Randomized trial of an inhibitor of secretory phospholipase A2 on atherogenic lipoprotein subclasses in statin-treated patients with coronary heart disease.

Abstract

AIMS:

To investigate the effects of secretory phospholipase A2 (sPLA(2)) inhibition on plasma lipoproteins. Secretory phospholipase A2 isoenzymes promote atherosclerosis by mechanisms that include lipoprotein modification, retention, and oxidation.

METHODS AND RESULTS:

Phospholipase Levels And Serological Markers of Atherosclerosis II (PLASMA II) is a Phase II, randomized, double-blind, placebo-controlled parallel-arm study of two once-daily doses of the novel sPLA(2) inhibitor, 1-H-indole-3-glyoxamide or varespladib methyl (Anthera Pharmaceuticals, Hayward, CA, USA). One hundred and thirty-five stable coronary heart disease patients were treated with either varespladib methyl 250 mg once daily, varespladib methyl 500 mg once daily, or placebo for 8 weeks. Varespladib methyl treatment resulted in statistically significant dose-dependent reductions that were different from placebo in sPLA(2) concentration, low-density lipoprotein (LDL) cholesterol, and non-high-density lipoprotein (HDL) cholesterol. When compared with placebo, varespladib methyl 500 mg once daily reduced LDL cholesterol by 15% (P < 0.001), non-HDL cholesterol by 15% (P < 0.001), total very LDL (VLDL) particle concentration by 14% (P = 0.022), and small VLDL particle concentration by 24% (P = 0.030). Relative to baseline, varespladib methyl 500 mg once daily reduced total LDL particle concentration (7%, P = 0.002) and small LDL particle concentration (11%, P = 0.014).

CONCLUSION:

Reductions in atherogenic lipoproteins suggest that varespladib methyl 500 mg once daily may be an effective anti-atherosclerotic agent. Trial registered at ClinicalTrials.gov, identifier: NCT00525954.

• Authors: Robert S Rosenson, Michael Elliott, Yuri Stasiv, Colin Hislop, PLASMA II Investigators
• Journal: European heart journal (Eur Heart J) Vol. 32 Issue 8 Pg. 999-1005 (Apr 2011) ISSN: 1522-9645 [Electronic] England
• PMID: 21081550 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Apolipoproteins B
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Indoles
• Keto Acids
• Triglycerides
• varespladib methyl
• C-Reactive Protein
• Cholesterol
• Phospholipases A2, Secretory

Topics

• Acetates (administration & dosage)
• Aged
• Apolipoproteins B (metabolism)
• C-Reactive Protein (metabolism)
• Cholesterol (metabolism)
• Coronary Disease (blood, drug therapy)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Indoles (administration & dosage)
• Keto Acids
• Male
• Phospholipases A2, Secretory (antagonists & inhibitors)
• Triglycerides (metabolism)