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Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and

Robert S Rosenson1, R Scott Wright, Michael Farkouh

  • 1Department of Cardiometabolic Disorders, Mount Sinai School of Medicine, New York, NY 10029, USA. Robert.rosenson@mssm.edu

American Heart Journal
|November 10, 2012
PubMed

Insights

Dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists show promise for reducing cardiovascular disease (CVD) complications in type 2 diabetes beyond current treatments. Further research into PPARs is crucial for developing new therapeutic molecules.

Area of Science:

  • Endocrinology and Metabolism
  • Cardiovascular Research
  • Pharmacology

Background:

  • Patients with type 2 diabetes mellitus (T2DM) have a higher absolute risk of cardiovascular disease (CVD) events, even with single risk factor modification.
  • Despite multifactorial risk-factor modification, macrovascular and microvascular complications in T2DM remain high, indicating a residual risk.
  • Conventional risk-factor management has limitations in fully mitigating CVD and its complications in diabetic populations.

Purpose of the Study:

  • To explore the potential of dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists in addressing residual CVD risk in T2DM.
  • To differentiate compound-specific versus class-effect properties of PPARs for future drug development.
  • To leverage past experiences with PPAR agonists (thiazolidinediones, glitazars) to inform future challenges and opportunities.

Main Methods:

  • Review of clinical trial data focusing on CVD prevention in T2DM.
  • Analysis of multifactorial risk-factor modification strategies.
  • Examination of the pharmacology and clinical outcomes of PPAR agonists, including dual PPAR α/γ agonists.

Main Results:

  • Dual PPAR α/γ agonists present a potential therapeutic avenue to reduce macrovascular and microvascular complications in T2DM.
  • Understanding PPAR compound-specific versus class-effect properties is key for developing novel therapeutic agents.
  • Previous trials with PPAR agonists offer valuable insights into risk-benefit profiles and regulatory pathways.

Conclusions:

  • Dual PPAR α/γ agonists may offer superior benefits for T2DM complications compared to conventional therapies.
  • Future drug development should focus on the specific properties of PPAR compounds.
  • Lessons learned from thiazolidinediones and glitazars highlight the complexities of nuclear receptor targeting and regulatory approval for T2DM treatments.

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