Potent CETP inhibitor reduces LDL by increasing LDL ApoB clearance

Millar JS, Reyes-Soffer G, Jumes P, et al.,
J Clin Invest.2015. May 11 doi: 10.1172/JCI80025

Background

Cholesteryl ester transfer protein (CETP) promotes bidirectional transfer of cholesteryl esters and triglycerides between and among HDL particles and atherogenic apolipoprotein B (apoB)-containing lipoproteins [1-3]. Mutations causing a CETP deficiency are associated with elevated HDL-c and lower LDL-c [1]. Pharmacologically inhibiting CETP yields higher HDL-c levels in humans and generally reduced LDL-c levels [4-7].
The LDL-lowering mechanism is largely unknown, but an ApoB kinetic study suggested that administration of the CETP-inhibitor torcetrapib may lower LDL ApoB by increasing the fractional catabolic rate (FCR). When torcetrapib was administered with atorvastatin (ATV), LDL ApoB production seemed lower. These observations were, however, not statistically significant [8].
Anacetrapib is a potent and highly selective CETP inhibitor, which is currently in clinical development [9]. Anacetrapib has been shown to yield dose-dependent decreases in LDL-c (up to 40%) and apoB-100 (referred to as ApoB, up to 30%) and increases in HDL-c (up to 139%) [4,10]. Adding anacetrapib to statin treatment yielded further LDL-c reductions and HDL-c increases over 1.5 years of treatment [6].
Although no head-to-head comparison has been done, anacetrapib appears to be more potent at lowering LDL-c than torcetrapib. A sufficiently powered study of the kinetic effects of anacetrapib treatment on ApoB may clarify its mechanism of LDL-c reduction. This study therefore analysed the effect of anacetrapib alone or in combination with ATV on the kinetics of ApoB in VLDL, IDL and LDL, in 39 mildly hypercholesterolaemic subjects. Subjects were randomised to ATV 20mg or placebo for 4 weeks as background treatment, after subjects in both groups received anacetrapib 100 mg for 8 weeks.

Main results

• Following anacetrapib treatment, subjects on a background of ATV showed 18% lower LDL ApoB pool size than with ATV alone (in period 1), which was due to a 18% increase in FCR of LDL-ApoB, without a significant change in production rate (PR) of LDL-APoB.
  Subjects on anacetrapib monotherapy also showed 18% lower LDL-ApoB PS than in period 1, accompanied by increased LDL-apoB FCR and unchanged LDL ApoB PR.
• When comparing an ATV background with placebo, subjects showed 28% and 43% lower apoB PS of VLDL and IDL with anacetrapib. The lower VLDL apoB PS appeared to be explained by an increased FCR of 32%, and unchanged PR of VLDL ApoB, and IDL-APoB FCR was 19% higher and IDL-APoB PR was 26% lower.
• Concentrations or activity of candidate factors known to be associated with ApoB clearance, such as plasma lipoprotein lipase or hepatic lipase, were not significantly altered in response to anacetrapib in either monotherapy or statin-treated subjects.
• Significant increases were seen in plasma lipoproteins known to influence the metabolism of ApoB-containing lipoproteins, namely APoE (25%), ApoC-II (16%) and APoC-III (50%) in statin-treated subjects with vs. without anacetrapib treatment.  
• PCSK9 plasma concentrations were significantly reduced (-19%) after anacetrapib monotherapy, while no change was seen in subjects in response to anacetrapib on a background of statins.
  In subjects on anacetrapib monotherapy, there was a trend towards a higher FCR of PCSK9, but no change in PCKS9 PR, while no such changes were seen in statin-treated subjects.

Conclusion

This kinetic study into the effects of the potent CETP inhibitor anacetrapib showed that it lowered LDL-c levels via increasing the LDL-ApoB fractional catabolic rate, in mildly hyperlipidaemic subjects on background therapy with either statins or placebo. These findings suggest that anacetrapib treatment promotes LDL-ApoB clearance. Several potential underlying mechanisms are considered.

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