Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects

John S. Millar, Gissette Reyes-Soffer, Patricia Jumes, Richard L. Dunbar, Emil M. DeGoma, Amanda L. Baer, Wahida Karmally, Daniel S. Donovan, Hashmi Rafeek, Laura Pollan, Junichiro Tohyama, Amy O. Johnson-Levonas, John A. Wagner, Stephen Holleran, Joseph Obunike, Yang Liu, Rajasekhar Ramakrishnan, Michael E. Lassman, David E. Gutstein, Henry N. GinsbergDaniel J. Rader

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

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.

Original languageEnglish
Pages (from-to)2510-2522
Number of pages13
JournalJournal of Clinical Investigation
Volume125
Issue number6
DOIs
StatePublished - 1 Jun 2015
Externally publishedYes

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