Abstract 15652: Comparison of the Novel Peroxisome Proliferator-Activated Receptor Alpha Agonist K-877 and Fenofibrate on High-Density Lipoprotein Subclass Distribution Determined by High-Performance Liquid Chromatography in Patients With Dyslipidemia
Introduction: HDL is a class of structurally and functionally heterogeneous particles. Among the HDL particles, small HDL (HDL3) are more functional than large HDL (HDL2) in reverse cholesterol transport, and the shift in HDL subclasses distribution could be translated to atherosclerosis risk reduction. K-877 is a potent and specific peroxisome proliferator-activated receptor alpha (PPARα) agonist. Here, we hypothesize that K-877 modifies HDL subclasses, which could be translated into atherosclerosis risk reduction.
Methods: A total of 526 patients with fasting hypertriglyceridemia (≥200mg/dL, <1000 mg/dL) and low HDL-C (<50mg/dL for males, <55mg/dL for females) were randomized to 12 weeks treatment with placebo, K-877 0.1, 0.2, 0.4mg/day bid, or fenofibrate 100, 200mg/day qd. HDL subclasses (very large, large, medium (classified as HDL2 by ultracentrifuge, UC), small and very small (classified as HDL3 by UC)) determined by the HPLC method on the basis of lipoprotein particle size (diameter) were compared among the groups.
Results: The dose strength of K-877 inversely associated with the effect to very large, large and medium HDL while fenofibrate showed no such tendency. In contrast, K-877 and fenofibrate increased small and very small HDL dose dependently (small: +28.1% to +40.5% and 26.5% to 38.3%, very small: +17.0% to 28.9% and 21.3% to 25.2% in K-877 and fenofibrate, respectively). Consistent with these results, HDL2 increase was weaker in K-877 higher dose but it was dose dependent in fenofibrate groups. HDL3 increased dose dependently among all groups. In addition, HDL particle size decreased up to -1.1% in K-877 groups and -0.5% in fenofibrate groups. The cholesterol content in HDL was increased, while that of triglyceride in HDL was reduced markedly in K-877 groups compared to fenofibrate groups.
Conclusions: K-877 shifted the HDL composition to smaller and cholesterol-rich particles rather than fenofibrate. These results suggest that K-877 could reduce the atherosclerosis risk by increasing small HDL particles with antiatherogenic functions.
- © 2013 by American Heart Association, Inc.