Role of CETP Inhibitors in Cardiovascular Risk Reduction: Will Past Failures Lead to Future Success?

The global burden of atherosclerotic cardiovascular disease (ASCVD) is on the rise. Increased levels of low-density lipoprotein cholesterol (LDL-C) are recognized as a primary risk factor for ASCVD, which remains the leading cause of death worldwide. Lipid-lowering therapies play a central role in the prevention of ASCVD. Multiple promising LDL-C"lowering therapies have been developed over the past decade, enforcing the current basis of statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 monoclonal antibodies. However, a significant lipid-driven residual burden of ASCVD remains, particularly following data-driven implementation of more stringent LDL-C guideline goals and especially for patients at high and very high risk for future cardiovascular events. Cholesteryl ester transfer protein (CETP) inhibitors are novel agents that increase serum high-density lipoprotein cholesterol (HDL-C) levels by inhibiting an enzyme that catalyzes the exchange of cholesteryl esters and triglycerides between HDL and LDL. Due to past failures, the development of CETP inhibitors for ASCVD has yet to deliver approved medicines. In this CME expert panel, faculty will review the burden of ASCVD; discuss the rationale for use of additional nonstatin LDL-C"lowering therapies; and summarize the characteristics of CETP inhibitors, their mechanism of action, and reasons for past failures. Finally, the latest clinical evidence for the safety and efficacy of CETP inhibitors as well as plans for future investigation will be addressed.