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

• Published in: The journal of clinical endocrinology and metabolism 2011-09, Vol.96 (9), p.2889-2897
• Main Authors: Bays, Harold E, Schwartz, Sherwyn, Littlejohn, Thomas, Kerzner, Boris, Krauss, Ronald M, Karpf, David B, Choi, Yun-Jung, Wang, Xueyan, Naim, Sue, Roberts, Brian K
• Format: Article
• Language: English
• Subjects: Adult; Aged; Atorvastatin Calcium; Biological and medical sciences; C-Reactive Protein - metabolism; Double-Blind Method; Drug Therapy, Combination; Dyslipidemias - complications; Dyslipidemias - drug therapy; Dyslipidemias - metabolism; Endocrinopathies; Enzymes; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Heptanoic Acids - pharmacology; Heptanoic Acids - therapeutic use; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Lipids; Lipids - blood; Liver; Liver - drug effects; Liver - metabolism; Male; Medical sciences; Middle Aged; Obesity; Overweight - complications; Overweight - drug therapy; Overweight - metabolism; Patients; PPAR delta - agonists; Proteins; Pyrroles - pharmacology; Pyrroles - therapeutic use; Research (statistical design); Self efficacy; Treatment Outcome; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Women
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2011-1061

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.