Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

Abstract

BACKGROUNDThe cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODSIn a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTSAt 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P = 0.91). CONCLUSIONSAlthough the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998.)

The importance of dyslipidaemia in the pathogenesis of cardiovascular disease in people with diabetes

“…Dalcetrapib had little or no effect on apoB and LDL‐C but increased HDL‐C by about 30% . Evacetrapib reduced LDL by about 30% and raised HDL‐C by about 133% and did not reduce CVD . In contrast anacetrapib which is the largest of these studies enrolling over 30 000 patients and had double the number of events as prior studies with twice the follow‐up and was powered on putative LDL‐C difference rather than HDL‐C raising showed a 8.5% relative reduction in CVD .…”

Trials in “True” Dyslipidemic Patients Are Urged to Reconsider Comprehensive Lipid Management as a Means to Reduce Residual Cardiovascular Risk

“…CETP inhibitors induce a much greater HDL‐C raising effect than nicotinic acid, and early studies focusing on lipid changes in patients with low HDL‐C levels had nurtured great expectation. However, in the cardiovascular outcome trials ILLUMINATE (torcetrapib), DAL‐OUTCOMES (dalcetrapib), and ACCELERATE (evacetrapib), the trapibs performed not better, or even worse, than placebo. The last trapib trial, REVEAL (anacetrapib), showed a meager 9% relative reduction in the risk of events among patients receiving anacetrapib, and the producer decided not to submit applications for regulatory approval.…”

Residual cardiovascular risk among people with diabetes

“…79 Despite a 30% to 40% increase in HDL-C (and no significant changes in LDL-C), there was no difference in major cardiovascular outcomes. 79 More recently, the CETP inhibitor evacetrapib 80 increased HDL-C by 130% and lowered LDL-C by 31% compared to placebo in patients at high risk of CVD, including 68% with diabetes, but did not affect major cardiovascular events. Finally, in patients with established atherosclerotic disease, 37% of whom had diabetes, addition of the CETP inhibitor anacetrapib, increased HDL-C by 104% and reduced non-HDL cholesterol by 18%.…”