A Mechanistic Study of the Effects of LY518674 on High-Density Lipoprotein Cholesterol (HDL-C) Metabolism
Condition: Metabolic Syndrome X
MeSH terms: Metabolic Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      Agents that increase HDL-C via reverse cholesterol transport could provide a new therapeutic
      option for the prevention of atherosclerotic cardiovascular disease. The investigators
      propose to investigate the effects of LY518674 on components that may likely affect
      atherogenesis in patients with the metabolic syndrome including HDL-C metabolism and reverse
      cholesterol transport pathways, the inflammatory response, and oxidative stress in human
      subjects.

      As an agonist of the nuclear peroxisome proliferator activated receptor (PPAR) alpha,
      LY518674 may affect the transcription of genes that encode various proteins involved in
      atherogenesis. This study will explore the consequences of altered transcription such as
      changes in messenger ribonucleic acid (mRNA) and protein levels as well as protein activity.
    

Detailed description: 
      Study Objectives

      I. Primary Objective:

        -  To determine the effects of LY518674 on the Apo A-I production rate (calculated from the
           fractional synthetic rate and the fractional catabolic rate) in subjects with the
           metabolic syndrome and low HDL-C.

      II. Secondary Objectives:

        -  To determine the effects of LY518674 on markers of reverse cholesterol transport by
           analyzing changes in serum cholesterol efflux capacity (an in vitro cell-based assay).

        -  To determine the effects of LY518674 on the activity of lecithin cholesterol
           acyltransferase (LCAT), cholesterol ester transfer protein (CETP), lipoprotein lipase,
           hepatic lipase, and endothelial lipase.

        -  To determine the effects of LY518674 on plasma lipids, lipid subfractions, free fatty
           acids, and the free fatty acid metabolite, beta-OH butyrate.

        -  To determine the effects of LY518674 on high-density lipoprotein (HDL), low-density
           lipoprotein (LDL) and very low-density lipoprotein (VLDL) particle size using nuclear
           magnetic resonance (NMR).

        -  To determine the effects of LY518674 on Apo A-II and Apo B-100 kinetics.

        -  To determine the effects of LY518674 on hsCRP.

        -  To determine the safety and tolerability of LY518674

      Study Design:

      Study H8D-MC-EMBG is a single site, randomized, placebo-controlled, double-blind, parallel
      study. A minimum of 40 subjects with low HDL cholesterol and metabolic syndrome will be
      randomized to receive double-blind administration of LY518674 100 mcg/day or placebo for 8
      weeks. There is a safety visit every 2 weeks after treatment has been initiated, resulting in
      7 visits over 10 weeks. There are 2 inpatient visits at zero and eight weeks.
    

Intervention name(s): LY518674
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Low HDL; Metabolic syndrome; low HDL Cholesterol in setting of metabolic syndrome