CETP inhibitors boost 'good' cholesterol to no avail Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet. Common variation in cholesteryl ester transfer protein: relationship of first major adverse cardiovascular events with the apolipoprotein B/apolipoprotein A-I ratio and the total cholesterol/high-density lipoprotein cholesterol ratio. Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes. Plasma cholesteryl ester synthesis, cholesteryl ester transfer protein concentration and activity in hypercholesterolemic women: effects of the degree of saturation of dietary fatty acids in the fasting and postprandial states. The human cholesteryl ester transfer protein I405V polymorphism is associated with plasma cholesterol concentration and its reduction by dietary phytosterol esters. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk Pharmacogenetic study of apolipoprotein E, cholesteryl ester transfer protein and hepatic lipase genes and simvastatin therapy in Brazilian subjects. Variation in the cholesteryl ester transfer protein (CETP) gene does not influence individual plasma cholesterol response to changes in the nature of dietary fat. Effects of vitamin E and HMG‐CoA reductase inhibition on cholesteryl ester transfer protein and lecithin‐cholesterol acyltransferase in hypercholesterolemia Effects of torcetrapib in patients at high risk for coronary events. The effect of atorvastatin therapy on lecithin:cholesterol acyltransferase, cholesteryl ester transfer protein and the antioxidant paraoxonase. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies CETP genotype and changes in lipid levels in response to weight-loss diet intervention in the POUNDS LOST and DIRECT randomized trials1 Cholesteryl Ester Transfer Protein Gene Polymorphism Is a Determinant of HDL Cholesterol and of the Lipoprotein Response to a Lipid-Lowering Diet in Type 1 Diabetes
5 ( Arteriosclerosis 8 , 737–741 , 1988 ) . Animal data appeared to support the concept as well — mice and rats are naturally deficient in CETP and do not develop atherosclerosis , whereas rabbits , which have high levels of CETP , appeared to benefit from inhibition . But , following failures in large-scale outcomes trials , drug developers have lost faith in the idea that raising HDL-c is beneficial . “ The goal posts have moved now , ” says Sekar Kathiresan , director of preventive cardiology at Massachusetts General Hospital , in Boston . “ I think there is some suggestive evidence , at least , from human genetics that the LDL-lowering properties of CETP might be protective , ” he says . “ That part of the hypothesis is still in play . ” Merck , of Kenilworth , New Jersey , is banking on this aspect of the mechanism in a mammoth outcomes trial , dubbed REVEAL ( R and omized Evaluation of the Effects of Anacetrapib Through Lipid-modification ) , which is recruiting 30,000 patients . “ They ’ve powered their study entirely for the LDLlowering effect , ” says Kathiresan . The scale of the trial is huge — in contrast , Lilly ’s trial of evacetrapib , called ACCELERATE ( Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes ) , recruited 12,000 patients . Not only will it improve Eli Lilly ’s decision to stop phase 3 studies of its cholesteryl ester transfer protein ( CETP ) inhibitor evacetrapib in patients with atherosclerotic cardiovascular disease adds another expensive , late-stage failure to a drug class that has confounded the pharma industry ’s expectations for a decade . This drug class was once bullishly pursued by big pharma originally because its effects on raising high-density lipoprotein cholesterol ( HDL-c ) were considered to be complementary to the effect of statins on lowering low density-lipoprotein cholesterol ( LDL-c ) . But Lilly ’s trial failure — the third major disappointment for this drug class — raises wider questions surrounding the utility of the CETP inhibitor class as a whole . If the CETP inhibitor class is to be ab and oned due to lack of efficacy , it will necessitate a revision of the LDL hypothesis , which holds that lowering LDL-c by any means is beneficial . CETP inhibitors raise cholesterol levels in high-density lipoprotein ( HDL ) and at the same time lower cholesterol in low-density lipoprotein ( LDL ) , by preventing the net transfer of cholesterol esters from HDL to LDL and other lipoprotein fractions . So far , at least , no