Lp-PLA(2) Inhibitors for the Reduction of Cardiovascular Events

Evidence suggests that inflammation plays a central role in the pathogenesis of atherosclerosis (Libby, Nature 420:868–874, 2002). Inflammation is a physiologic process with highly regulated and often redundant mechanisms to balance pro-inflammatory and anti-inflammatory responses. The complexity of these networks has made it challenging to identify those specific pathways or key enzymes that contribute directly to atherogenesis and could act as a valuable therapeutic target. Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a member of the phospholipase A(2) family of enzymes and is believed to contribute to atherosclerotic plaque progression and instability by promoting inflammation. A large number of epidemiologic studies have demonstrated that elevated levels of Lp-PLA(2) are associated with an increased risk of cardiovascular events across diverse patient populations, independent of established risk factors including low-density lipoprotein cholesterol. Further, a growing number of preclinical and genetic studies support a causal role for Lp-PLA(2) in atherosclerosis. The development of a novel therapeutic agent that directly inhibits the Lp-PLA(2) enzyme has provided a unique opportunity to directly test the hypothesis that inhibition of this inflammatory enzyme will translate into improved clinical outcomes. In this article, we will review the evidence to support the notion that Lp-PLA(2) is causally implicated in the pathobiology of atherogenesis and discuss the potential utility of inhibiting this enzyme as a therapeutic target.