Abstract 676: HDLc and ApoB-Particle Benefits in Metabolic Syndrome Patients From a Selective PPARdelta Agonist (GW501516): Mechanism Beyond Peripheral Metabolism Alone
A predominant PPARdelta-induced upregulation in skeletal muscle fatty acid oxidation, would predict modulation of lipid/lipoproteins based on associated serum free fatty acid (FFA) levels. Lipid/lipoprotein changes with PPARd have not been investigated in large human cohorts.
Methods: GW501516 or placebo was given for 3 month duration in patients with features of metabolic syndrome (n = 268), identified by low HDLc (< 40mg/dl). Lipids/apolipoproteins and FFA were measured and demographics recorded. Percent change from baseline was calculated for lipid variables and these placed as response variables in analysis of covariance models with dose, age, sex, waist and baseline lipid value as predictors.
Results: In an overall cohort (mean age-46yrs, 86% men, waist 102cm, and baseline HDLc, TG, LDLc: 37 ± ,1, 202 ± 6, 140 ± 2 mg/dL,), GW501516 demonstrated significant increases in HDLc, and ApoA1 and reductions in LDLc, triglycerides, ApoB and FFAs (table⇓). Changes in HDLc, ApoA1 and FFA did not demonstrate a dose relationship (p = 0.20, 0.95, 0.94 respectively), in contrast to LDLc, TG and ApoB which revealed comparable dose dependent effects (p = 0.05, 0.003, 0.008 respectively. Interestingly, HDLc change correlated with change in LDLc (r = 0.25, p < 0.001) and TG changes (r = −.22, p < 0.001), but did not correlate with the apoB change (r = 0.04, p = 0.52).
Conclusions: In the first large cohort administered a PPARd agonist, GW501516 produced significant changes in HDLc, apoAI, LDLc, and apoB, suggesting potential benefit toward vascular disease. Dose-response discordance between FFA and apoB related particles implies more than one PPARd mechanism directing lipoprotein metabolism, perhaps both a central and peripheral effect.