Despite a reduction in cardiovascular risk conferred by
therapies that modify circulating
lipids, a need remains for novel treatments to further decrease the occurrence of complications of atherosclerotic
cardiovascular diseases.
Lipoprotein-associated phospholipase-A(2) is an important regulator of lipid metabolism and
inflammation that circulates with
lipoprotein particles and is carried into the arterial wall with
low-density lipoprotein particles during the progression of
atherosclerosis. Within the vessel wall,
lipoprotein-associated phospholipase-A(2) releases small molecules that stimulate macrophage recruitment and evolution to foam cells, leading to plaque vulnerability. Epidemiologic studies demonstrate that elevated circulating levels of
lipoprotein-associated phospholipase-A(2) predict an increased risk of
myocardial infarction and
stroke, whereas histologic examination of diseased human coronary arteries reveals intense presence of the
enzyme in
atherosclerotic plaques that are prone to
rupture. These considerations suggest
lipoprotein-associated phospholipase-A(2) as a promising therapeutic target, and a specific inhibitor,
darapladib, has been under development for this application. This review summarizes the completed preclinical and early phase clinical studies that underlie two recently commenced phase III clinical trials that will investigate the efficacy and safety of
darapladib in nearly 13,000 individuals with
coronary heart disease. When completed, these trials should provide important insights into the utility of
darapladib to reduce
myocardial infarction,
stroke and cardiovascular death.