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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).1

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 …