CETP inhibitors boost 'good' cholesterol to no avail Evacetrapib and Cardiovascular Outcomes in High‐Risk Vascular Disease Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Effects of dalcetrapib in patients with a recent acute coronary syndrome. Effects of torcetrapib in patients at high risk for coronary events. An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. Mediterranean Diet Improves High-Density Lipoprotein Function in High-Cardiovascular-Risk Individuals: A Randomized Controlled Trial Orange juice decreases low-density lipoprotein cholesterol in hypercholesterolemic subjects and improves lipid transfer to high-density lipoprotein in normal and hypercholesterolemic subjects. 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. Lipid lowering agents, cognitive decline, and dementia: the three-city study. Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet. Different effects of palmitic and stearic acid-enriched diets on serum lipids and lipoproteins and plasma cholesteryl ester transfer protein activity in healthy young women. Effects of vitamin E and HMG‐CoA reductase inhibition on cholesteryl ester transfer protein and lecithin‐cholesterol acyltransferase in hypercholesterolemia Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Effect of fish oil on lipoproteins, lecithin:cholesterol acyltransferase, and lipid transfer protein activity in humans. Common genetic variation of the cholesteryl ester transfer protein gene strongly predicts future cardiovascular death in patients with coronary artery disease. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease Safety of anacetrapib in patients with or at high risk for coronary heart disease. Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)—A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics Serum cholesterol, cholesteryl ester, and high-density lipoprotein development in newborn infants: response to formulas supplemented with cholesterol and gamma-linolenic acid. Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. Effect of treatment with simvastatin on serum cholesteryl ester transfer in patients on dialysis. PERFECT Study Collaborative Group.
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 BACKGROUND The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high‐density lipoprotein ( HDL ) cholesterol level , reduces the low‐density lipoprotein ( LDL ) cholesterol level , and enhances cellular cholesterol efflux capacity . We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high‐risk vascular disease . METHODS In a multicenter , r and omized , double‐blind , placebo‐controlled phase 3 trial , we enrolled 12,092 patients who had at least one of the following conditions : an acute coronary syndrome within the previous 30 to 365 days , cerebrovascular atherosclerotic disease , peripheral vascular arterial disease , or diabetes mellitus with coronary artery disease . Patients were r and omly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo , administered daily , in addition to st and ard medical therapy . The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes , myocardial infa rct ion , stroke , coronary revascularization , or hospitalization for unstable angina . RESULTS At 3 months , a 31.1 % decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0 % increase with placebo , and a 133.2 % increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6 % increase with placebo . After 1363 of the planned 1670 primary end‐point events had occurred , the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy . After a median of 26 months of evacetrapib or placebo , a primary end‐point event occurred in 12.9 % of the patients in the evacetrapib group and in 12.8 % of those in the placebo group ( hazard ratio , 1.01 ; 95 % confidence interval , 0.91 to 1.11 ; P=0.91 ) . CONCLUSIONS Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers , treatment with evacetrapib did not result in a lower rate of cardiovascular events  than placebo among patients with high‐risk vascular disease . ( Funded by Eli Lilly ; ACCELERATE Clinical Trials.gov number , NCT01687998 . BACKGROUND High-density lipoprotein cholesterol ( HDL-C ) levels are inversely associated with cardiovascular risk . Cholesteryl ester transfer protein inhibition is one strategy for increasing HDL-C. This study evaluated the lipid-altering efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy or coadministered with atorvastatin in patients