Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C
Branko Simic1, Pavani Mocharla1, Margot Crucet1
1Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Insights
Cholesteryl ester transfer protein (CETP) inhibitors like anacetrapib and evacetrapib raise HDL-C but do not guarantee vascular protection. Anacetrapib impaired endothelial function, suggesting risks beyond CETP inhibition.
Area of Science:
- Cardiovascular Pharmacology
- Lipid Metabolism Research
- Translational Medicine
Background:
- High-density lipoprotein cholesterol (HDL-C) inversely correlates with cardiovascular disease risk.
- Cholesteryl ester transfer protein (CETP) inhibitors are a novel therapeutic class aimed at increasing HDL-C.
- Understanding the multifaceted effects of CETP inhibition beyond HDL-C elevation is crucial for cardiovascular health.
Purpose of the Study:
- To investigate the impact of CETP inhibitors anacetrapib and evacetrapib on lipid profiles, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function.
- To evaluate the differential effects of anacetrapib and evacetrapib in a mouse model expressing human CETP (E3L.CETP mice).
Main Methods:
- E3L.CETP mice on a high-cholesterol diet were treated with anacetrapib, evacetrapib, or placebo.
- Lipid levels, cholesterol efflux, PON-1 activity, ROS production, and endothelial function (vasorelaxation) were assessed.
- Serum lipoproteins were analyzed using fast-performance liquid chromatography.
Main Results:
- Both anacetrapib and evacetrapib significantly increased HDL-C and reduced triglycerides.
- Anacetrapib, but not evacetrapib, reduced total cholesterol.
- Evacetrapib decreased ROS production, while anacetrapib impaired endothelium-dependent vasorelaxation, unlike evacetrapib.
Conclusions:
- Despite increasing HDL-C, evacetrapib did not improve endothelial function, and anacetrapib impaired it.
- These findings suggest that CETP inhibition may not confer vascular protection and can have detrimental endothelial effects.
- The results highlight potential risks associated with CETP inhibitors, possibly explaining neutral outcomes in large clinical trials.
Background And Aims:
High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function in E3L and E3L.CETP mice.
Methods:
Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L.CETP mice on high cholesterol diet and treated with anacetrapib (3 mg/kg/day), evacetrapib (3 mg/kg/day) or placebo. Cholesterol efflux was assessed ex-vivo in mice treated with CETP inhibitors for 3 weeks on a normal chow diet. Endothelial function was analyzed at week 21 in isolated aortic rings, and serum lipoproteins assessed by fast-performance liquid chromatography.
Results:
Anacetrapib and evacetrapib increased HDL-C levels (5- and 3.4-fold, resp.) and reduced triglycerides (-39% vs. placebo, p = 0.0174). Total cholesterol levels were reduced only in anacetrapib-treated mice (-32%, p = 0.0386). Cholesterol efflux and PON-1 activity (+45% and +35% vs. control, p < 0.005, resp.) were increased, while aortic ROS production was reduced with evacetrapib (-49% vs. control, p = 0.020). Anacetrapib, but not evacetrapib, impaired endothelium dependent vasorelaxation (p < 0.05). In contrast, no such effects were observed in E3L mice for all parameters tested.
Conclusions:
Notwithstanding a marked rise in HDL-C, evacetrapib did not improve endothelial function, while anacetrapib impaired it, suggesting that CETP inhibition does not provide vascular protection. Anacetrapib exerts unfavorable endothelial effects beyond CETP inhibition, which may explain the neutral results of large clinical trials in spite of increased HDL-C.
