Lipid Effects of Peroxisome Proliferator-Activated Receptor-Δ Agonist GW501516 in Subjects With Low High-Density Lipoprotein Cholesterol: Characteristics of Metabolic Syndrome

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 9; pp. 2289 - 2294
• Main Authors: Olson, Eric J., Pearce, Gregory L., Jones, Nigel P., Sprecher, Dennis L.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2012; Lippincott Williams & Wilkins
• Subjects: Adult; Analysis of Variance; Apolipoprotein A-I - blood; Apolipoproteins B - blood; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Biomarkers - blood; Blood and lymphatic vessels; Blood Glucose - drug effects; Blood Glucose - metabolism; Blood. Blood coagulation. Reticuloendothelial system; Cardiology. Vascular system; Chi-Square Distribution; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Cholesterol, VLDL - blood; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Double-Blind Method; Dyslipidemias - blood; Dyslipidemias - drug therapy; Fatty Acids, Nonesterified - blood; Female; Humans; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - therapeutic use; Insulin - blood; Male; Medical sciences; Metabolic Syndrome - blood; Metabolic Syndrome - drug therapy; Middle Aged; Pharmacology. Drug treatments; PPAR gamma - agonists; PPAR gamma - metabolism; Thiazoles - administration & dosage; Thiazoles - therapeutic use; Time Factors; Treatment Outcome; Triglycerides - blood; Endocrinopathy; Human; Pancreatic hormone; free fatty acid insulin; Lipids; Metabolic diseases; Cardiovascular disease; peroxisome proliferator-activated receptor-δ; Free fatty acid; Lipoprotein; Metabolic syndrome; Insulin; Cholesterol; Peroxisome proliferator; Vascular disease; Atherosclerosis; serum lipids
• ISSN: 1079-5642; 1524-4636; 1524-4636
• DOI: 10.1161/ATVBAHA.112.247890

OBJECTIVE—Peroxisome proliferator-activated receptor-δ–induced upregulation in skeletal muscle fatty acid oxidation would predict the modulation of lipid/lipoproteins. METHODS AND RESULTS—GW501516 (2.5, 5.0, or 10.0 mg) or placebo was given for 12 weeks to patients (n=268) with high-density lipoprotein (HDL) cholesterol <1.16 mmol/L. Fasting lipids/apolipoproteins (apos), insulin, glucose, and free fatty acid were measured; changes from baseline were calculated and assessed. A second smaller exploratory study (n=37) in a similar population was conducted using a sequence of 5 and 10 mg dosing for the assessment of lipoprotein particle concentration. GW501516 demonstrated HDL cholesterol increases up to 16.9% (10 mg) and apoA-I increases up to 6.6%. Reductions were observed in low-density lipoprotein (LDL) cholesterol (−7.3%), triglycerides (−16.9%), apoB (−14.9%), and free fatty acids (−19.4%). The exploratory study showed significant reductions in the concentration of very LDL (−19%), intermediate-density lipoprotein (−52%), and LDL (−14%, predominantly a reduction in small particles), whereas the number of HDL particles increased (+10%; predominantly medium and large HDL). CONCLUSION—GW501516 produced significant changes in HDL cholesterol, LDL cholesterol, apoA1, and apoB. Fewer very LDL and larger LDL support a transition toward less atherogenic lipoprotein profiles. These data are consistent with peroxisome proliferator-activated receptor-δ being a potentially important target for providing cardiovascular protection in metabolic syndrome-like patients.