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

Kher, Uma; Shah, Sukrut; Cannon, Christopher P.; Gotto, Antonio M.; Ashraf, Tanya B.; Sisk, Christine McCrary; Dansky, Hayes M.; Mitchel, Yale; Barter, Philip J.; Gerstman, M.; Howes, L. G.; Kostner, Karam; Nestel, Paul J.; Sullivan, David; Brath, Helmut; Patsch, J; Paulweber, Bernhard; Toplak, Hermann; Constance, Christian; Howlett, E.; Mymin, David; Pliamm, Lew; Saunders, K.K.; Tardif, Jean‐Claude; Tytus, Richard; Aschner, Pablo; Keinänen-Klukaanniemi, S.; Strandberg, T. E.; Taskinen, Marja‐Riitta; Luc, Gérald; Richter, Dimitri; Schlienger, J.-L.; Zaïr, Yassine; Appel, Karl‐Friedrich; Baar, Michel P. de; Luley, Claus; Overhoff, U.; Pomykaj, T.; Schaefer, Tori L.; Lau, SL; Lee, K.L.F.; Tan, K. C. B.; Tomlinson, Brian; Tsang, Man-Wo; K, Badacsonyi; Kalina, Ákos; Kanakaridisz, N.; Márk, László; Péterfai, É.; Regös, L; Rácz, I; Takács, J.; András, Vértes; Elis, Avishay; Gavish, Dov; Harats, Dror; Hussein, Omnia E.; Hayek, Tony; Leitersdorf, Eran; Ghapar, A.K. Bin Abdul; Chee, Kok Han; Ismail, Soha; Ling, Kah Hiing John; Ramanathan, Gajalakshmi; Sim, Kui-Hian; Alvarado, Ramírez; Benavides, M.; Cardona, G; González, Gabriel Villarrubia; Verdejo, Juan; Basart, D.C.G.; Imholz, B.P.M.; Jonker, J.J.C.; Nierop, P R; Posma, Jan L.; Twickler, Th.B.; Barrington-Ward, Elaine; Cutfield, Richard; Friedlander, D; Scott, Russell S.; Istad, Helge; Langslet, Gisle; Skjelvan, G.K.; Hoyos, S.J. Campodónico; Araniya, R. Coloma; Morales, Clotilde; Watanabe, Lígia Moriguchi; Arutyunov, G. P.; Blokhin, Andrei; Bubnova, M. G; Marcevich, S.Y.; Sánchez, César; Walther, Luis Antonio Álvarez-Sala; Extremera, Blas Gil; Jiménez, Francisco Pérez; Parreño, L. de Teresa; Anderberg, Camilla; Hedin, Ulf; Hellberg, Anders; Hook, Patrick; Kjellström, Thomas; Nilsson, Peter; Olsson, Anders; Rosenqvist, Ulf; Tolagen, Kerstin; Wolff, Tomas; Baskin, Alison S.; Bays, Harold; Bernstein, RalphE; Bittar, Neville; Brinton, Eliot A.; Chee, L.H.K.; Cottiero, R.A.; D'Agostino, Rita; Davidson, Michael; Denker, Paul S.; Garcia, Raymundo; Hippert, R.K.; Isakov, T.; Kaster, Steven Richard; Kerzner, Boris; Klein, E.; Koren, Michael; Kutner, Mark E; Liljenquist, David R.; Lorch, Daniel; Lorraine, Richard S.; Lubin, Barry C.; Lunde, Norman M.; Majchrzak, T.J.; McKenney, James M.; Mukherjee, Swati; Muse, Derek; Otruba, M.S.; Pappas, Jodi; Patrick, Kennerly S.; Powell, Steve; Riffer, Ernie; Rink, Lothar; Rohlf, J.L.; Rosen, Jeffrey B.; Rosenbilt, P.D.; Röth, Erzsébet; Rubenstein, Carl J.; Rubino, Joseph; Rudolph, Laura A.; Schneider, A; Short, W.G.; Silverfield, Joel C.; Suresh, Damodhar P.; Tarshis, Gary A.; Toth, Phillip D.; Townsend, Ray; Wahl, Timothy

doi:10.1016/j.jacl.2014.10.005

Cited by 26 publications

(22 citation statements)

References 21 publications

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“…The phase 3 study of evacetrapib in High-Risk Vascular Disease (ACCELERATE) trial investigating evacetrapib, and the Study of RO4607381 in Stable Coronary Heart Disease Patients with Recent Acute Coronary Syndrome (dal-OUTCOMES) investigating dalcetrapib, were also ended early due to lack of efficacy with respect to clinical cardiovascular outcomes (15,51 ). Newer generations of CETP inhibitors, such as anacetrapib and TA-8995, have demonstrated favorable lipid effects and tolerability in early-stage clinical trials, while investigations into CVD outcomes (e.g., DEFINE and REVEAL trials) remain ongoing (52)(53)(54).…”

Section: The Evolving Role Of Hdl: Rct and Beyondmentioning

confidence: 99%

The Changing Face of HDL and the Best Way to Measure It

Karathanasis¹,

Freeman

Gordon

et al. 2017

Clinical Chemistry

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BACKGROUND: HDL cholesterol (HDL-C) is a commonly used lipid biomarker for assessing cardiovascular health. While a central focus has been placed on the role of HDL in the reverse cholesterol transport (RCT) process, our appreciation for the other cardioprotective properties of HDL continues to expand with further investigation into the structure and function of HDL and its specific subfractions. The development of novel assays is empowering the research community to assess different aspects of HDL function, which at some point may evolve into new diagnostic tests. CONTENT:This review discusses our current understanding of the formation and maturation of HDL particles via RCT, as well as the newly recognized roles of HDL outside RCT. The antioxidative, antiinflammatory, antiapoptotic, antithrombotic, antiinfective, and vasoprotective effects of HDL are all discussed, as are the related methodologies for assessing these different aspects of HDL function. We elaborate on the importance of protein and lipid composition of HDL in health and disease and highlight potential new diagnostic assays based on these parameters.

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Section: The Evolving Role Of Hdl: Rct and Beyondmentioning

confidence: 99%

The Changing Face of HDL and the Best Way to Measure It

Karathanasis¹,

Freeman

Gordon

et al. 2017

Clinical Chemistry

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“…In the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition with AnacEtrapib) trial including 1623 patients with known cardiovascular heart disease or at high risk of CHD, co-administration of anacetrapib 100 mg once daily with a statin for 24 weeks provided an additional 40% reduction in LDL-cholesterol and 138% increase in HDL-cholesterol compared with the statin plus placebo group, 191 irrespective of the patient subgroup. 192 A post hoc analysis found that 2.0% of anacetrapib-and 2.6% of placebo-treated subjects experienced a primary end-point at 76…”

Section: Fibratesmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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“…The percent decreases in Friedewald calculation (Fc)-LDL-C and increases in HDL-C with anacetrapib were similar subgroups by age, gender, diabetes status, lipidmodifying 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 [78]. The clinical impact of the lipid-modifying effects of anacetrapib on CVD outcome (n = 30 624 patients) will be reported in 2017, when the Randomized EValuation of the Effects of Anacetrapib through Lipidmodification (REVEAL) trial will be finished (https:// clinicaltrials.gov/ct2/show/NCT01252953).…”

Section: Hdl-c Remains a Target For Therapy?mentioning

confidence: 83%

“…The patients on anacetrapib had a slight increase of CV events compared to placebo (2 % vs. 0 %, p = 0.1544), but a similar number of adverse events resulting in discontinuation (6 % vs 5 %) [77]. The effects of anacetrapib 100 mg daily vs placebo on plasma lipids at 24 weeks was evaluated in the Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) trial [78]. The percent decreases in Friedewald calculation (Fc)-LDL-C and increases in HDL-C with anacetrapib were similar subgroups by age, gender, diabetes status, lipidmodifying regimen, and baseline Fc-LDL-C, HDL-C, or TG.…”

Section: Hdl-c Remains a Target For Therapy?mentioning

confidence: 99%