Dual PPARα/γ agonists have been explored for metabolic syndrome, aiming for complementary therapeutic actions.

Purpose of the Study:

• To review preclinical and clinical adverse events associated with PPAR agonists.
• To discuss safety concerns that have led to development failures of PPAR agonists.
• To highlight the importance of selective PPAR modulation for future drug development.

Main Methods:

• Literature review of preclinical and clinical studies on PPAR agonists.
• Analysis of safety data and adverse events reported for various PPAR agonists.
• Evaluation of potential mechanisms underlying PPAR agonist-associated toxicities.

Main Results:

• PPAR agonists, including specific PPARγ and dual PPARα/γ agonists, have faced late-stage development failures due to safety concerns.
• Reported adverse events include potential carcinogenicity, myopathy, fluid retention, and cardiac issues.
• The specific reasons for discontinuation are compound-specific, not always a class effect.

Conclusions:

• Despite therapeutic potential, PPAR agonists present safety challenges that require careful risk assessment.
• Evaluating adverse events necessitates considering the drug's PPAR profile, pharmacokinetics, and mechanism of action.
• Selective modulation of PPAR activity offers a promising strategy to develop safer and effective drugs for metabolic disorders.