Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects
John S. Millar, … , Henry N. Ginsberg, Daniel J. Rader
John S. Millar, … , Henry N. Ginsberg, Daniel J. Rader
Published June 1, 2015; First published May 11, 2015
Citation Information: J Clin Invest. 2015;125(6):2510-2522. https://doi.org/10.1172/JCI80025.
View: Text | PDF | Corrigendum
Clinical Medicine Cardiology Therapeutics Vascular biology

Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects

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).

Authors

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. Ginsberg, Daniel J. Rader

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

ICMJE disclosure forms - Download (609.59 KB)

Advertisement