CETP inhibitor has demonstrated in a largescale outcomes trial that these effects reduce the risk of death or major coronary events , such as heart attack or stroke . With Lilly ’s drug out of the running , Merck ’s drug anacetrapib , currently undergoing a large-scale outcomes trial , is now the lead molecule in the class ( Table 1 ) . Differences between the two study protocol s and between the two drug molecules may be sufficient to explain differing outcomes , but why Merck ’s drug may yet succeed where evacetrapib failed remains moot for now . CETP inhibition first emerged as a therapeutic concept on the back of observations in the Framingham heart study — and in other population -based studies —of an apparent inverse association between high levels of HDL-c and risk of death from cardiovascular disease CETP inhibitors boost ‘ good ’ cholesterol to no OBJECTIVES We sought to evaluate the association between cholesteryl ester transfer protein ( CETP ) genotypes and the risk of future cardiovascular mortality in patients with coronary artery disease ( CAD ) . BACKGROUND Polymorphisms of the CETP gene influence CETP activity and high-density lipoprotein ( HDL ) cholesterol concentration and might affect the long-term prognosis and response to statin therapy in patients with CAD . METHODS We used serum sample s and deoxyribonucleic acid collected at baseline from a prospect i ve cohort of 1,211 patients with CAD prospect ively followed up ( median follow-up of 4.1 years ) , 82 of whom experienced a fatal cardiovascular event . The CETP/C-629A and I405V polymorphisms , CETP activity , and HDL cholesterol were determined . RESULTS Patients carrying the -629A allele had significantly lower CETP activity and higher HDL cholesterol levels . There was a significant association between this polymorphism and the risk of future cardiovascular death . Mortality decreased from 10.8 % in CC homozygotes to 4.6 % in CA heterozygotes and 4.0 % in AA homozygotes ( p < 0.0001 ) . This association was independent of potential confounders , particularly HDL cholesterol and CETP activity levels . The clinical benefit of statin therapy was restricted to CC homozygotes , in whom cardiovascular mortality was divided by half ( p = 0.01 for treatment x genotype interaction ) . Similar trends were observed with the CETP/I405V polymorphism , but these effects seemed to be mainly the consequence of linkage disequilibrium with the CETP/C-629A polymorphism . CONCLUSIONS In patients with CAD , the CETP/-629A allele had a strong protective effect on future mortality from cardiovascular causes , independent of its role on HDL cholesterol and CETP activity levels . Additionally , this common polymorphism appeared to predict which patients with CAD will experience a survival benefit from statin therapy The trans isomer of oleic acid ( elaidic acid ) increases low density lipoprotein ( LDL ) cholesterol and decreases high density lipoprotein ( HDL ) cholesterol in man . One possible mechanism for this effect is that trans fatty acids increase plasma cholesteryl ester transfer protein ( CETP ) activity . We examined the effect of dietary trans fatty acids on activity of this protein in plasma from 27 men in a double blind crossover comparison . The background diet , containing 15 % energy as fat from dairy products , meat , bread and cereals , was supplemented with oleic or elaidic acid providing a further 20 % energy . The elaidic supplement provided about 6 % energy as trans fatty acid .  Activity of CETP in plasma was significantly higher ( P < 0.001 ) after the elaidic acid-rich diet ( 23.95 + /- 1.26 % ) compared with the diet enriched with oleic acid ( 19.61 + /- 0.89 % ) . A significant correlation between the change in plasma trans 18:1 fatty acids and the change in plasma CETP activity ( r = 0.58 , P < 0.002 ) was independent of changes in LDL-cholesterol . The increase in CETP activity was in turn significantly correlated with a fall in HDL-cholesterol among subjects during the elaidic acid-rich period ( r = -0.57 , P < 0.01 ) . We have shown that CETP demonstrates substrate specificity and that the increase in activity with dietary trans fatty acids may contribute to a more atherogenic lipoprotein profile BACKGROUND The preference of the apolipoprotein ( apo ) B/apoA-I ratio over the total cholesterol/HDL cholesterol ( TC/HDL-C ) ratio in cardiovascular risk prediction is disputed . Cholesteryl ester transfer protein ( CETP ) is instrumental in lipoprotein remodelling and affects the cholesterol content in pro- and antiatherogenic lipoproteins relative to their major apolipoproteins . We tested the influence of common CETP variations on the strength of associations of a first major adverse cardiovascular event ( MACE ) with the apoB/apoA-I ratio compared with the TC/HDL-C ratio . METHODS A prospect i ve case-cohort study was performed ( PREVEND cohort ; no previous cardiovascular disease and no use of lipid-lowering drugs initially ) .  