with dyslipidemia . METHODS A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia ( 53.8 % of the study population had low HDL-C ) were r and omized equally to one of 10 groups : 5 groups received background statin therapy of atorvastatin 20 mg and 5 did not , and each of these was r and omized to placebo , anacetrapib 10 , 40 , 150 , and 300 mg once daily for 8 weeks . An equal proportion of patients had triglycerides > 150 mg/dL in each group . RESULTS For placebo and anacetrapib monotherapy ( 10 , 40 , 150 , and 300 mg ) , least squares mean percent changes from baseline to week 8 for low-density lipoprotein cholesterol ( LDL-C ) were 2 % , -16 % , -27 % , -40 % , and -39 % , respectively , and for HDL-C were 4 % , 44 % , 86 % , 139 % , and 133 % , respectively ( P < .001 vs placebo for all doses ) . Coadministration of anacetrapib with atorvastatin produced significant incremental LDL-C reductions and similar HDL-C increases versus atorvastatin monotherapy . For both anacetrapib monotherapy and coadministration with atorvastatin , the LDL-C reductions were similar in patients with baseline triglyceride levels greater than and less than or equal to the median . Anacetrapib was well tolerated , and the incidence of adverse events was similar for placebo and all active treatment groups . There were no increases in systolic or diastolic blood pressure in any treatment arm . CONCLUSIONS Anacetrapib , as monotherapy or coadministered with atorvastatin , produced significant reductions in LDL-C and increases in HDL-C ; the net result of treatment with anacetrapib + atorvastatin was approximately 70 % lowering of LDL-C and more than doubling of HDL-C.  Anacetrapib was generally well tolerated with no discernable effect on blood pressure BACKGROUND In observational analyses , higher levels of high-density lipoprotein ( HDL ) cholesterol have been associated with a lower risk of coronary heart disease events . However , whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain . Inhibition of cholesteryl ester transfer protein ( CETP ) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes . METHODS We r and omly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib  , at a dose of 600 mg daily , or placebo , in addition to the best available evidence -based care . The primary efficacy end point was a composite of death from coronary heart disease , nonfatal myocardial infa rct ion , ischemic stroke , unstable angina , or cardiac arrest with resuscitation . RESULTS At the time of r and omization , the mean HDL cholesterol level was 42 mg per deciliter ( 1.1 mmol per liter ) , and the mean low-density lipoprotein ( LDL ) cholesterol level was 76 mg per deciliter ( 2.0 mmol per liter ) . Over the course of the trial , HDL cholesterol levels increased from baseline by 4 to 11 % in the placebo group and by 31 to 40 % in the dalcetrapib group . Dalcetrapib had a minimal effect on LDL cholesterol levels . Patients were followed for a median of 31 months . At a prespecified interim analysis that included 1135 primary end-point events ( 71 % of the projected total number ) , the independent data and safety monitoring board recommended termination of the trial for futility . As compared with placebo , dalcetrapib did not alter the risk of the primary end point ( cumulative event rate , 8.0 % and 8.3 % , respectively ; hazard ratio with dalcetrapib , 1.04 ; 95 % confidence interval , 0.93 to 1.16 ; P=0.52 ) and did not have a significant effect on any component of the primary end point or total mortality . The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo ( P<0.001 for both comparisons ) . CONCLUSIONS In patients who had had a recent acute coronary syndrome , dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events . ( Funded by F. Hoffmann-La Roche ; dal- OUTCOMES Clinical Trials.gov number , NCT00658515 . ) 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 ] . ) A remarkable reduction of plasma concentrations of high-density lipoproteins ( HDL ) , especially of the HDL(2 ) subfraction , is one of the typical lipoprotein alterations found in patients with familial combined hyperlipidemia ( FCHL ) . Fourteen FCHL patients received 4 capsules daily of Omacor ( an omega-3 polyunsaturated fatty acid [ omega3 FA ] concentrate providing 1.88 g of eicosapentaenoic acid [ EPA ] and 1.48 g of docosahexaenoic acid [ DHA ] per day ; Pronova Biocare , Oslo , Norway ) or placebo for 8 weeks in