CETP Inhibitors: Should We Continue to Pursue This Pathway?

Purpose of Review For more than 20 years there has been considerable interest in the development of pharmacological inhibitors of cholesteryl ester transfer protein (CETP) by virtue of their ability to raise levels of high-density lipoprotein cholesterol. This review endeavors to integrate existing data from prior clinical trials with emerging data to understand whether there is a pathway forward to develop CETP inhibitors to prevent cardiovascular disease. Recent Findings Large clinical trials have proved disappointing with successive reports of a failure to reduce cardiovascular events. The one clinical development program that did demonstrate a reduction in cardiovascular risk found adipose tissue accumulation and did not proceed for regulatory approval. More recent observations suggest that less CETP activity may prevent cardiovascular events, but due to lipid lowering rather than raising high-density lipoprotein cholesterol. In addition, treatment with CETP inhibitors appears to have a beneficial impact on glycemic control in the setting of diabetes. Advances in the field of CETP inhibition suggest a potentially protective effect on the risk of both cardiovascular disease and diabetes. This has implications for how to best design future clinical development programs and leaves the door open to potentially bring CETP inhibitors to the preventive cardiology clinic.

Automated summary

Pharmacological inhibitors of CETP have attracted considerable interest for their ability to raise high-density lipoprotein cholesterol levels. However, recent large clinical trials have shown disappointing results in reducing cardiovascular events. Observations suggest that lower CETP activity may be beneficial in preventing cardiovascular events, but through lipid lowering rather than raising high-density lipoprotein cholesterol. In addition, CETP inhibitors may have a positive impact on glycemic control in diabetes. Advances in CETP inhibition suggest a potential protective effect on the risk of cardiovascular disease and diabetes, leaving room for future clinical development programs to explore.