👤 Sheila A Doggrell

The actions of the cholesteryl ester transfer protein (CETP) inhibitors (torcetrapib, dalcetrapib and evacetrapib) include increasing high-density lipoprotein (HDL) cholesterol, but they do not reduce cardiovascular outcomes in subjects with high cardiovascular risk. Anacetrapib also inhibits CETP, increases HDL cholesterol and lowers low-density lipoprotein (LDL) cholesterol. Areas covered: This evaluation is of the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification) trial, which was a cardiovascular outcomes trial with anacetrapib in subjects with high cardiovascular risk. Consideration is given as to whether increasing HDL cholesterol, lowering LDL cholesterol or other mechanisms/factors underlying the positive outcome with this CETP inhibitor. Expert opinion: After three years, the REVEAL trial with anacetrapib, demonstrated cardiovascular benefits, but not a reduction in coronary artery deaths. The reductions were not significant in years one and two. Thus, in my opinion, the benefits of anacetrapib were not major, and may not apply in 'real' world populations where adherence to medicines is lower than in REVEAL. Also, lowering LDL cholesterol and off-target mechanisms of anacetrapib may have contributed to any beneficial and/or toxic effects. Anacetrapib has a good safety profile. Show less

Increasing high-density lipoprotein(HDL) cholesterol levels predict improved cardiovascular outcomes. However, inhibiting cholesteryl ester transfer protein (CETP) to increase HDL cholesterol, with the 'cetrapibs' (torcetrapib and dalcetrapib), did not improve cardiovascular clinical outcomes. Despite these findings, the clinical outcomes trial with evacetrapib continued. Areas covered: Treatment with evacetrapib increased the levels of HDL by ~130%, and decreased low-density lipoprotein (LDL) cholesterol by ~37%. However, The Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial did not show reduced cardiovascular outcomes with this cetrapib. Evacetrapib may have failed because increasing HDL cholesterol may not be beneficial in the presence of coronary artery disease and/or it is possible that evacetrapib has toxic effects that counter any beneficial effects. Expert opinion: In addition to our understanding of the relationships between CETP, HDL cholesterol and cardiovascular disease being incomplete, recent meta-analysis evidence suggests that increasing HDL cholesterol does not improve cardiovascular outcomes in subjects taking statins, and this may explain the failure of evacetrapib. Also, the preclinical characteristics of the cetrapibs, especially off-target mechanisms, were not explored prior to clinical trial, and may have contributed to the failure of cetrapibs, including evacetrapib. Show less