a r and omized , double-blind , crossover study . Plasma triglycerides were 44 % lower , and LDL cholesterol and apoliporpotein (apo)B were 25 % and 7 % higher after Omacor than placebo . HDL cholesterol was higher ( + 8 % ) after Omacor than placebo , but this difference did not achieve statistical significance . Omacor caused a selective increase of the more buoyant HDL(2 ) subfraction ; plasma HDL(2 ) cholesterol and total mass increased by 40 % and 26 % , respectively , whereas HDL(3 ) cholesterol and total mass decreased by 4 % and 6 % . Both HDL(2 ) and HDL(3 ) were enriched in cholesteryl esters and depleted of triglycerides after Omacor . No changes were observed in the plasma concentration of major HDL apolipoproteins , LpA-I and LpA-I : A-II particles , lecithin : cholesterol acyltransferase ( LCAT ) , and cholesteryl ester transfer protein ( CETP ) . The plasma concentration of the HDL-bound antioxidant enzyme paraoxonase increased by 10 % after Omacor . Omacor may be helpful in correcting multiple lipoprotein abnormalities and reducing cardiovascular risk in FCHL patients Background : The biological functions of high-density lipoproteins ( HDLs ) contribute to explaining the cardioprotective role of the lipoprotein beyond quantitative HDL cholesterol levels . A few small-scale interventions with a single antioxidant have improved some HDL functions . However , to date , no long-term , large-scale , r and omized controlled trial has been conducted to assess the effects of an antioxidant-rich dietary pattern ( such as a traditional Mediterranean diet [ TMD ] ) on HDL function in humans . Methods : This study was performed in a r and om sub sample of volunteers from the PREDIMED Study ( Prevención con Dieta Mediterránea ; n=296 ) after a 1-year intervention . We compared the effects of 2 TMDs , one enriched with virgin olive oil ( TMD-VOO ; n=100 ) and the other enriched with nuts ( TMD-Nuts ; n=100 ) , with respect to a low-fat control diet ( n=96 ) . We assessed the effects of both TMDs on the role of HDL particles on reverse cholesterol transport ( cholesterol efflux capacity , HDL ability to esterify cholesterol , and cholesteryl ester transfer protein activity ) , HDL antioxidant properties ( paraoxonase-1 arylesterase activity and total HDL antioxidant capacity on low-density lipoproteins ) , and HDL vasodilatory capacity ( HDL ability to induce the release of nitric oxide in endothelial cells ) . We also studied the effects of a TMD on several HDL quality -related characteristics ( HDL particle oxidation , resistance against oxidative modification , main lipid and protein composition , and size distribution ) . Results : Both TMDs increased cholesterol efflux capacity relative to baseline ( P=0.018 and P=0.013 for TMD-VOO and TMD-Nuts , respectively ) . The TMD-VOO intervention decreased cholesteryl ester transfer protein activity ( relative to baseline , P=0.028 ) and increased HDL ability to esterify cholesterol , paraoxonase-1 arylesterase activity , and HDL vasodilatory capacity ( relative to control , P=0.039 , P=0.012 , and P=0.026 , respectively ) . Adherence to a TMD induced these beneficial changes by improving HDL oxidative status and composition . The 3 diets increased the percentage of large HDL particles ( relative to baseline , P<0.001 ) . Conclusions : The TMD , especially when enriched with virgin olive oil , improved HDL atheroprotective functions in humans . Clinical Trial Registration : URL : http://www.controlled-trials.com . Unique identifier : IS RCT N35739639 Orange juice ( OJ ) is regularly consumed worldwide , but its effects on plasma lipids have rarely been explored . This study hypothesized that consumption of OJ concentrate would improve lipid levels and lipid metabolism , which are important in high-density lipoprotein ( HDL ) function in normolipidemic ( NC ) and hypercholesterolemic ( HCH ) subjects . Fourteen HCH and 31 NC adults consumed 750 mL/day OJ concentrate ( 1:6 OJ/water ) for 60 days . Eight control subjects did not consume OJ for 60 days . Plasma was collected before and on the last day for biochemical analysis and an in vitro assay of transfers of radioactively labeled free-cholesterol , cholesteryl esters , phospholipids , and triglycerides from lipoprotein-like nanoemulsions to HDL . Orange juice consumption decreased low-density lipoprotein cholesterol ( 160 ± 17 to 141 ± 26 mg/dL , P < .01 ) in the HCH group but not in the NC