Fasting serum TC/HDL-C , apoB/apoA-I , triglycerides , and common CETP variations ( TaqIB [ rs708272 ] and -629C > A [ rs1800775 ] polymorphisms ) were measured at baseline . The composite end point was incident MACE . RESULTS A total of 532 of 6780 subjects experienced a first MACE during 10.8 years follow-up . The age- and sex-adjusted hazard ratio was 1.31 ( 95 % confidence interval 1.23 - 1.41 ) for the apoB/apoA-I ratio and 1.22 ( 95 % confidence interval 1.26 - 1.39 ) for the TC/HDL-C ratio ( both P < .001 ) . These relationships were essentially similar within each TaqIB and -629C > A CETP genotype group . No interactions of the apoB/apoA-I ratio and the TC/HDL-C ratio with the TaqIB and the -629C > A CETP variations on incident MACE were observed ( P > .20 for all ) . CONCLUSION The relationship of first MACE with the TC/HDL-C and the apoB/apoA-I ratio is not to an important extent dependent on common CETP variations . CETP variations are unlikely to affect the strength of the relationship of first MACE with the apoB/apoA-I ratio compared with the TC/HDL-C ratio OBJECTIVE The cholesteryl ester transfer protein ( CETP ) plays a key role in the remodeling of triglyceride (TG)-rich and HDL particles . Sequence variations in the CETP gene may interfere with the effect of lipid-lowering treatment in type 2 diabetes . RESEARCH DESIGN AND METHODS We performed a 30-week r and omized double-blind placebo-controlled trial with atorvastatin 10 mg ( A10 ) and 80 mg ( A80 ) in 217 unrelated patients with diabetes . RESULTS CETP TaqIB and A-629C polymorphisms were tightly concordant ( P < 0.001 ) . At baseline , B1B1 carriers had lower plasma HDL cholesterol ( 0.99 + /- 0.2 vs. 1.11 + /- 0.2 mmol/l , P < 0.05 ) , higher CETP mass ( 2.62 + /- 0.8 vs. 2.05 + /- 0.4 mg/l , P < 0.001 ) , and slightly increased , though not significant , plasma TGs ( 2.7 + /- 1.05 vs. 2.47 + /- 0.86 , P = 0.34 ) compared with B2B2 carriers . Atorvastatin treatment significantly reduced CETP mass dose-dependently by 18 % ( A10 ) and 29 % ( A80 ; both vs. placebo P < 0.001 , A10-A80 P < 0.001 ) . CETP mass and activity were strongly correlated ( r = 0.854 , P < 0.0001 ) . CETP TaqIB polymorphism appeared to modify the effect of atorvastatin on HDL cholesterol elevation ( B1B1 7.2 % , B1B2 6.1 % , B2B2 0.5 % ; P < 0.05 ) , TG reduction ( B1B1 39.7 % , B1B2 38.4 % , B2B2 18.4 % ; P = 0.08 ) , and CETP mass reduction ( B1B1 32.1 % , B1B2 29.6 % , B2B2 21.9 % ; P = 0.27 , NS ) . Similar results were obtained for the A-629C polymorphism . CONCLUSIONS In conclusion , the B1B1/CC carriers of the CETP polymorphisms have a more atherogenic lipid profile , including low HDL , and they respond better to statin therapy . These results favor the hypothesis that CETP polymorphisms modify the effect of statin treatment and may help to identify patients who will benefit most from statin therapy Hypercholesterolemic women ( n = 19 ) sequentially maintained on a long-term saturated ( SAT ) or a polyunsaturated ( PUFA ) fatty acid-rich diet , respectively  , were studied in the fasting state and after a meal rich in SAT or PUFA . When apo B-containing lipoprotein was excluded from plasma the in vitro HDL-14C-cholesterol esterification rate was identical for the saturated ( SAT ) and polyunsaturated ( PUFA ) fatty acid diets , and did not increase during the postpr and ial period . Rates of transfer of 14C-cholesteryl ester to apo B-containing lipoproteins from HDL were also similar for both diets in the fasting state and increased to the same extent in the postpr and ial period in parallel with the rise in plasma triglycerides . When transfer data were related to the plasma concentration of apo B , the gain of cholesteryl ester by the triglyceride-containing particles ( VLDL + LDL ) also increased in the postpr and ial period to a similar extent for both diets . Cholesteryl ester transfer protein ( CETP ) concentration measured by radioimmunoassay was similar during both experimental diets , although greater in the postpr and ial period for the PUFA diet . The rate limiting factor for CETP-mediated transfer of HDL-derived cholesteryl ester ( CE ) was the plasma triglyceride concentration , that is , the content of triglycerides per lipoprotein particle and the quantity of TG-containing particles ( VLDL + LDL ) . In contrast , the fatty acid composition of these particles had less effect on CETP-mediated CE transfer We examined the relationships of I405V cholesteryl ester transfer protein ( CETP ) , Taq1B CETP and apolipoprotein (apo)E polymorphisms with the pattern of response to dietary plant sterol ester ( PSE ) by plasma lipids and CETP concentrations as well as lecithin-cholesterol acyltransferase ( LCAT ) activity . Subjects with moderate primary hypercholesterolemia ( 20 - 60 y old ; 50 women ; 10 men ) consumed margarine ( 20 g/d ) without ( placebo ) or with PSE ( 2.8 g/d = 1.68 g/d phytosterols ) for 4 wk each period , in a crossover , double-blind study . Plasma CETP concentration was measured by ELISA ; endogenous LCAT activity was expressed as the percentage of esterification ( 30 min incubation ) of the subjects ' (14)C-unesterified cholesterol HDL . PSE reduced concentrations of plasma total cholesterol ( TC ) ( 10 % ) and LDL cholesterol ( LDL-C ) ( 12 % ) . In relation to the I405V CETP polymorphism , the percentage reductions in TC with consumption of PSE for the II , IV and VV phenotypes were 7.2 , 4.2 and not significant , respectively , whereas LDL-C significant reductions occurred only for II ( 9.5 % ) . However , the CETP concentration diminished only in the II phenotype BACKGROUND The high-density lipoprotein ( HDL ) cholesterol concentration is inversely related to the risk of coronary artery disease . The cholesteryl ester transfer protein ( CETP ) has a central role in the metabolism of this lipoprotein and may therefore alter the susceptibility to atherosclerosis . METHODS The DNA of 807 men with angiographically documented coronary atherosclerosis was analyzed for the presence of a polymorphism in the gene coding for CETP . The presence of this DNA variation was referred to as B1 , and its absence as B2 . All patients participated in a cholesterol-lowering trial design ed to induce the regression of coronary atherosclerosis and were r and omly assigned to treatment with either pravastatin or placebo for two years . RESULTS The B1 variant of the CETP gene was associated with both higher plasma CETP concentrations ( mean [ + /-SD ] , 2.29+/-0.62 microg per milliliter for the B1B1 genotype vs. 1.76+/-0.51 microg per milliliter for the B2B2 genotype ) and lower HDL cholesterol concentrations ( 34+/-8 vs. 39+/-10 mg per deciliter ) . In addition , we observed a significant dose-dependent association between this marker and the progression of coronary atherosclerosis in the placebo group ( decrease in mean luminal diameter : 0.14+/-0.21 mm for the B1B1 genotype , 0.10+/-0.20 mm for the B1B2 genotype , and 0.05+/-0.22 mm for the B2B2 genotype ) . This association was abolished by pravastatin . Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers ( representing 16 percent of the patients taking pravastatin ) . CONCLUSIONS There is a significant relation between variation at the CETP gene locus and the progression of coronary atherosclerosis that is independent of plasma HDL cholesterol levels and the activities of lipolytic plasma enzymes . This common DNA variant appears to predict whether men with coronary artery disease will benefit from treatment with pravastatin to delay the progression of coronary atherosclerosis Importance Some cholesteryl ester transfer protein ( CETP ) inhibitors lower low-density lipoprotein cholesterol ( LDL-C ) levels without reducing cardiovascular events , suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered . Objective To estimate the association between changes in levels of LDL-C ( and other lipoproteins ) and the risk of cardiovascular events related to variants in the CETP gene , both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase ( HMGCR ) gene . Design , Setting , and Participants Mendelian r and omization analyses