No cardiovascular benefit with evacetrapib - is this the end of the road for the 'cetrapibs'?

INTRODUCTION: 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.