Evacetrapib used as monotherapy and in combination with statins can increase total cholesterol efflux capacity (CEC), adenosine triphosphate-binding cassette transporter A1 (ABCA1)-specific CEC and pre-beta-1 high density lipoprotein cholesterol (HDL-C), according to research published in the Journal of the American College of Cardiology.

“These results reveal the complex effects of potent CETP inhibition on HDL remodeling and function that require more investigation,” the authors wrote. “They also raise the possibility, in light of recent prospective data that inversely linked CEC to incident cardiovascular events, that this increase in CEC might have the potential to reduce cardiovascular risk.”

Cholesteryl ester transfer protein (CETP) inhibitors can HDL-C levels in monotherapy and in combination with statins. CEC from peripheral tissues is essential to the function of HDL particles and the first step of reverse cholesterol transport to the liver for biliary secretion. However, the effects of CETP drugs on CEC are limited.


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Researchers analyzed blood samples from 377 subjects enrolled in a Phase 2 trial of evacetrapib, who had elevated low-density lipoprotein cholesterol (LDL-C) or low HDL-C with triglyceride levels <400 mg/dL.  They recorded percentage changes from baseline to 12 weeks in total, non-ABCA1-specific, and ABCA1-specific CEC.  The HDL subpopulations were evaluated after treatment with either placebo, statin monotherapy, evacetrapib monotherapy (daily doses of 30, 100, or 500 mg), or an evacetrapib with statin combination therapy.

Evacetrapib monotherapy increased dose-dependent total CEC up to 34% at the 500 mg dose (18% at the 30 mg dose), non-ABCA1-specific CEC up to 47% at the 500 mg dose, and ABCA1-specific CEC at both 100 and 500 mg doses (17% overall and up to 26% across the 3 doses).  Evacetrapib 100 mg with statins also increased total, non-ABCA1-specific, and ABCA1-specific CEC (21%, 27%, and 15%, respectively). Evacetrapib monotherapy and evacetrapib combined with statins both increased pre-beta-1 HDL levels compared with placebo.

Of the 3 statins tested in combination with evacetrapib, rosuvastatin and simvastatin also reduced total CEC (–13% and –10%, respectively) and ABCA1-specific CEC (–20% and –19%, respectively), and atorvastatin had no significant effect.

The findings suggest that evacetrapib has effects on HDL function beyond its ability to raise plasma levels in HDL-C. They also suggest that CETP activity may influence CEC and the generation of pre-beta-1 HDL, but the effects of CETP inhibition on HDL remodeling are complex and require additional research. 

“CEC is strongly and inversely associated with prevalent carotid intimal-medial thickness, angiographic coronary artery disease, and prevalent clinical coronary artery disease after adjusting for HDL-C levels. Prospectively, CEC is strongly and inversely associated with incident cardiovascular events after adjusting for HDL-C levels,” the authors noted. “These results have raised the question of whether interventions that increase CEC might favorably affect reduction if cardiovascular events.”

Reference

  1. Nicholls SJ, Ruotolo G, Brewer HB, et al. Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated with Evacetrapib. J Am Coll Cardiol. 2015;66(20):2201-2210. doi: 10.1016/j.jacc.2015.09.013.