group . HDL-cholesterol and triglycerides remained unchanged in both groups . Free-cholesterol transfer to HDL increased ( HCH : 4.4 ± 2 to 5.6 ± 1 % , NC : 3.2 ± 2 to 6.2 ± 1 % , P < .05 ) whereas triglyceride ( HCH 4.9 ± 1 to 3.1 ± 1 % , NC 4.4 ± 1 to 3.4 ± 1 % , P < .05 ) and phospholipid ( HCH 21.6 ± 2 to 18.6 ± 3 % , NC 20.2 ± 2 to 18.4 ± 2 % , P < .05 ) transfers decreased in both groups . Cholesteryl-ester transfer decreased only in HCH ( 3.6 ± 1 to 3.1 ± 1 % , P < .05 ) , but not in NC . In control subjects , plasma lipids and transfers were unaltered for 60 days . Thus , by decreasing atherogenic low-density lipoprotein cholesterol in HCH and increasing HDL ability to take up free cholesterol in HCH and NC , OJ may be beneficial to both groups as free-cholesterol transfer to HDL is crucial for cholesterol esterification and reverse cholesterol transport 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 The aim of this prospect i ve cohort study was to evaluate the effects of lipid lowering agent ( LLA ) intake on cognitive function in 6,830 community-dwelling elderly persons .  Cognitive performance ( global cognitive functioning , visual memory , verbal fluency , psychomotor speed , and executive function ) , clinical diagnosis of dementia , and fibrate and statin use , were evaluated at baseline , and 2 , 4 , and 7 year follow-up . Multivariate Cox models were stratified by gender and adjusted for sociodemographic characteristics , mental and physical health including vascular risk factors , and genetic vulnerability ( apolipoprotein E and cholesteryl ester transfer protein ) . For women but not men , fibrate use was specifically associated with an increased risk over 7 years of decline in visual memory only ( HR = 1.29 , 95 % CI = 1.09 - 1.54 , p = 0.004 ) , and did not increase risk for incident dementia . This association was independent of genetic vulnerability related to apolipoprotein E and cholesteryl exchange transfer protein polymorphisms and occurred only in women with higher low density lipoprotein (LDL)-cholesterol levels and treated with fibrate ( HR = 1.39 , 95 % CI = 1.08 - 1.79 , p = 0.01 ) and not in those with lower LDL-cholesterol levels irrespective of fibrate treatment . For both genders , no significant associations were found between statins ( irrespective of their lipophilicity ) and either cognitive decline or dementia incidence . This prospect i ve study , adjusting for multiple confounders , found no evidence that LLA given in late life reduced the risk of cognitive decline and dementia , but did raise the possibility that women with treatment-resistant high LDL-cholesterol may be at increased risk of decline in visual memory 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 The effects of palmitic and stearic acid-enriched diets on serum lipids , lipoproteins , apolipoproteins ( apo ) A-I and B , and plasma cholesteryl ester transfer protein ( CETP ) activity were examined in 12 healthy young women . Subjects followed the two experimental diets for 4 weeks according to a r and omized crossover design . Both experimental diet periods were preceded by consumption of a baseline diet for 2 weeks . The diets provided 37 % of total energy intake ( E% ) as fat , and differed only with respect to fatty acid composition . There was a substitution of 5E% of palmitic acid or stearic acid in the experimental diets for 5E% of monounsaturated fatty acids in the baseline diet . After the palmitic acid diet , serum total and high-density lipoprotein ( HDL ) cholesterol and apo A-I concentrations were higher ( 8 % , P = .015 , 9 % , P = .040 , and 11%,P = .011 , respectively ) and mean serum low-density lipoprotein ( LDL ) cholesterol concentration tended to be higher ( 8 % , P = .077 ) as compared with values after the stearic acid diet .  