title: Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists.
abstract: Dyslipidemia is a major risk factor for cardiovascular (CV) disease - the primary cause of death, worldwide. Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk, a high level of residual risk persists, especially in people with obesity-related conditions, such as metabolic syndrome and type 2 diabetes mellitus. Peroxisome proliferator-activated receptor alpha- (PPARα-) agonists (e.g. fibrates), play a central role in the reduction of macro- and microvascular risk in these patients. However, the currently available fibrates are weak (PPARα-agonists) with limited efficacy due to dose-related adverse effects. To address this problem, a new generation of highly potent and selective PPARα-modulators (SPPARMα) is being developed that separate the benefits of the PPARα-agonists from their unwanted side effects. Among these, aleglitazar (a dual PPARα/γ agonist) and GFT505 (a dual PPAR α/δ agonist) have recently entered late-phase development. Although both compounds are more potent PPARα-activators than fenofibrate in vitro, only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol (HDL-C) in humans. However, it is also associated with a potential risk of adverse effects. More recently, a highly potent, specific PPARα-agonist (K-877) has emerged with SPPARMα characteristics. Compared to fenofibrate, K-877 has more potent PPARα-activating efficacy in vitro, greater effects on triglycerides- and HDL-C levels in humans, and a reduced risk of adverse effects. If successful, K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes.
authors.affiliation: Fondation coeur et arteres, 96, rue Nationale, 59000, Lille, France. jean-charles.fruchart@fondacoeur.com
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Fruchart
mesh_terms: D001583:Benzoxazoles / Q000627:therapeutic use*; D002087:Butyrates / Q000627:therapeutic use*; D002318:Cardiovascular Diseases; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D050171:Dyslipidemias / Q000188:drug therapy*; D058607:Fibric Acids / Q000627:therapeutic use*; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists; D012307:Risk Factors
chemical_list: D001583:Benzoxazoles; D002087:Butyrates; D058607:Fibric Acids; D000960:Hypolipidemic Agents; C000603947:K-877 compound; D047493:PPAR alpha; D047495:PPAR gamma