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  • Title: Lipid effects of peroxisome proliferator-activated receptor-δ agonist GW501516 in subjects with low high-density lipoprotein cholesterol: characteristics of metabolic syndrome.
    Author: Olson EJ, Pearce GL, Jones NP, Sprecher DL.
    Journal: Arterioscler Thromb Vasc Biol; 2012 Sep; 32(9):2289-94. PubMed ID: 22814748.
    Abstract:
    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). CONCLUSIONS: 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.
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