Abstract 1928: Effects of a Selective Inhibitor of Secretory Phospholipase A2 on Low Density and Very Low Density Lipoprotein Subclasses in Stable Coronary Heart Disease Patients
Secretory phospholipase A2 (sPLA2) represents a family of pro-inflammatory enzymes that contribute to the development of atherosclerosis in part through adverse modification of lipoproteins that results in small dense LDL particles (LDL-P). Phospholipase Levels And Serological Markers of Atherosclerosis (PLASMA-II) is a Phase II, randomized, double-blind, placebo-controlled parallel-arm study of two doses of the novel selective sPLA2 inhibitor, 1-H-indole-3-glyoxamide or varespladib methyl (Varespladib, Anthera Pharmaceuticals, San Mateo, CA). 135 stable CHD patients (90% statins) were treated with varespladib 250mg QD, 500mg QD or placebo for 8 weeks. Treatment with varespladib resulted in statistically significant dose-dependent reductions that were different from placebo in: sPLA2 mass (78% vs. +8.3%, p<0.0001); LDL-cholesterol (LDL-C, 8.3% vs. 0.7%, p=0.012) and VLDL-cholesterol (VLDL-C, 9.2% vs. +1.2%, p=0.037) as shown in the table⇓. Compared to baseline, varespladib also reduced LDL-P number (10.0%, p=0.001); small LDL-P number (9.1%, p=0.006); VLDL-P number (12.2%, p=0.012); small VLDL-P number (18.3%, p=0.012) and increased LDL particle size (0.11 ± 0.05 nm, p=0.038). Varespladib 500mg QD reduced LDL-C by 11.3 mg/dL, 14.6 ± 2.4% (p=0.0006), VLDL-P by 13.5% (p=0.022) and small VLDL-P by 24.2% (p=0.030) compared to placebo. Relative to placebo, treatment with varespladib resulted in a significant dose-dependent decreases in sPLA2 mass, LDL-C and VLDL-P while LDL-P and VLDL-C were decreased compared to baseline. The reductions in LDL-C and LDL-P as well as VLDL-C and VLDL-P suggest that varespladib 500mg QD may be an effective anti-atherosclerotic agent.