Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial

Eliot A Brinton; Uma Kher; Sukrut Shah; Christopher P Cannon; Michael Davidson; Antonio M Gotto; Tanya B Ashraf; Christine McCrary Sisk; Hayes Dansky; Yale Mitchel; Philip Barter; DEFINE Investigators

doi:10.1016/j.jacl.2014.10.005

Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial

J Clin Lipidol. 2015 Jan-Feb;9(1):65-71. doi: 10.1016/j.jacl.2014.10.005. Epub 2014 Nov 4.

Authors

Collaborators

DEFINE Investigators:
M Gerstman, L Howes, K Kostner, P Nestel, D Sullivan, H Brath, J Patsch, B Paulweber, H Toplak, C M Constance, E Howlett, D Mymin, L Pliamm, K K Saunders, J-C Tardif, R Tytus, P Aschner, S Keinänen-Klukaanniemi, T Strandberg, M-R Taskinen, G Luc, D Richter, J L Schlienger, Y Zaïr, K-F Appel, M Baar, C Luley, U Overhoff, T Pomykaj, T Schaefer, S T Lau, K L F Lee, K Tan, B Tomlinson, M W Tsang, K Badacsonyi, Á Kalina, N Kanakaridisz, L Márk, É Péterfai, L Regos, I Reiber, J Takács, A Vértes, A Elis, D Gavish, D Harats, O Hussein, T Hayek, E Leitersdorf, A K Bin Abdul Ghapar, K H Chee, S B Ismail, K H Ling, G R L Ramanathan, K H Sim, R Alvarado, M Benavides, G E Cardona, G Gonzalez, J Verdejo, D C G Basart, B P M Imholz, J J C Jonker, P R Nierop, J L Posma, Th B Twickler, E Barrington-Ward, R Cutfield, D H Friedlander, R S Scott, H Istad, G Langslet, G K Skjelvan, S J Campodónico Hoyos, R Coloma Araniya, A Gallegos C, C A Pino Morales, L Watanabe, G P Arutyunov, A B Blokhin, M G Bubnova, S Y Marcevich, C Álvarez Sánchez, L A Álvarez-Sala Walther, B Gil Extremera, F Perez Jimenez, L de Teresa Parreño, C-P Anderberg, U Hedin, A Hellberg, P Höök, T Kjellström, P Nilsson, A G Olsson, U Rosenqvist, K Tolagen, T Wolff, A Baskin, H E Bays, R I Bernstein, N Bittar, E A Brinton, L H K Chee, R A Cottiero, R D D'Agostino, M H Davidson, P S Denker, R K Garcia, R K Hippert, T Isakov, S R Kaster, B Kerzner, E J Klein, M J Koren, M E Kutner, D Liljenquist, D G Lorch Jr, R Lorraine, B C Lubin, N M Lunde, T J Majchrzak, J M McKenney, S Mukherjee, D D Muse, M S Otruba, J E Pappas, K Patrick, S J Powell, E Riffer, L D Rink, J L Rohlf, J B Rosen, P D Rosenbilt, E M Roth, C J Rubenstein, J Rubino, L A Rudolph, A Schneider, W G Short, J C Silverfield, D P Suresh, G A Tarshis, P D Toth, R W Townsend, T O Wahl

Affiliations

¹ Department of Atherometabolic Research, Utah Foundation for Biomedical Research, Utah Lipid Center, Salt Lake City, UT, USA. Electronic address: eliot.brinton@utah.edu.
² Biostatistics, Merck & Co., Inc., Kenilworth, NJ, USA.
³ Clinical Research, Merck & Co., Inc., Kenilworth, NJ, USA.
⁴ Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Radiant Research, Chicago, IL, USA.
⁶ Cardiac Disease Prevention, Weill Cornell Medical College, New York, NY, USA.
⁷ Clinical Operations, Merck & Co., Inc., Kenilworth, NJ, USA.
⁸ Scientific Affairs, Merck & Co., Inc., Kenilworth, NJ, USA.
⁹ Early Discovery, Merck & Co., Inc., Kenilworth, NJ, USA.
¹⁰ Centre for Vascular Research, University of New South Wales, Sydney, Australia.

PMID: 25670362
DOI: 10.1016/j.jacl.2014.10.005

Abstract

Background: In the Determining the Efficacy and Tolerability of cholesteryl ester transfer protein (CETP) INhibition with AnacEtrapib (DEFINE) trial, anacetrapib added to statin produced robust low-density lipoprotein cholesterol (LDL-C)-lowering and high-density lipoprotein cholesterol (HDL-C)-raising vs placebo in patients with coronary heart disease (CHD). Predictors of the degree of LDL-C and HDL-C responses to anacetrapib, however, are poorly understood.

Objective: Lipid effects of anacetrapib in patient subgroups within the DEFINE trial (clinicaltrials.gov: NCT00685776) are reported.

Methods: The percent of placebo-corrected changes from baseline for LDL-C (estimated by Friedewald calculation [Fc-LDL-C]) and HDL-C after 24 weeks of anacetrapib 100 mg/day were compared among patients by age, gender, race, diabetes status, type of concomitant statin with or without other lipid therapies, and baseline HDL-C, Fc-LDL-C, and triglyceride (TG) levels.

Results: Percent decreases in Fc-LDL-C and increases in HDL-C with anacetrapib were similar (magnitude of difference generally <1/5 of the overall treatment effect) across subgroups by age, gender, diabetes status, lipid-modifying regimen, and baseline Fc-LDL-C, HDL-C, or TG. On the other hand, anacetrapib effects on Fc-LDL-C (-24% vs -41%) and HDL-C (+75% vs +139%) appeared to be less in black vs white patients, respectively.

Conclusion: Effects of anacetrapib on Fc-LDL-C and HDL-C were generally comparable across subgroups, including being relatively independent of baseline Fc-LDL-C, HDL-C, or TG levels. The clinical impact of the lipid-modifying effects of anacetrapib is being evaluated in the cardiovascular disease outcomes trial, Randomized EValuation of the Effects of Anacetrapib though Lipid-modification (REVEAL).

Keywords: Anacetrapib; Cholesteryl ester transfer protein inhibitors; High-density lipoproteins; Low-density lipoproteins; Plasma triglycerides.

Publication types

Clinical Trial
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Anticholesteremic Agents / therapeutic use*
Cholesterol Ester Transfer Proteins / antagonists & inhibitors*
Cholesterol Ester Transfer Proteins / metabolism
Cholesterol, HDL / blood
Cholesterol, LDL / blood
Coronary Disease / drug therapy*
Double-Blind Method
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Least-Squares Analysis
Lipids / blood*
Male
Middle Aged
Oxazolidinones / therapeutic use*
Placebo Effect
Treatment Outcome

Substances

Anticholesteremic Agents
CETP protein, human
Cholesterol Ester Transfer Proteins
Cholesterol, HDL
Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lipids
Oxazolidinones
anacetrapib

Associated data

ClinicalTrials.gov/NCT00685776