evaluating the association between CETP and HMGCR scores , changes in lipid and lipoprotein levels , and the risk of cardiovascular events involving 102 837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012 . The associations with cardiovascular events were externally vali date d in 189 539 participants from 48 studies conducted between 2011 and 2015 . Exposures Differences in mean high-density lipoprotein cholesterol ( HDL-C ) , LDL-C , and apolipoprotein B ( apoB ) levels in participants with CETP scores at or above vs below the median . Main Outcomes and Measures Odds ratio ( OR ) for major cardiovascular events . Results The primary analysis included 102 837 participants ( mean age , 59.9 years ; 58 % women ) who experienced 13 821 major cardiovascular events . The validation analyses included 189 539 participants ( mean age , 58.5 years ; 39 % women ) with 62 240 cases of coronary heart disease ( CHD ) . Considered alone , the CETP score was associated with higher levels of HDL-C , lower LDL-C , concordantly lower apoB , and a corresponding lower risk of major vascular events ( OR , 0.946 [ 95 % CI , 0.921 - 0.972 ] ) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C ( and apoB ) . When combined with the HMGCR score , the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events ( OR , 0.985 [ 95 % CI , 0.955 - 1.015 ] ) . In external validation analyses , a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level ( OR , 0.782 [ 95 % CI , 0.720 - 0.845 ] vs 0.793 [ 95 % CI , 0.774 - 0.812 ] ; P = .79 for difference ) , but a significantly attenuated risk of CHD per unit change in LDL-C level ( OR , 0.916 [ 95 % CI , 0.890 - 0.943 ] vs 0.831 [ 95 % CI , 0.816 - 0.847 ] ; P < .001 ) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB. Conclusions and Relevance Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles BACKGROUND In recent years , one of the focuses of genetic investigation in cardiology has been to identify the genetic factors associated with variable response to statin treatment . Polymorphisms in apolipoprotein E ( APOE ) , cholesteryl ester transfer protein ( CETP ) and hepatic lipase ( LIPC ) , proteins with major roles in lipid metabolism and homeostasis have been shown associated with lipid-lowering drugs response . METHODS One hundred forty-six hypercholesterolemic patients of European descent were prospect ively enrolled and treated with simvastatin 20 mg per day for over 6 months . Ninety-nine subjects completed the 6-month follow-up .  Plasma lipids and lipoproteins were measured before and throughout the study . APOE ( E*2 , E*3 and E*4 ) , LIPC-250A > G and CETP TaqIB genotypes were determined by PCR and restriction mapping . RESULTS After a 6-month follow-up , no differences among genotypes in the percentage variation in lipid and lipoprotein concentrations for APOE and LIPC SNPs were observed . After adjustment for covariates , CETP B2B2 homozygotes showed a greater HDL-cholesterol increase compared to B1B2 and B1B1 subjects ( 14.1 % vs. 1.7 % and 1.3 % , P < 0.05 , respectively ) . CONCLUSION Our study demonstrates that individual plasma HDL-cholesterol response to simvastatin is mediated , in part , by the CETP gene locus , with the B2 homozygotes having more benefit in HDL-C improvement than carriers of B1 allele BACKGROUND AND AIMS Some individuals respond to a greater extent than others to changes in dietary fat and cholesterol even when dietary intake is consistent . A prospect i ve study has been undertaken in which two groups of individuals according to cholesteryl ester transfer protein ( CETP ) genotype were compared in terms of plasma lipid response to altering the nature of dietary fat in a free-living situation . METHODS AND RESULTS Following genotyping , 35 individuals with the CETP Taq1 B1B1 genotype were paired with age and sex-matched individuals with one or two CETP B2 alleles , to undertake a single crossover trial with a diet high in saturated fat and a diet high in polyunsaturated fat . There was no washout period between the two 4-week phases . Plasma lipoproteins were measured at the beginning and end of each phase . The difference ( 95 % CI ) in plasma LDL-cholesterol concentration at the end of the PUFA and SAFA diets was 0.95 ( 0.71 , 1.19 ) mmol/l in the CETP B1B1 group and 0.80 ( 0.57 , 1.04 ) mmol/l in the group with at least one CETP B2 allele . The dietary induced changes in the two genotype groups were not significantly different ( p=0.38 ) from each other . Comparable results were observed for plasma total cholesterol . The high PUFA and SAFA diets did not significantly alter plasma HDL concentration in either of the CETP genotype groups . Response was also similar according to apolipoprotein E genotype ( E3E3 vs E4 + ) and lipoprotein lipase genotype ( S447X ) . CONCLUSIONS The results of this study do not support previous studies in which CETP genotype predicted plasma LDL-cholesterol response to diet . CETP genotype does not significantly affect the change in plasma total and LDL-cholesterol concentrations that occur when altering the nature of dietary fat . These data suggest that the influence of genetic factors on total and LDL-cholesterol may be relatively small in comparison with the effect of dietary manipulation Background The enzyme lecithin-cholesterol acyl transferase ( LCAT ) esterifies free cholesterol on highdensity lipoprotein ( HDL ) and the cholesteryl ester transfer protein ( CETP ) transfers cholesteryl esters to very-low-density lipoproteins ( VLDL ) and low-density lipoproteins ( LDL ) . Using statins , contradictory findings have been made regarding CETP activity in normolipidemic individuals and in those with familial dysbetatlipoproteinemia . In contrast , LCAT activity appears to be unaffected by simvastatin . Antioxidants have also been proposed for use in anti-atherosclerotic treatment , because the oxidation of LDL may have a key role in the pathophysiology of atherogenesis . Objective To investigate , in hypercholesterolemic patients , whether a combination of pravastatin with the antioxidant , vitamin E , has greater effects on the activity of CETP and of LCAT than does pravastatin alone . Methods This  placebo-diet-controlled multicenter trial included 220 hypercholesterolemic patients who were assigned r and omly to groups to receive : diet and 20–40 mg pravastatin ( n = 52 ) , diet and pravastatin in combination with 100 mg/day vitamin E ( 100 IU ) as DL-α-tocopherol ( n = 56 ) , diet and α-tocopherol ( n = 60 ) , or diet associated with placebo ( n = 52 ) . Plasma LCAT activity was determined using excess exogenous substrate , containing [3H]cholesterol . Plasma CETP activity was measured in the supernatant fraction after precipitation of endogenous apo B-containing lipoproteins with phosphotungstate-Mg2 + . The exchange of cholesteryl esters between [14C]cholesteryl esterlabeled LDL and unlabeled HDL was measured during a 16-h incubation , while LCAT was inhibited . Results The addition of pravastatin to the diet induced a significant decrease in plasma CETP activity ( P < 0.05 ) ; this effect was less evident in the group cotreated with vitamin E. For the first time , it was shown that CETP concentrations increased significantly after vitamin E alone ( P < 0.05 ) . No significant differences in the plasma activity of LCAT were observed among the groups . Conclusions Pravastatin  reduced CETP activity , but not that of LCAT . Addition of vitamin E prevented the decrease in CETP activity and had no effect on LCAT activity . The mechanism responsible for these effects is unknown , but could involve the prevention of radical-induced damage to CETP by vitamin E. Coronary Artery Dis BACKGROUND Inhibition of cholesteryl ester transfer protein ( CETP ) has been shown to have a substantial effect on plasma lipoprotein levels . We investigated whether torcetrapib , a potent CETP inhibitor , might reduce major cardiovascular events . The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib .  METHODS We conducted a r and omized , double-blind study involving 15,067 patients at high cardiovascular risk . The patients received either torcetrapib plus atorvastatin or atorvastatin alone . The primary outcome was the time to the first major cardiovascular event , which was defined as death from coronary heart disease , nonfatal myocardial infa rct ion , stroke , or hospitalization for unstable angina . RESULTS At 12 months in patients who received torcetrapib , there was an increase of 72.1 % in high-density lipoprotein cholesterol and a decrease of 24.9 % in low-density lipoprotein cholesterol , as compared with baseline ( P<0.001 for both comparisons ) , in addition to an increase of 5.4 mm Hg in systolic blood pressure , a decrease in serum potassium , and increases in serum sodium , bicarbonate , and aldosterone ( P<0.001 for all comparisons ) . There was also an increased risk of cardiovascular events ( hazard ratio , 1.25 ; 95 % confidence interval [ CI ] , 1.09 to 1.44 ; P=0.001 ) and death from any cause ( hazard ratio , 1.58 ; 95 % CI , 1.14 to 2.19 ; P=0.006 ) . Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change . CONCLUSIONS Torcetrapib therapy result ed in an increased risk of mortality and morbidity of unknown mechanism . Although there was evidence of an off-target effect of torcetrapib , we can not rule out adverse effects related to CETP inhibition . ( Clinical Trials.gov number , NCT00134264 [ Clinical Trials.gov ] . ) OBJECTIVES The aim of our study was to examine the influence of atorvastatin on lipid parameters , particularly on HDL , and on the activity of LCAT and CETP and how they affect the activity of the HDL-associated antioxidant enzyme paraoxonase . DESIGN AND METHODS Thirty-three patients with types II.a and II.b primary hyperlipoproteinemia were enrolled into our study . The patients received atorvastatin , 20 mg daily , for 3 months . We measured the serum paraoxonase activity and concentration , oxidized LDL , LCAT and CETP activities . RESULTS Atorvastatin significantly reduced the levels of cholesterol , triglyceride , LDL-C and apoB , while it did not influence the levels of HDL-C and apo A-I. The increases in serum PON-specific activity , PON/HDL ratio and LCAT activity were significant , while oxLDL and CETP activities were significantly decreased . CONCLUSION Atorvastatin may influence the composition and function of HDL , thereby possibly increasing the activity of paraoxonase and preventing atherosclerosis BACKGROUND The inhibition of cholesteryl ester transfer protein ( CETP ) is considered a potential new mechanism for treatment of dyslipidaemia .  Anacetrapib ( MK-0859 ) is a CETP inhibitor currently under development . We aim ed to assess anacetrapib 's effects as monotherapy on low-density lipoprotein cholesterol ( LDL-C ) and high-density lipoprotein cholesterol ( HDL-C ) and on 24-h ambulatory blood pressure . METHODS We did two double-blind , r and omised , placebo-controlled phase I studies . In the first study , 50 patients with dyslipidaemia ( LDL-C 100 - 190 mg/dL ; 40 active , 10 placebo ) aged 18 - 75 years received anacetrapib doses of 0 , 10 , 40 , 150 , or 300 mg orally once a day with a meal for 28 days . St and ard lipid and lipoprotein monitoring , safety monitoring , and anacetrapib concentrations for pharmacokinetics were done . In the second study , 22 healthy participants aged 45 - 75 years received either 150 mg of anacetrapib once a day or matching placebo with a meal for 10 days in each crossover period , in a r and omised sequence , with at least a 14-day washout between the treatment periods . Continuous 24-h ambulatory blood pressure monitoring was done on day -1 and day 10 of each treatment period in this study . The primary or secondary endpoints of safety and tolerability were assessed in both studies by monitoring clinical adverse experiences , physical examinations , vital signs , 12-lead electrocardiogram , and laboratory safety . Analysis was per protocol . These trials are registered with Clinical Trials.gov , number NCT00565292 and NCT00565006 . FINDINGS In the dyslipidaemia study , one patient withdrew consent and one was excluded from the data analysis for HDL-C and LDL-C because complete pre-dose measurements were not available . Anacetrapib produced dose-dependent lipid-altering effects with peak lipid-altering effects of 129 % ( mean 51.1 [ SD 3.8]-114.9 [ 7.9 ] mg/dL ) increase in HDL-C and a 38 % ( 138.2 [11.4]-77.6 [ 7.9 ] mg/dL ) decrease in LDL-C in patients with dyslipidaemia . In the 24-h ambulatory blood pressure study in healthy individuals , least squares difference between anacetrapib and placebo groups on day 10 were 0.60 ( 90 % CI -1.54 to 2.74 ; p=0.634 ) mm Hg for systolic blood pressure and 0.47 ( 90 % CI -0.90 to 1.84 ; p=0.561 ) mm Hg for diastolic blood pressure . INTERPRETATION Anacetrapib seems to exhibit HDL-C increases greater than those seen with other investigational drugs in this class and LDL-C lowering effects similar to statins . Despite greater lipid-altering effects relative to other members of this class , anacetrapib seems