Selective peroxisome proliferator-activated receptorα modulators (SPPARMα): The next generation of peroxisome proliferator-activated receptor α-agonists

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.