The spin stops here: inhibition of lipoprotein-associated phospholipase A2-- a promising target but a negative initial trial?

Current treatment strategies have resulted in significant reductions in morbidity and mortality associated with cardiovascular disease; however, significant residual risk remains. As an example, in the PROVE IT– TIMI 22 trial (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22), 22.4% of patients experienced an adverse event despite achieving a median LDL cholesterol concentration of 62 mg/dL (1.6 mmol/L) (1 ). These and similar findings have led to the search for novel therapeutic modalities. A logical place to start is control of inflammation. Darapladib (GlaxoSmithKline) is a novel oral therapeutic agent with potential antiinflammatory properties that inhibits lipoprotein-associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is produced by macrophages and circulates bound to LDL. In experimental models, it appears to be central in the atherosclerotic process. Lp-PLA2 acts on oxidized phospholipids to produce free oxidized fatty acids and lysophosphatidylcholine, a proatherogenic inflammatory mediator that increases expression of adhesion molecules and cytokines, is a chemoattractant for macrophages, and induces vascular smooth muscle migration (2, 3 ). Immunohistochemical studies have shown that Lp-PLA2 is present in atherosclerotic lesions, and is particularly intense in “rupture-prone lipid laden” lesions with thin-cap fibroatheromas, (4 ). Unlike many other inflammatory mediators, Lp-PLA2 is not an acute-phase reactant (5 ); thus issues associated with acute-phase reactants are averted. For these reasons, Lp-PLA2 has emerged recently as an independent marker of cardiovascular risk and events. Although not all prospective studies have demonstrated an association between high plasma Lp-PLA2 concentrations and poor cardiovascular outcomes, the majority of studies reported are strongly positive. In a recent metaanalysis (6 ) including more than 20 000 patients from 14 epidemiologic studies, high Lp-PLA2 concentration was an independent risk factor for cardiovascular events. This is especially true in regard to the associations with stroke, which seem particularly strong (7, 8 ). These findings have persisted despite multiple iterations of the immunologic assay used with very different analytic characteristics and thus widely disparate absolute values (9 ).