MBX-8025, A Novel Peroxisome Proliferator Receptor-δ Agonist: Lipid and Other Metabolic Effects in Dyslipidemic Overweight Patients Treated with and without Atorvastatin

Context: Preclinical and clinical studies suggest that peroxisome proliferator-activated receptor (PPAR)-δ agonists favorably affect multiple metabolic parameters that are otherwise proatherogenic, many that are not optimally managed with statins alone. Objective: The aim of this study was to evaluate the effects of MBX-8025 (a novel PPAR-δ agonist) on lipid and other metabolic parameters associated with increased atherosclerotic risk, administered alone and in combination with atorvastatin. Design and Setting: This was a randomized, double-blind, placebo-controlled, parallel group proof-of-concept study conducted at 30 U.S. research sites. Participants: This study evaluated 181 overweight men and women with mixed dyslipidemia. Intervention(s): Subjects were administered once daily placebo, atorvastatin 20 mg, or MBX-8025 at 50 or 100 mg alone or combined with atorvastatin for 8 wk. Main Outcome Measures: The main efficacy measures included change from baseline in apolipoprotein B-100, lipid levels, high-sensitivity C-reactive protein, and additional metabolic parameters, as well as the effect on the metabolic syndrome and LDL particle size. Results: Compared to placebo, MBX-8025 alone and in combination with atorvastatin significantly (P < 0.05) reduced apolipoprotein B-100 20–38%, LDL 18–43%, triglycerides 26–30%, non-high-density lipoprotein cholesterol 18–41%, free fatty acids 16–28%, and high-sensitivity C-reactive protein 43–72%; it raised high-density lipoprotein cholesterol 1–12% and also reduced the number of patients with the metabolic syndrome and a preponderance of small LDL particles. MBX-8025 was safe and generally well-tolerated. MBX-8025 also reduced liver enzyme levels. Conclusion: MBX-8025, a novel PPAR-δ agonist, favorably affected multiple metabolic parameters with and without atorvastatin. A more complete understanding of MBX-8025 requires a larger future study.