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

2012; Lippincott Williams & Wilkins; Volume: 32; Issue: 9 Linguagem: Inglês

10.1161/atvbaha.112.247890

1524-4636

Eric J. Olson, Gregory L. Pearce, Nigel C. Jones, Dennis L. Sprecher,

Metabolism, Diabetes, and Cancer

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.