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Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans.
Arterioscler Thromb Vasc Biol. 2006 Jun; 26(6):1350-6.AT

Abstract

OBJECTIVE

Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins.

METHODS AND RESULTS

Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production.

CONCLUSIONS

These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.

Authors+Show Affiliations

Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. jsmillar@mail.med.upenn.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Controlled Clinical Trial
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16574893

Citation

Millar, John S., et al. "Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib On Apolipoprotein B100 Metabolism in Humans." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 6, 2006, pp. 1350-6.
Millar JS, Brousseau ME, Diffenderfer MR, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans. Arterioscler Thromb Vasc Biol. 2006;26(6):1350-6.
Millar, J. S., Brousseau, M. E., Diffenderfer, M. R., Barrett, P. H., Welty, F. K., Faruqi, A., Wolfe, M. L., Nartsupha, C., Digenio, A. G., Mancuso, J. P., Dolnikowski, G. G., Schaefer, E. J., & Rader, D. J. (2006). Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans. Arteriosclerosis, Thrombosis, and Vascular Biology, 26(6), 1350-6.
Millar JS, et al. Effects of the Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib On Apolipoprotein B100 Metabolism in Humans. Arterioscler Thromb Vasc Biol. 2006;26(6):1350-6. PubMed PMID: 16574893.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans. AU - Millar,John S, AU - Brousseau,Margaret E, AU - Diffenderfer,Margaret R, AU - Barrett,P Hugh R, AU - Welty,Francine K, AU - Faruqi,Aisha, AU - Wolfe,Megan L, AU - Nartsupha,Chorthip, AU - Digenio,Andres G, AU - Mancuso,James P, AU - Dolnikowski,Gregory G, AU - Schaefer,Ernst J, AU - Rader,Daniel J, Y1 - 2006/03/30/ PY - 2006/4/1/pubmed PY - 2006/6/17/medline PY - 2006/4/1/entrez SP - 1350 EP - 6 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 26 IS - 6 N2 - OBJECTIVE: Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins. METHODS AND RESULTS: Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production. CONCLUSIONS: These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/16574893/Effects_of_the_cholesteryl_ester_transfer_protein_inhibitor_torcetrapib_on_apolipoprotein_B100_metabolism_in_humans_ L2 - https://www.ahajournals.org/doi/10.1161/01.ATV.0000219695.84644.56?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -