Dalcetrapib and anacetrapib differently impact HDL structure and function in rabbits and monkeys

Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P < 0.01). The levels of α- and preβ-HDL were reduced by 16% (P < 0.001) and 69% (P < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment. Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% (P < 0.01). The levels of α- and preβ-HDL were reduced by 16% (P < 0.001) and 69% (P < 0.01), resulting in a decrease of the serum cholesterol efflux capacity. CETPis modulate the plasma levels of mature and small HDL in vivo and consequently the cholesterol efflux capacity. The opposite effects of dalcetrapib in different species indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment. HDL cholesterol (HDL-C) levels are inversely correlated with cardiovascular disease (1Gordon T. Castelli W.P. Hjortland M.C. Kannel W.B. Dawber T.R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study.Am. J. Med. 1977; 62: 707-714Abstract Full Text PDF PubMed Scopus (4089) Google Scholar). This protective effect could be, at least in part, associated with the ability of HDL to remove cholesterol from peripheral tissues through a process called cholesterol efflux, the first step of reverse cholesterol transport (RCT) (2Khera A.V. Cuchel M. de la Llera-Moya M. Rodrigues A. Burke M.F. Jafri K. French B.C. Phillips J.A. Mucksavage M.L. Wilensky R.L. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.N. Engl. J. Med. 2011; 364: 127-135Crossref PubMed Scopus (1540) Google Scholar). In light of these concepts, a variety of therapeutic strategies to modify HDL have been tested in clinical settings. Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein with a molecular mass of 74 kDa, which is secreted primarily by the liver in primates (3Tall A.R. Plasma cholesteryl ester transfer protein.J. Lipid Res. 1993; 34: 1255-1274Abstract Full Text PDF PubMed Google Scholar) and in rabbits (4McPherson R. Lau P. Kussie P. Barrett H. Tall A.R. Plasma kinetics of cholesteryl ester transfer protein in the rabbit. Effects of dietary cholesterol.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 203-210Crossref PubMed Scopus (22) Google Scholar). In vitro CETP activity reduces the HDL-C level by facilitating the transfer of cholesteryl esters (CEs) from HDL to apoB-containing lipoproteins (heterotypic transfer) (3Tall A.R. Plasma cholesteryl ester transfer protein.J. Lipid Res. 1993; 34: 1255-1274Abstract Full Text PDF PubMed Google Scholar, 5Hesler C.B. Swenson T.L. Tall A.R. Purification and characterization of a human plasma cholesteryl ester transfer protein.J. Biol. Chem. 1987; 262: 2275-2282Abstract Full Text PDF PubMed Google Scholar). Accordingly, numerous studies have demonstrated that CETP inhibition increases HDL-C and generates larger mature HDL particles (6Sugano M. Makino N. Sawada S. Otsuka S. Watanabe M. Okamoto H. Kamada M. Mizushima A. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits.J. Biol. Chem. 1998; 273: 5033-5036Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 7Rittershaus C.W. Miller D.P. Thomas L.J. Picard M.D. Honan C.M. Emmett C.D. Pettey C.L. Adari H. Hammond R.A. Beattie D.T. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2106-2112Crossref PubMed Scopus (304) Google Scholar, 8Zhang B. Fan P. Shimoji E. Xu H. Takeuchi K. Bian C. Saku K. Inhibition of cholesteryl ester transfer protein activity by JTT-705 increases apolipoprotein E-containing high-density lipoprotein and favorably affects the function and enzyme composition of high-density lipoprotein in rabbits.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 1910-1915Crossref PubMed Scopus (53) Google Scholar, 9Okamoto H. Yonemori F. Wakitani K. Minowa T. Maeda K. Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.Nature. 2000; 406: 203-207Crossref PubMed Scopus (509) Google Scholar, 10Huang Z. Inazu A. Nohara A. Higashikata T. Mabuchi H. Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia.Clin. Sci. (Lond.). 2002; 103: 587-594Crossref PubMed Scopus (108) Google Scholar). Despite the recent disappointing clinical results obtained with the CETP inhibitors (CETPis) (11Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2609) Google Scholar, 12Schwartz G.G. Olsson A.G. Abt M. Ballantyne C.M. Barter P.J. Brumm J. Chaitman B.R. Holme I.M. Kallend D. Leiter L.A. dal-OUTCOMES Investigators Effects of dalcetrapib in patients with a recent acute coronary syndrome.N. Engl. J. Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1559) Google Scholar, 13.Eli Lilly and Company. 2015. Lilly to discontinue development of evacetrapib for high-risk atherosclerotic cardiovascular disease. October 2015. at anacetrapib and dalcetrapib J.C. E. J.C. S. A. D. of the cardiovascular effects of PubMed Scopus Google Scholar, K. studies as a for PubMed Scopus Google Scholar, J.C. D. M. R. S. M. S. J.C. effects of dalcetrapib on cholesterol efflux and with clinical PubMed Scopus Google Scholar) are being tested in clinical outcome In the effects of dalcetrapib on cardiovascular outcome have been to vary greatly in different J.C. E. J.C. S. A. D. of the cardiovascular effects of PubMed Scopus Google Scholar, J.C. D. M. R. S. M. S. J.C. effects of dalcetrapib on cholesterol efflux and with clinical PubMed Scopus Google Scholar). This the of the impact of dalcetrapib in species that could and in the of the effects of dalcetrapib in the human a of the in vivo effects of CETP activity on lipoprotein structure and function is HDL by CETP been in the of small preβ-HDL C.M. apolipoprotein lipoproteins of and Lipid Res. Full Text PDF PubMed Google Scholar, Barter P.J. and metabolism of apolipoprotein Thromb. Vasc. Biol. 2004; 24: PubMed Scopus Google Scholar). particles are to produced by transfer of are produced HDL transfer) L. Barter P.J. in the density distribution of high density lipoproteins in of cholesterol transfer Full Text PDF PubMed Scopus Google Scholar). small particles are in cholesterol efflux M. T. of and of the efflux of cholesterol and 1993; PubMed Scopus Google Scholar) that cholesterol and to D.P. is the apolipoprotein that cholesterol from Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, N. P. Tall A.R. of cholesterol efflux, and plasma in Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The in vitro inhibition of CETP activity by torcetrapib and anacetrapib is associated with inhibition of preβ-HDL dalcetrapib C. N. Okamoto H. E. H. E. D. cholesteryl ester transfer protein activity and increases reverse cholesterol Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). However, in vivo studies demonstrated that anacetrapib increased preβ-HDL levels in dalcetrapib impact on preβ-HDL levels in E. J. H. In vivo effects of anacetrapib on in HDL effects on cholesterol Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar) and M. Kallend D. R. J. M. Holme Investigators The effect of cholesteryl ester transfer protein inhibition on and of HDL function acute coronary the J. PubMed Scopus Google Scholar). was demonstrated that of anacetrapib to human CETP increased HDL-C and in dalcetrapib reduced HDL-C, the of these CETPis in a model that the could by the of of anacetrapib generates a CETP and HDL, dalcetrapib the of a which is in its This CETP activity by the of the human protein H. Yonemori F. Wakitani K. Minowa T. Maeda K. Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits.Nature. 2000; 406: 203-207Crossref PubMed Scopus (509) Google Scholar, C. A. E. C. P. for a of CETP in HDL and cholesterol of of PubMed Scopus (22) Google Scholar). and L. Cholesteryl ester transfer from different species have Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrated that a that reduces rabbit CETP increases and human CETP activity in demonstrated that the human and CETP activity transfer in the of with and are the two of CETP is results that CETP could HDL-C and preβ-HDL on the of and the species The study was to the in vivo impact of dalcetrapib and anacetrapib on HDL subclass distribution in New Zealand White rabbits and vervet monkeys, two species with a high CETP activity level K. A. The plasma high density lipoprotein cholesterol levels and cholesteryl ester transfer protein activity in species of 24: PubMed Scopus Google Scholar) that in opposite to a in and monkeys were to dalcetrapib and anacetrapib and the cholesterol associated to the different lipoprotein and by the distribution HDL by and and the ability of serum to cholesterol efflux. that dalcetrapib and anacetrapib increased HDL-C and in large and small HDL in rabbits, and that these effects were associated with increased cholesterol efflux capacity. In similar results were with anacetrapib in vervet monkeys, dalcetrapib reduced HDL-C associated to and cholesterol efflux that effects on CETP are species The and were obtained from the was from and dalcetrapib was produced and by New Zealand White rabbits were first for of as of from from and from the rabbits were according to HDL-C to as to of dalcetrapib of of anacetrapib of and were the studies to were obtained from and on from for Plasma cholesterol HDL-C, cholesterol and levels were with rabbit were by the and of the monkeys called vervet monkeys, were obtained from a and in the of the according to the for the and of for and the The was at a of and a of were a of human with cholesterol from from and from cholesterol as in M. D. J.J. P. D. for effect and in vervet 1987; Full Text PDF PubMed Scopus Google for for to the of that was increased by to and was associated with anacetrapib was for two of at and by of anacetrapib in were a the of the a of to to to dalcetrapib was at for two of at a and by a of on the was the of the were by at and at the of the of the of and were the HDL-C and LDL-C were clinical The plasma of was mass that the of dalcetrapib in K. F. M. A. E. J. T. T. of dalcetrapib by mass 2012; PubMed Scopus Google Scholar). Plasma serum obtained from rabbits monkeys was at and of CETP mass in plasma was by as for rabbit and The antibodies were and to of these antibodies were by F. CETP activity was by vivo CETP activity New C. A. E. C. P. for a of CETP in HDL and cholesterol of of PubMed Scopus (22) Google Scholar). the were by plasma with the to a of at for CETP activity was in rabbits and monkeys transfer as C. N. Okamoto H. E. H. E. D. cholesteryl ester transfer protein activity and increases reverse cholesterol Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). of < < was with and with plasma from in the of and for at the apoB-containing lipoprotein was by for at in the and HDL were by CETP activity was as the mass of to the The of with was and by and by vervet plasma was by a as in for lipoprotein Lipid Res. 1998; Full Text Full Text PDF PubMed Google Scholar). The cholesterol of was with a The was by a of the by L. of plasma of 1993; PubMed Scopus Google Scholar). were on a and at for at in a and lipoproteins were to a at for at in a the was and was with by F. by on was to the preβ-HDL level in was by a against human by The to preβ-HDL was by with human were from rabbit plasma with the plasma was to and with a density of were by a with were a of and of cholesterol of apolipoprotein Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). and were in with were in The was with and were in at and were a with were and for to the were in for for at of human were the to were with for for at with to efflux was in the of rabbit serum for vervet plasma for of HDL for The serum was obtained by of in to of were for at and at for at the of the the was and were and were for in a The of efflux was by the in the in the of cholesterol from the in the of and by the of the in the the was by the are as were for rabbit vervet were with the level of CETP first the activity of CETP in the plasma of and in dalcetrapib and anacetrapib reduced rabbit CETP activity by 42% (P < impact of CETP activity was with a on the and anacetrapib caused of CETP activity of and that the was by the lipoprotein levels of the In vervet monkeys, anacetrapib reduced CETP activity by and (P < 0.001) at and dalcetrapib decrease CETP activity the impact of on the levels of circulating CETP mass was in of rabbits In vervet monkeys, CETP mass was increased by dalcetrapib at < and of anacetrapib raised by and (P < the and to were in monkeys. Plasma of the of dalcetrapib were a a of and of and In rabbits, in plasma was of dalcetrapib at The of was in for was in monkeys and the results demonstrated that anacetrapib plasma and of and of anacetrapib, that monkeys were to of with effects on CETP activity and the impact of CETPis on plasma levels The results in that HDL-C levels were increased by (P < and (P < in and rabbits, HDL-C levels were associated with of < < CETPis impact on The level was increased in the rabbit anacetrapib < 0.01). Accordingly, CETPis to rabbits increased in to HDL in was In vervet monkeys, with dalcetrapib in a decrease in HDL-C from and < at and with a in LDL-C from < at and in HDL-C and increases in which were by that dalcetrapib the cholesterol transfer from HDL to in vervet monkeys. In anacetrapib in HDL-C from and < at and and a decrease in LDL-C < < at and these results because cholesterol levels were increased in HDL and reduced in by anacetrapib levels were by of on New Zealand White rabbit < < < < < were for with a dalcetrapib anacetrapib and were are as the of < < in a of on vervet < < < < < < < < were a dalcetrapib anacetrapib and were and are as the of < < < in a of dalcetrapib and anacetrapib on were with dalcetrapib and anacetrapib were by and were obtained in are as of were for with a dalcetrapib anacetrapib and were are as the of were a dalcetrapib anacetrapib and were and are as the of the distribution of rabbit in HDL by was in large α-migrating HDL of that of the rabbit was associated to small α-migrating was in the of the level of in the impact of on distribution in HDL by that dalcetrapib and anacetrapib increased associated with HDL < < in This was in large < < and small < < α-migrating HDL was to and preβ-HDL of vervet monkeys. obtained by of plasma from and monkeys are in the in the α- and and of the vervet of plasma from monkeys of preβ-HDL < and < at and and and < at and levels with In although anacetrapib increases of preβ-HDL and and and at and the effects of CETPis on the HDL capacity of plasma from rabbits and vervet monkeys. were for at and was to and small rabbit HDL that of plasma effect on the level of small HDL in However, the level of small HDL was reduced by (P < and (P < in plasma from with dalcetrapib and anacetrapib, In monkeys, results that the level of preβ-HDL was in plasma at However, of plasma from monkeys increased preβ-HDL levels and < at and as with plasma with that plasma increased HDL capacity. In preβ-HDL at was by the of anacetrapib the of distribution by CETPis impact on cholesterol efflux by HDL, tested the capacity of serum to cholesterol from that cholesterol efflux by serum from rabbits with dalcetrapib anacetrapib increased by (P < and cholesterol efflux from was increased by (P < and (P < with these Cholesterol efflux was with HDL from rabbits with CETPis in and the results that dalcetrapib and anacetrapib increased cholesterol efflux by 48% (P < 0.001) and (P < 0.01), vervet monkeys, cholesterol efflux capacity was with to to cholesterol efflux by plasma was by dalcetrapib in monkeys, decreased by (P < with monkeys a and < at and results that the opposite of HDL-C level by dalcetrapib and anacetrapib is associated with opposite in cholesterol efflux. although efflux by plasma was decreased by (P < at the efflux was decreased In monkeys a of efflux and < at and resulting in a of efflux and < at and studies have demonstrated that HDL-C is a of coronary heart disease risk and the development of strategies to HDL-C levels Castelli W.P. S. lipoprotein cholesterol and cardiovascular disease. PubMed Scopus Google Scholar, D. on strategies to HDL and PubMed Scopus Google Scholar). However, clinical HDL have disappointing results (11Barter P.J. Caulfield M. Eriksson M. Grundy S.M. Kastelein J.J. Komajda M. Lopez-Sendon J. Mosca L. Tardif J.C. Waters D.D. Effects of torcetrapib in patients at high risk for coronary events.N. Engl. J. Med. 2007; 357: 2109-2122Crossref PubMed Scopus (2609) Google Scholar, 12Schwartz G.G. Olsson A.G. Abt M. Ballantyne C.M. Barter P.J. Brumm J. Chaitman B.R. Holme I.M. Kallend D. Leiter L.A. dal-OUTCOMES Investigators Effects of dalcetrapib in patients with a recent acute coronary syndrome.N. Engl. J. Med. 2012; 367: 2089-2099Crossref PubMed Scopus (1559) Google Scholar, 13.Eli Lilly and Company. 2015. Lilly to discontinue development of evacetrapib for high-risk atherosclerotic cardiovascular disease. October 2015. at Scholar, M. J.J. P.J. P. B. D. A. in high density lipoprotein cholesterol and cardiovascular disease and and PubMed Scopus Google Scholar, R. J.C. S. T. J. K. M. L. Effects of with in high-risk Engl. J. Med. PubMed Scopus Google Scholar). large clinical of anacetrapib and dalcetrapib J.C. E. J.C. S. A. D. of the cardiovascular effects of PubMed Scopus Google Scholar, K. studies as a for PubMed Scopus Google Scholar, J.C. D. M. R. S. M. S. J.C. effects of dalcetrapib on cholesterol efflux and with clinical PubMed Scopus Google Scholar) are and to the for the characterization of the effects of these two CETPis on the structure and function of HDL in vivo was demonstrated that a CETP activity according to the the impact of CETPis in two that in vitro to in opposite rabbits and for which of CETP by reduces L. Cholesteryl ester transfer from different species have Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). 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PubMed Scopus Google Scholar) that torcetrapib increases HDL-C and level by its as demonstrated that of dalcetrapib and anacetrapib for in rabbits increased the in A similar effect of anacetrapib was in vervet monkeys. dalcetrapib reduced the level of and HDL-C in vervet monkeys. for could a decrease in the of by dalcetrapib that to vervet monkeys. effect by increased of from mature studies have demonstrated in human preβ-HDL is by because transfer of cholesterol by CETP HDL is and to the of preβ-HDL C. N. Okamoto H. E. H. E. D. cholesteryl ester transfer protein activity and increases reverse cholesterol Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). Accordingly, that of vervet plasma at increased the level of CETP and HDL the of In that of rabbit plasma at was associated with a of the level of small HDL, a of these particles in larger HDL CETP This of preβ-HDL in monkeys with dalcetrapib could with the decreased HDL-C level in vivo in monkeys. This HDL-C could by increased CETP activity in the of dalcetrapib in monkeys, because the decrease in HDL-C was associated with of and LDL-C levels. Accordingly, was demonstrated that a to to CETP transfer activity L. Cholesteryl ester transfer from different species have Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). However, the by which to CETP activity remains to is that dalcetrapib CETP activity by with of the protein C. A. E. C. P. for a of CETP in HDL and cholesterol of of PubMed Scopus (22) Google is that with the CETP to of CETP with that the of anacetrapib on CETP from different species is because similar effects were in rabbits and monkeys. studies to the of dalcetrapib with of CETP the the of HDL-C and the capacity of preβ-HDL in monkeys that dalcetrapib increases CETP of CETP activity in plasma from monkeys. remains that the of lipoprotein metabolism in the of a of CETP dalcetrapib could in However, results demonstrated that the of dalcetrapib was in in with studies that the in the plasma of monkeys K. and metabolism in the 2011; PubMed Scopus Google Scholar, H. T. H. T. T. H. M. and of dalcetrapib in and PubMed Scopus Google Scholar). was demonstrated that dalcetrapib reduces the level of HDL-C in J. Inhibition of cholesteryl ester transfer protein increases cholesteryl ester of large HDL of in vitro in vivo anacetrapib and J. PubMed Scopus Google a species CETP Accordingly, A. S. R. 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Full Text Full Text PDF PubMed Scopus Google Scholar). the of apoB-containing lipoproteins in the efflux of cholesterol the apoB-containing lipoproteins could the cholesterol efflux because cholesterol from HDL through the of This is in the inhibition of CETP in the and the different levels of particles in the monkeys. to the of HDL, the apoB-containing The results demonstrated that cholesterol efflux by serum from a of HDL-C was However, these results the for that de la Llera-Moya la Llera-Moya M. D. Cuchel M. The ability to efflux the capacity of serum with similar high-density lipoprotein cholesterol to remove cholesterol from Thromb. Vasc. Biol. PubMed Scopus Google Scholar) a the level of preβ-HDL and cholesterol efflux. small HDL preβ-HDL particles were increased by CETPis the of dalcetrapib in the ABCA1-induced cholesterol efflux. The of small HDL particles in plasma was associated with of ABCA1-induced and efflux. In the decrease of preβ-HDL in monkeys with dalcetrapib was by decreased efflux that in a decrease of efflux, that the of preβ-HDL by dalcetrapib in monkeys was to efflux. study the function of HDL from rabbits with CETPis were in cholesterol efflux with a model to high levels of D. L. The of in the for J. Biol. 2004; PubMed Scopus Google Scholar). CETPis increased the capacity of to cholesterol efflux. the of in cholesterol efflux mature HDL B. N. M.L. Phillips M.C. Tall A.R. high density cholesterol Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google these results that produced by dalcetrapib anacetrapib are to these results indicate that produced by for the first step of the preβ-HDL particles in the first step of the of small in rabbits preβ-HDL in monkeys by could However, preβ-HDL been to increased in patients with cardiovascular C. 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The results of the study that of small HDL is associated with a in the of HDL, because demonstrated the of large HDL particles and increased cholesterol efflux. anacetrapib and and dalcetrapib in a of HDL particles were the of a level of cholesterol in these In in monkeys with preβ-HDL could from the HDL In study demonstrated that CETPis modulate the in vivo levels of HDL-C and preβ-HDL and in vitro cholesterol efflux capacity, these effects species and The opposite effects of dalcetrapib in different species are in to and indicate that its impact on HDL metabolism could vary greatly according to the metabolic environment. The the of the at with cholesteryl ester cholesteryl ester transfer protein cholesteryl ester transfer protein inhibitor HDL cholesterol cholesterol reverse cholesterol transport cholesterol

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