Plasma CETP activity increased in the palmitic acid diet as compared with the stearic acid diet ( 12 % , P = .006 ) . In conclusion , palmitic acid and stearic acid-enriched diets had different effects on serum lipids and lipoproteins and also on plasma CETP activity in young healthy women 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 We have investigated the effects of two fibric acid derivatives , bezafibrate mono ( 400 mg daily ) and gemfibrozil ( 600 mg b.d . ) , in 29 patients with type IIb hyperlipoproteinaemia . All patients received placebo and each drug for 8 weeks in r and omised order in a double-blind , cross-over study design ed to evaluate any different effects of the drugs on serum lipoproteins , cholesteryl ester transfer protein ( CETP ) , cholesteryl ester transfer activity ( CETA ) , plasma fibrinogen , plasminogen activator inhibitor-I ( PAI-1 ) or paraoxonase . Serum cholesterol decreased ( P < 0.05 ) with gemfibrozil , but the effect of bezafibrate on serum cholesterol did not achieve statistical significance ( placebo 8.34 + /- 1.05 ( mean + /- S.D. ) , gemfibrozil 7.70 + /- 1.23 and bezafibrate 7.8 + /- 1.37 mmol/l ) . Both drugs decreased the serum triglyceride concentration ( both P < 0.001 ) ( placebo 4.39 ( 3.13 - 5.75 ) ( median ( interquartile range ) ) , bezafibrate 2.26 ( 1.89 - 3.89 ) and gemfibrozil 2.00 ( 1.30 - 3.30 ) mmol/l ) and very low density lipoprotein ( VLDL ) cholesterol ( both P < 0.001 ) ( placebo 1.18 ( 0.74 - 2.30 ) , bezafibrate 0.59 ( 0.34 - 0.85 ) and gemfibrozil 0.48 ( 0.34 - 0.68 ) mmol/l ) . Discontinuous gradient ultracentrifugation ( DGU ) revealed that Sf 60 - 400 ( large VLDL ) decreased by more than 50 % and Sf 20 - 60 ( small VLDL ) by more than 30 % with each of the drugs ( both P < 0.001 ) , neither of which affected the composition of these lipoproteins . Gemfibrozil decreased the concentration of Sf 12 - 20 lipoprotein ( intermediate density lipoprotein ; IDL ) by 23 % ( P < 0.01 ) , whereas the effect of bezafibrate on this lipoprotein did not achieve statistical significance . Neither drug altered the concentration of apolipoprotein B or of total Sf 0 - 12 lipoproteins ( low density lipoprotein , ( LDL ) ) . Both , however , significantly increased the quantity of free cholesterol in Sf 0 - 12 lipoproteins ( P < 0.05 ) . Overall the concentration of triglycerides decreased significantly in all lipoproteins isolated by DGU ( Sf 0 - 12 , Sf 12 - 20 , Sf 20 - 60 , Sf 60 - 400 ) on gemfibrozil treatment , but only in Sf 20 - 60 and Sf 60 - 400 on bezafibrate ( all P < 0.05 ) . Both drugs also increased serum high density lipoprotein ( HDL ) cholesterol ( placebo 1.15 + /- 0.29 , bezafibrate 1.27 + /- 0.38 ( P < 0.01 ) and gemfibrozil 1.26 + /- 0.49 ( P < 0.05 ) mmol/l ) and HDL3 cholesterol concentration ( placebo 0.59 + /- 0.12 , bezafibrate 0.72 + /- 0.23 ( P < 0.001 ) and gemfibrozil 0.70 + /- 0.24 ( P < 0.01 ) mmol/l ) . Serum apolipoprotein A1 ( apo A1 ) was increased ( P < 0.05 ) by bezafibrate compared to gemfibrozil ( placebo 103 + /- 26 , bezafibrate 111 + /- 28 and gemfibrozil 102 + /- 25 mg/dl ) and CETA from HDL to VLDL and LDL was decreased ( P < 0.05 ) by bezafibrate compared to placebo , but the apparent decrease with gemfibrozil did not achieve statistical significance ( placebo 39.6 + /- 17.7 , bezafibrate 32.3 + /- 14.7 and gemfibrozil 33.8 + /- 15.0 nmol/ml/h ) . Neither drug affected the circulating concentration of CETP . Plasma fibrinogen was increased ( P < 0.05 ) by gemfibrozil ( placebo 4.16 ( 3.38 - 4.71 ) and gemfibrozil 4.65 ( 4.05 - 5.77 ) g/l ) and was significantly lower ( P < 0.001 ) on bezafibrate ( 3.60 ( 3.18 - 4.54 ) g/l ) than on gemfibrozil treatment . There was a significant ( P < 0.05 ) increase in PAI-1 activity with bezafibrate and a similar trend with gemfibrozil ( placebo 41.2 ( 25.6 - 64.5 ) , bezafibrate 50.5 ( 35.1 - 73.9 ) and gemfibrozil 48.5 ( 31.5 - 5.4 U/l ) . Neither fibrate influenced plasma concentrations of PAI-1 nor were the activities of lecithin : cholesterol acyl transferase or paraoxonase affected . The major difference in the action of the two drugs on lipoprotein metabolism was the greater effect of gemfibrozil in decreasing the overall serum concentration of Sf 12 - 20 lipoproteins and the triglycerides in Sf 12 - 20 and 0 - 12 lipoproteins . Bezafibrate , however , increased serum apo A1 concentration and significantly decreased CETA . The two drugs also had different effects on the plasma fibrinogen levels , which increased with gemfibrozil and tended to A group of 33 mildly hypercholesterolemic men were stratified into three groups on diets closely matched except for the polyunsaturated fatty acid supplement . The first group received 14 g/day of linoleic acid ( safflower oil ) ; the second group , 9 g of alpha-linolenic acid ( linseed oil ) ; and the third group , 3.8 g of n-3 fatty acids ( fish oil ) . Only fish oil lowered plasma triglycerides ( by 24 % at 6 weeks , p less than 0.05 compared to safflower oil ) . Very low density lipoprotein ( VLDL ) apoprotein ( apo ) B , triglyceride , and cholesterol all fell significantly with the fish-oil diet ( p less than 0.01 ) . Low density lipoprotein ( LDL ) cholesterol fell by 0.18 and 0.10 mmol/l , respectively , with the safflower-oil and linseed-oil diets , but rose by 0.24 mmol/l with the fish-oil diet ( p less than 0.05 ) . There was a strong correlation between the changes in VLDL triglyceride and LDL cholesterol with the fish-oil diet ( r = -0.84 , p less than 0.002 ) . High density lipoprotein ( HDL ) cholesterol fell slightly in all three groups ( p less than 0.02 with the linseed-oil diet only ) . However , the apo A-I/A-II ratio rose by 5 % ( p less than 0.05 ) , and the HDL2/HDL3 protein ratio increased by 28 % with the fish-oil diet ( p less than 0.005 ) . Fish oil reduced the capacity for transfer of cholesteryl ester between LDL and HDL by 23 % ( p less than 0.02 compared to baseline ) , reduced plasma lecithin : cholesterol acyltransferase activity by 21 % ( p less than 0.05 ) , and reduced maximal stimulated thromboxane production by 9 % ( p less than 0.05 ) . Thus fish oil produced three potentially beneficial changes : significant decreases in VLDL concentration and in thromboxane production and an increase in the HDL2/HDL3 ratio . The increase in the average HDL particle size probably reflected reduced cholesteryl ester acceptor capacity within the smaller pool of VLDL , as well as the decline in lipid transfer activity in plasma involving transfer protein itself , LDL , and HDL 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 BACKGROUND Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin‐based treatment of low‐density lipoprotein ( LDL ) cholesterol levels . The inhibition of cholesteryl ester transfer protein ( CETP ) by anacetrapib reduces LDL cholesterol levels and increases high‐density lipoprotein ( HDL ) cholesterol levels . However , trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes . METHODS We conducted a r and omized , double‐blind , placebo‐controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter ( 1.58 mmol per liter ) , a mean non‐HDL cholesterol level of 92 mg per deciliter ( 2.38 mmol per liter ) , and a mean HDL cholesterol level of 40 mg per deciliter ( 1.03 mmol per liter ) . The patients were assigned to receive either 100 mg of anacetrapib once daily ( 15,225 patients ) or matching placebo ( 15,224 patients ) . The primary outcome was the first major coronary event , a composite of coronary death , myocardial infa rct ion , or coronary revascularization . RESULTS During the median follow‐up period of 4.1 years , the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group ( 1640 of 15,225 patients [ 10.8 % ] vs. 1803 of 15,224 patients [ 11.8 % ] ; rate ratio , 0.91 ; 95 % confidence interval , 0.85 to 0.97 ; P=0.004 ) . The relative difference in risk was similar across multiple prespecified subgroups . At the trial midpoint , the mean level of HDL cholesterol was higher by 43 mg per deciliter ( 1.12 mmol per liter ) in the anacetrapib group than in the placebo group ( a relative difference of 104 % ) , and the mean level of non‐HDL cholesterol was lower by 17 mg per deciliter ( 0.44 mmol per liter ) , a relative difference of ‐18 % . There were no significant between‐group differences in the risk of death , cancer , or other serious adverse events . CONCLUSIONS Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy , the use of anacetrapib result ed in a lower incidence of major coronary events than the use of placebo . ( Funded by Merck and others ; Current Controlled Trials number , IS RCT N48678192 ; Clinical Trials.gov number , NCT01252953 ; and EudraCT number , 2010‐023467‐18 . BACKGROUND Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein ( HDL ) cholesterol and reduces low-density lipoprotein ( LDL ) cholesterol . METHODS We conducted a r and omized , double-blind , placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease . Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of  anacetrapib or placebo daily for 18 months . The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks ( HDL cholesterol level was a secondary end point ) and the safety and side-effect profile of anacetrapib through 76 weeks . Cardiovascular events and deaths were prospect ively adjudicated . RESULTS A total of 1623 patients underwent r and omization . By 24 weeks , the LDL cholesterol level had been reduced from 81 mg per deciliter ( 2.1 mmol per liter ) to 45 mg per deciliter ( 1.2 mmol per liter ) in the anacetrapib group , as compared with a reduction from 82 mg per deciliter ( 2.1 mmol per liter ) to 77 mg per deciliter ( 2.0 mmol per liter ) in the placebo group (P<0.001)--a 39.8 % reduction with anacetrapib beyond that seen with placebo . In addition , the HDL cholesterol level increased from 41 mg per deciliter ( 1.0 mmol per liter ) to 101 mg per deciliter ( 2.6 mmol per liter ) in the anacetrapib group , as compared with an increase from 40 mg per deciliter ( 1.0 mmol per liter ) to 46 mg per deciliter ( 1.2 mmol per liter ) in the placebo group (P<0.001)--a 138.1 % increase with anacetrapib beyond that seen with placebo . Through 76 weeks , no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo . Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib ( 2.0 % ) and 21 patients receiving placebo ( 2.6 % ) ( P = 0.40 ) . The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability ( confidence ) of 94 % that anacetrapib would not be associated with a 25 % increase in cardiovascular events , as seen with torcetrapib . CONCLUSIONS Treatment with anacetrapib had robust effects on LDL and HDL cholesterol , had an acceptable side-effect profile , and , within the limits of the power of this study , did not result in the adverse cardiovascular effects observed with torcetrapib . ( Funded by Merck Research Laboratories ; Clinical Trials.gov number , NCT00685776 . ) Background Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin – based treatment . Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low‐density lipoprotein ( LDL ) cholesterol by around 25 % to 40 % and more than doubles high‐density lipoprotein ( HDL ) cholesterol . However , it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events . Methods The REVEAL study is a r and omized , double‐blind , placebo‐controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL‐lowering treatment with atorvastatin for an average of at least 4 years among patients with preexisting atherosclerotic vascular disease . The primary assessment is an intention‐to‐treat comparison among all r and omized participants of the effects of allocation to anacetrapib on major coronary events ( defined as the occurrence of coronary death , myocardial infa rct ion , or coronary revascularization ) . Results Between August 2011 and October 2013 , 30,449 individuals in Europe , North America , and China were r and omized to receive anacetrapib 100 mg daily or matching placebo .  Mean ( SD ) age was 67 ( 8) years , 84 % were male , 88 % had a history of coronary heart disease , 22 % had cerebrovascular disease , and 37 % had diabetes mellitus . At the r and omization visit ( after at least 8 weeks on a protocol ‐defined atorvastatin regimen ) , mean plasma LDL cholesterol was 61 ( 15 ) mg/dL and HDL cholesterol was 40 ( 10 ) mg/dL. Interpretation The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen . Results are anticipated in 2017 Healthy newborn infants were either breast-fed or r and omly design ated  to receive a st and ard formula , formula plus cholesterol , or formula plus gamma-linolenic acid at birth . At 0 , 7 , and 30 days of life , the following variables were measured : cholesteryl esters ( cholesteryl arachidonate , cholesteryl oleate , cholesteryl palmitate , and cholesteryl linoleate ) , high-density lipoprotein ( HDL ) cholesterol , apoproteins ( A-I , A-II , B , C-II , C-III , and E ) , and the cholesterol and apoprotein A-I content of the HDL subfractions HDL-2b , HDL-(2a + 3a ) , and HDL-(3b + 3c ) . Breast-fed infants had higher serum levels of cholesterol , cholesteryl oleate , cholesteryl palmitate , cholesteryl arachidonate , and HDL-2b than had formula-fed infants . Addition of gamma-linolenic acid to formula raised cholesteryl-arachidonate levels , and cholesterol and gamma-linolenic acid raised serum HDL-2b levels compared with those produced by unsupplemented formula . Our data suggest that both exogenous cholesterol and gamma-linolenic acid contribute to the maturation of HDL particles associated with human milk consumption in newborn infants . They may also promote adequate delivery of cholesterol and arachidonic acid to the developing brain 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 OBJECTIVES The aim of this study was to determine whether a novel small molecule RVX-208 affects apolipoprotein (apo)A-I and high-density lipoprotein cholesterol ( HDL-C ) levels in vitro and in vivo . BACKGROUND Increased apoA-I and HDL-C levels are potential therapeutic targets for reducing atherosclerotic disease . METHODS HepG2 cells were treated with 0 to 60 mumol/l RVX-208 followed by assays for apoA-I and HDL-C production . For in vivo studies , African green monkeys ( AGMs ) received 15 to 60 mg/kg/day RVX-208  , and the serum was analyzed for lipoprotein levels , HDL-subparticle distribution , cholesterol efflux , and activity of lipid-modifying enzymes . A phase I clinical trial was conducted in healthy volunteers ( given 1 to 20 mg/kg/day of RVX-208 ) to assess safety , tolerability , and pharmacokinetics . RESULTS The RVX-208 induced apoA-I messenger ribonucleic acid and protein synthesis in HepG2 cells , leading to increased levels of pre-beta-migrating and alpha-lipoprotein particles containing apoA-I ( LpA-I ) in spent media . Similarly , in AGMs , RVX-208 treatment for 63 days increased serum apoA-I and HDL-C levels ( 60 % and 97 % , respectively ) . In addition , the levels of pre-beta(1)-LpA-I and alpha1-LpA-I HDL-subparticles were increased as well as adenosine triphosphate binding cassette AI , adenosine triphosphate binding cassette G1 , and scavenger receptor class B type I-dependent cholesterol efflux . These changes were not mediated by cholesteryl-ester-transfer protein . Treatment of humans for 1 week with oral RVX-208 increased apoA-I , pre-beta-HDL , and HDL functionality . CONCLUSIONS RVX-208 increases apoA-I and HDL-C in vitro and in vivo . In AGMs , RVX-208 raises serum pre-beta(1)-LpA-I and alpha-LpA-I levels and enhances cholesterol efflux . Data in humans point to beneficial features of RVX-208 that might be useful for treating atherosclerosis BACKGROUND Plasma cholesteryl ester transfer activity is increased in patients with chronic renal failure on dialysis who have elevated levels of apolipoprotein B (apoB)-containing lipoproteins .  Simvastatin , a 3-hydroxy-3-methylglutaryl coenzyme A ( HMG CoA ) reductase inhibitor , reduces levels of these lipoproteins but the effect of treatment on cholesteryl ester transfer activity in patients on dialysis remains to be determined . METHODS We measured serum newly synthesized cholesteryl ester transfer ( NCET ) activity , lecithin : cholesterol acyltransferase ( LCAT ) activity and serum lipid , lipoprotein and apolipoprotein concentrations before and immediately after 6 months treatment with simvastatin ( 10 mg daily , n = 24 ) or placebo ( n = 29 ) in 53 patients with chronic renal failure receiving haemodialysis or continuous ambulatory peritoneal dialysis ( CAPD ) . RESULTS Simvastatin therapy significantly reduced serum cholesterol , LDL cholesterol , apoB concentrations , and both NCET ( P = 0.001 ) and LCAT ( P = 0.012 ) rates . The decrease in NCET activity was correlated significantly with the corresponding decrease in apoB concentration ( r = 0.715 , P < 0.001 ) and LCAT activity ( r = 0.715 , P < 0.001 ) during simvastatin therapy and was no longer significant when apoB concentration ( P = 0.14 ) or LCAT activity ( P = 0.07 ) were controlled . CONCLUSIONS These data show that simvastatin therapy reduces serum NCET rates , and suggest that this may be linked to the concomitant decrease in levels of apoB-containing lipoproteins which are acceptors of transferred cholesteryl esters , and to the decrease in serum LCAT rates in patients with chronic renal failure with treatment
This significant effect was derived by the use of fibrates ( RR 0.80 , 95 % CI 0.73–0.87 , P < 0.001 , I2 = 22 % ) and meta-regression analysis showed that this benefit was consistent with an absolute reduction in low-density lipoprotein cholesterol .
Meta-regression analyses failed to demonstrate a significant association of pharmacologically increased high-density lipoprotein cholesterol with key endpoints .
Conclusion The use of high-density lipoprotein cholesterol modifying treatments had no significant effect on cardiovascular mortality , stroke or all-cause mortality .
The beneficial effect on myocardial infa rct ion was lost when drugs were used with statin therapy
Background The effects of increasing high-density lipoprotein cholesterol on cardiovascular outcomes remain uncertain .
Design We conducted a meta- analysis to investigate the effects of high-density lipoprotein cholesterol modifiers ( niacin , fibrates and cholesteryl ester transfer protein inhibitors ) on cardiovascular outcomes .