Evacetrapib provides no benefit on cardiovascular outcomes in high-risk patients
Treatment with the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib does not appear to effectively reduce the rate of cardiovascular events in patients with high-risk vascular disease compared with placebo, although the drug has positive effects on established lipid biomarkers, a study has shown.
The multicentre, randomized phase III trial randomized 12,092 patients to receive either evacetrapib 130 mg or matching placebo, administered daily in addition to standard medical therapy. All patients presented with 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.
First occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina was assessed as the primary efficacy endpoint.
After a median of 26 months of treatment, the primary endpoint occurred in 12.9 percent of patients who received evacetrapib vs 12.8 percent of those who took placebo (hazard ratio, 1.01; 95 percent CI, 0.91 to 1.11; p=0.91). The lack of efficacy led to the early termination of the trial.
Despite the lack of efficacy, a 31.1-percent decrease in the mean low-density lipoprotein (LDL) cholesterol level was seen with evacetrapib vs a 6-percent increase with placebo at 3 months of treatment. Additionally, the mean high-density lipoprotein (HDL) cholesterol level increased by 133.2 percent with evacetrapib vs only by 1.6 percent with placebo.
CETP modulates the transfer of esterified cholesterol from HDL to apolipoprotein B–containing lipoproteins. Previous studies have found that CETP inhibition might potentially induce off-target toxic effects, such as increased blood pressure and increased plasma levels of aldosterone, resulting in higher rates of death and cardiovascular events. [Arterioscler Thromb Vasc Biol 2003;23:160-7; N Engl J Med 2007;357:2109-22]
Evacetrapib is a CETP inhibitor with no evidence the said off-target effects. It substantially raises the HDL cholesterol level, reduces the LDL cholesterol level and enhances cellular cholesterol efflux capacity. The lack of efficacy against cardiovascular events vs placebo in the present trial may be explained by several factors. One is that the beneficial vascular effects of HDL particles, such as cholesterol efflux capacity, may be attenuated in patients who have coronary artery disease or acute coronary syndromes. [Circ Res 2014;114:171-82; Nat Rev Cardiol 2016;13:48-60]
“Alternatively, some clinicians have expressed concern that the inhibition of CETP pathways may produce HDL particles that are dysfunctional, although the protective effects of genetic loss-of-function polymorphisms of CETP do not support this hypothesis,” researchers noted. [Nat Rev Drug Discov 2008;7:143-55]
“The profile of change in HDL lipid particles and the enhancement of cellular cholesterol efflux with evacetrapib suggest that the HDL cholesterol produced by this agent should be functional, but this concept of functionality has yet to be validated as a predictor of therapeutic benefit,” they added. [N Engl J Med 2014;371:2383-93; Lancet Diabetes Endocrinol 2015;3:507-13]