Lipid Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist GW501516 in Subjects With Low High-Density Lipoprotein Cholesterol
Characteristics of Metabolic Syndrome
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.
- Received December 17, 2010.
- Accepted June 28, 2012.
- © 2012 American Heart Association, Inc.