CETP-inhibitor improved cholesterol efflux in dyslipidaemic patients
Evacetrapib is a potent and selective inhibitor of CETP, which has been shown to substantially increase HDL-c and apolipoprotein A-I (apoA-I) levels as monotherapy and in combination with statins. A poster of Daniel Rader at the AHA Scientific Sessions showed data of secondary analyses that evaluated the effect of evacetrapib, as monotherapy and in combination with statins, on HDL particle distribution and cholesterol efflux, as measures of HDL function.
Patients with low HDL-c or high LDL-c levels, and with triglycerides < 400 mg/dL were eligible to participate in this study. They were randomised to receive either placebo, evacetrapib monotherapy, statin monotherapy or combination therapy (evacetrapib with either simvastatin, atorvastatin or rosuvastatin).
The ability of HDL to promote cholesterol efflux from macrophages is the most important and best understood of the potentially atheroprotective effects of HDL. Lipid-poor prebeta-1 (preβ-1) HDL particles are known to be primary acceptors of cholesterol from the ATP Binding Cassette transporter A1 pathway (ABCA1) transporter in macrophages. ABCA1-mediated cholesterol efflux is generally correlated with preβ-1 HDL levels.
Statins alone decreased global and ABCA1-mediated cholesterol efflux, while evacetrapib alone or combined with statins significantly increased global cholesterol efflux (28% and 21%, respectively). ABCA1- mediated cholesterol efflux was increased by 17% and 15% respectively, for mono- and combination therapy. Non-ABCA1-mediated cholesterol efflux was 35% and 27% higher after the respective evacetrapib treatments.
Furthermore, this study showed that statins alone decreased preβ-1 HDL levels, without significantly affecting any other HDL subclasses. Evacetrapib alone increased preβ-1, as well as large and very large HDL (α-1 and α-2), without affecting small HDL particles. Combination therapy increased preβ-1, large and very large HDL, and also decreased total and small HDL particles.
Thus, evacetrapib alone or in combination with statins improved cholesterol efflux in patients with dyslipidaemia. Cholesterol efflux is considered the most important atheroprotective function of HDL. Treatment with evacetrapib also affects HDL particle distribution, predominantly of preβ-1, large and very large HDL, suggestive of preserved regeneration of preβ-1 and improved maturation of HDL particles.