title: Examining the safety of PPAR agonists - current trends and future prospects.
abstract: BACKGROUND
  The peroxisome proliferator-activated receptor (PPAR)-α and -γ 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.
  
  
  METHODS
  This article reviews the profiles of PPAR-α, PPAR-γ, and dual PPAR-α/γ 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.
  
  
  CONCLUSIONS
  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-α and -γ 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-α and -γ have shown promise in retaining efficacy while reducing potential side effects.
authors.affiliation: Cardiometabolic Franchise Safety Science Leader, F. Hoffmann-La Roche, Ltd, PDS-Safety Risk Management, 663/2028, CH4070 Basel, Switzerland. michele.bortolini@roche.com
authors.forename: Michele
authors.initials: M
authors.lastname: Bortolini
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wright
authors.forename: Martin
authors.initials: M
authors.lastname: Bopst
authors.forename: Bogdana
authors.initials: B
authors.lastname: Balas
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000139:chemically induced; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced
chemical_list: D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047495:PPAR gamma