Anacetrapib
Anacetrapib lowers LDL-ApoB by accelerating its clearance, not by slowing its production (J Clin Invest 2015)
Original title: Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects
Mildly hypercholesterolemic subjects were randomized to background placebo (n equals 10) or atorvastatin 20 mg (n equals 29) for 4 weeks before all subjects added anacetrapib 100 mg for 8 weeks (NCT00990808), with metabolic kinetic studies after each period measuring LDL-ApoB-100 and PCSK9 production rate and fractional catabolic rate. Anacetrapib markedly reduced LDL-ApoB-100 pool size in both the placebo and atorvastatin groups, driven by substantial increases in LDL-ApoB-100 fractional catabolic rate in both, with no effect on LDL-ApoB-100 production rate in either group. PCSK9 pool size, fractional catabolic rate, and production rate were all unchanged in both groups, while anacetrapib treatment considerably raised the LDL triglyceride-to-cholesterol ratio and LDL particle size by NMR, indicating anacetrapib lowers LDL-ApoB-100, alone or with a statin, by accelerating ApoB-100 clearance rather than reducing its production.
Original abstract
Background: Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib.
Methods: We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR).
Results: Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR.
Conclusion: These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance.
Trial Registration: ClinicalTrials.gov NCT00990808.
Funding: Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.