Abstract 681: Treatment With A Potent & Selective PPAR-α Agonist LY518674 Significantly Increases ApoA-I and ApoA-II Production Rates In Patients With Metabolic Syndrome Despite No Change In HDL
Introduction: Patients with low HDL cholesterol (HDL-C) levels are at increased risk of atherosclerosis. Treatment with fibric acid derivatives, which activate PPAR-α, increases HDL-C levels. LY518674, a potent PPAR-β agonist, has been shown to significantly increase HDL-C and apoA-I levels in human apoA-I transgenic mice.
Hypothesis: We tested the hypothesis that treatment with LY518674 would raise HDL-C levels in humans by increasing the apoA-I production rate.
Methods: Patients with low HDL-C levels and metabolic syndrome (MetSyn) were recruited for participation. Patients were randomized to receive either placebo or LY518674 (100 ug) once daily for 8 weeks. All patients underwent a kinetic study using a primed constant infusion of [D3]-leucine to measure protein production and fractional catabolic rates (FCR) at baseline and following treatment.
Results: Patients treated with LY518674 (n= 13) significantly reduced total cholesterol (−6%, p = .005) and triglyceride (−23%, p = .002) levels as compared to patients treated with placebo (n = 15). There was no significant change in HDL-C or plasma apoA-I levels in response to LY518674 treatment while apoA-II levels increased by 25%. Despite the lack of change in HDL-C there was a significant increase in the apoA-I and apoA-II production rates (31% and 73%, p < .0001 for both) in response to LY518674. This was accompanied by a significant increase in the apoA-I and apoA-II FCRs (33% and 27%, p = .002 for both), resulting no net change in the apoA-I levels but a significant increase in apoA-II levels.
Conclusions: Treatment with LY518674 significantly increased the apoA-I, and to a greater extent, the apoA-II production rates in subjects with MetSyn and low HDL-C. This was accompanied by increased clearance resulting in no net change in apoA-I or HDL-C levels in plasma. Increased turnover of HDL in response to LY518674 may lead to enhanced cholesterol transport from peripheral tissues to liver.