Recent failures in antiatherosclerotic drug development: examples from the thyroxin receptor agonist, the secretory phospholipase A2 antagonist, and the acyl coenzyme A: cholesterol acyltransferase inhibitor programs

To review the published data related to the rise and fall of three different therapeutic approaches, which were investigated to lower cardiovascular disease (CVD) risk. CVD remains a major burden of morbidity and mortality, despite therapeutic interventions. Novel strategies to address this residual risk are eagerly awaited, and a number of novel targets for therapy have been identified. Lipids and lipoproteins have been shown to play an eminent role in atherosclerosis progression, and as such, interventions that influence these biomarkers are crucial in CVD risk prevention. In recent years, however, clinical studies investigating the effect of novel lipid-modifying drugs on cardiovascular risk prevention have not always resulted in the anticipated beneficial outcome. Moreover, the development of therapies directed toward bioactive proteins acting at the crossroads of lipids and inflammation has also been disappointing. In this review, we will specifically address the rationale, design, and results of the clinical trials investigating the effects of three of the failing therapies: the thyroxin receptor agonist, the secretory phospholipase A2 antagonist, and the acyl coenzyme A:cholesterol acyltransferase inhibitor