title: Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and future prospects.
abstract: Clinical trials of cardiovascular disease (CVD) prevention in patients with type 2 diabetes mellitus primarily have been directed at the modification of a single major risk factor; however, in trials that enroll patients with and without diabetes, the absolute risk in CVD events remains higher in patients with diabetes. Efforts to reduce the macrovascular and microvascular residual risk have been directed toward a multifactorial CVD risk-factor modification; nonetheless, long-term complications remain high. Dual-peroxisome proliferator-activated receptor (PPAR) α/γ agonists may offer opportunities to lower macrovascular and microvascular complications of type 2 diabetes mellitus beyond the reductions achieved with conventional risk-factor modification. The information presented elucidates the differentiation of compound-specific vs class-effect properties of PPARs as the basis for future development of a new candidate molecule. Prior experience with thiazolidinediones, an approved class of PPARγ agonists, and glitazars, investigational class of dual-PPARα/γ agonists, also provides important lessons about the risks and benefits of targeting a nuclear receptor while revealing some of the future challenges for regulatory approval.
authors.affiliation: Department of Cardiometabolic Disorders, Mount Sinai School of Medicine, New York, NY 10029, USA. Robert.rosenson@mssm.edu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Rosenson
authors.forename: R Scott
authors.initials: RS
authors.lastname: Wright
authors.forename: Michael
authors.initials: M
authors.lastname: Farkouh
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
mesh_terms: D000476:Alkanesulfonates / Q000494:pharmacology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D008024:Ligands; D010078:Oxazines / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism*; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D010666:Phenylpropionates / Q000494:pharmacology; D010766:Phosphorylation; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000476:Alkanesulfonates; D007004:Hypoglycemic Agents; D008024:Ligands; D010078:Oxazines; D010080:Oxazoles; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D010666:Phenylpropionates; D045162:Thiazolidinediones; D013876:Thiophenes; C542437:aleglitazar; C501413:tesaglitazar; C432703:ragaglitazar; D005998:Glycine; C500085:muraglitazar