Examining the safety of PPAR agonists - current trends and future prospects

Introduction: The peroxisome proliferator-activated receptor (PPAR)-alpha and -gamma agonists, fibrates and glitazones, are effective treatments for dyslipidemia and type 2 diabetes mellitus, respectively, but exhibit class-related, as well as compound-specific safety characteristics. Areas covered: This article reviews the profiles of PPAR-alpha, PPAR-gamma, and dual PPAR-alpha/gamma agonists with regard to class-related and compound-specific efficacy and adverse effects. We explore how learnings from first-generation drugs are being applied to develop safer PPAR-targeted therapies. Expert opinion: The finding that rosiglitazone may increase risk for cardiovascular events has led to regulatory guidelines requiring demonstration of cardiovascular safety in appropriate outcome trials for new type 2 diabetes mellitus drugs. The emerging data on the possibly increased risk of bladder cancer with pioglitazone may prompt the need for post-approval safety studies for new drugs. Since PPAR-alpha and -gamma affect key cardiometabolic risk factors (diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation) in a complementary fashion, combining their benefits has emerged as a particularly attractive option. New PPAR-targeted therapies that balance the relative potency and/or activity toward PPAR-alpha and -gamma have shown promise in retaining efficacy while reducing potential side effects.