not to increase blood pressure , suggesting that potent CETP inhibition by itself might not lead to increased blood pressure Little is known about whether cholesteryl ester transfer protein ( CETP ) genetic variation may modify the effect of weight-loss diets varying in fat content on changes in lipid levels . We analyzed the interaction between the CETP variant rs3764261 and dietary interventions on changes in lipid levels among 732 overweight/obese adults from a 2 year r and omized weight-loss trial [ Preventing Overweight Using Novel Dietary Strategies ( POUNDS LOST ) ] , and replicated the findings in 171 overweight/obese adults from an independent 2 year weight-loss trial [ Dietary Intervention R and omized Controlled Trial ( DIRECT ) ] . In the POUNDS LOST , participants with the CETP rs3764261 CC genotype on the high-fat diet had larger increases in HDL cholesterol ( P = 0.001 ) and decreases in triglycerides ( P = 0.007 ) than those on the low-fat diet at 6 months , while no significant difference between these two diets was observed among participants carrying other genotypes . The gene-diet interactions on changes in HDL-cholesterol and triglycerides were replicated in the DIRECT ( pooled P for interaction ≤ 0.01 ) . Similar results on trajectory of changes in HDL cholesterol and triglycerides over the 2 year intervention were observed in both trials . Our study provides replicable evidence that individuals with the CETP rs3764261 CC genotype might derive greater effects on raising HDL cholesterol and lowering triglycerides by choosing a low-carbohydrate/high-fat weight-loss diet instead of a low-fat diet The TaqlB cholesteryl ester transfer protein ( CETP ) gene polymorphism ( B1B2 ) is a determinant of HDL cholesterol in nondiabetic population s. Remarkably , this gene effect appears to be modified by environmental factors . We evaluated the effect of this polymorphism on HDL cholesterol levels and on the lipoprotein response to a linoleic acid-enriched , low-cholesterol diet in patients with type 1 diabetes . In 44 consecutive type 1 diabetic patients ( 35 men ) , CETP polymorphism , apolipoprotein ( apo ) E genotype , serum lipoproteins , serum CETP activity ( measured with an exogenous substrate assay , n = 30 ) , clinical variables , and a diet history were documented . The 1-year response to diet was assessed in 14 type 1 diabetic patients , including 6 B1B1 and 6 B1B2 individuals . HDL cholesterol was higher in 10 B2B2 than in 14 B1B1 homozygotes ( 1.63 ± 0.38 vs. 1.24 ± 0.23 mmol/l , P < 0.01 ) . HDL cholesterol , adjusted for triglycerides and smoking , was 0.19 mmol/l higher for each B2 allele present . CETP activity levels were not significantly different between CETP genotypes . Multiple regression analysis showed that VLDL + LDL cholesterol was associated with dietary polyunsaturated : saturated fatty acids ratio ( P < 0.02 ) and total fat intake ( P < 0.05 ) in the B1B1 homozygotes only and tended to be related to the presence of the apo E4 allele ( P < 0.10 ) . In response to diet , VLDL + LDL cholesterol fell ( P < 0.05 ) and HDL cholesterol remained unchanged in 6 B1B1 homozygotes . In contrast , VLDL + LDL cholesterol was unaltered and HDL cholesterol decreased ( P < 0.05 ) in 6 B1B2 heterozygotes ( P < 0.05 for difference in change in VLDL + LDL/HDL cholesterol ratio ) . This difference in response was unrelated to the apo E genotype . Thus , the TaqlB CETP gene polymorphism is a strong determinant of HDL cholesterol in type 1 diabetes . This gene effect is unlikely to be explained by a major influence on the serum level of CETP activity , as an indirect measure of CETP mass . Our preliminary data suggest that this polymorphism may be a marker of the lipoprotein response to dietary intervention
Conclusions : CETP inhibitors are not associated with an increased risk of MACE or all-cause mortality .
There is a trend towards small reductions in nonfatal MI and cardiovascular death , though the clinical importance of such reductions is likely modest
Background : Cholesteryl ester transfer protein ( CETP ) inhibitors increase serum high-density lipoprotein cholesterol ( HDL-c ) concentration ; however , their impact on cardiovascular outcomes is not clear .
This systematic review examines the effect of CETP inhibitors on serum lipid profiles , cardiovascular events , and all-cause mortality .