title: High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Effects of dalcetrapib in patients with a recent acute coronary syndrome. A Multiregional, Randomized Evaluation of the Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients With Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol. Lipid-modifying efficacy and tolerability of anacetrapib added to ongoing statin therapy in Japanese patients with dyslipidemia. Association of Genetic Variants Related to CETP Inhibitors and Statins With Lipoprotein Levels and Cardiovascular Risk Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Safety of anacetrapib in patients with or at high risk for coronary heart disease. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients with Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol. Evacetrapib and Cardiovascular Outcomes in High‐Risk Vascular Disease Effects of torcetrapib in patients at high risk for coronary events. Efficacy, safety, tolerability, and pharmacokinetic profile of evacetrapib administered as monotherapy or in combination with atorvastatin in Japanese patients with dyslipidemia.
abstract: The British Regional Heart Study ( BRHS ) reported in 1986 that much of the inverse relation of high-density lipoprotein cholesterol ( HDLC ) and incidence of coronary heart disease was eliminated by covariance adjustment . Using the proportional hazards model and adjusting for age , blood pressure , smoking , body mass index , and low-density lipoprotein cholesterol , we analyzed this relation separately in the Framingham Heart Study ( FHS ) , Lipid Research Clinics Prevalence Mortality Follow-up Study ( LRCF ) and Coronary Primary Prevention Trial ( CPPT ) , and Multiple Risk Factor Intervention Trial ( MRFIT ) . In CPPT and MRFIT ( both r and omized trials in middle-age high-risk men ) , only the control groups were analyzed . A 1-mg/dl ( 0.026 mM ) increment in HDLC was associated with a significant coronary heart disease risk decrement of 2 % in men ( FHS , CPPT , and MRFIT ) and 3 % in women ( FHS ) . In LRCF , where only fatal outcomes were documented , a 1-mg/dl increment in HDLC was associated with significant 3.7 % ( men ) and 4.7 % ( women ) decrements in cardiovascular disease mortality rates . The 95 % confidence intervals for these decrements in coronary heart and cardiovascular disease risk in the four studies overlapped considerably , and all contained the range 1.9 - 2.9 % . HDLC levels were essentially unrelated to non-cardiovascular disease mortality . When differences in analytic methodology were eliminated , a consistent inverse relation of HDLC levels and coronary heart disease event rates was apparent in BRHS as well as in the four American studies 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 . ) This phase 3 , multiregional , r and omized , double-blind , placebo-controlled study assessed the efficacy/safety profile of anacetrapib added to ongoing therapy with statin ± other lipid-modifying therapies in patients with hypercholesterolemia who were not at their low-density lipoprotein ( LDL-C ) goal ( as per the National Cholesterol Education Program Adult Treatment Panel III guidelines ) and in those with low high-density lipoprotein cholesterol ( HDL-C ) . Patients on a stable dose of statin ± other lipid-modifying therapies and with LDL-C ≥70 to < 115 , ≥100 to < 145 , ≥130 , or ≥160 mg/dl for very high , high , moderate , or low CHD risk or at LDL-C goal ( per CHD risk category ) with HDL-C ≤40 mg/dl were r and omized in a ratio of 1:1 to anacetrapib 100 mg ( n = 290 ) or placebo ( n = 293 ) for 24 weeks , followed by a 12-week off-drug phase . The co- primary end points were % change from baseline in LDL-C and HDL-C and the safety profile of anacetrapib  . Treatment with anacetrapib  reduced LDL-C ( BQ ) by 37 % ( 95 % confidence interval -42.5 , -31.0 ) and increased HDL-C by 118 % ( 95 % confidence interval 110.6 , 125.7 ) relative to placebo ( p < 0.001 for both ) . Anacetrapib also reduced non-HDL-C , apolipoprotein B , and lipoprotein a and increased apolipoprotein AI versus placebo ( p < 0.001 for all ) . There were no clinical ly meaningful differences between the anacetrapib and placebo groups in the % patients who discontinued drug due to an adverse event or in abnormalities in liver enzymes , creatine kinase , blood pressure , electrolytes , or adjudicated cardiovascular events . Treatment with anacetrapib substantially reduced LDL-C and also increased HDL-C and was well tolerated over 24 weeks in statin-treated patients with hypercholesterolemia or low BACKGROUND AND AIMS We aim ed to assess the effects of cholesteryl ester transfer protein inhibitor anacetrapib added to statin ± other lipid-modifying therapies ( LMT ) in Japanese patients with dyslipidemia who were not at their LDL-C goal . METHODS Patients on a stable dose of statin ± other LMT with LDL-C ≥100 mg/dL to < 145 mg/dL , ≥120 mg/dL to < 165 mg/dL , ≥140 mg/dL or ≥160 mg/dL for patients with a history of coronary heart disease ( CHD ) , high- , moderate- and low-risk patients respectively , were r and omized 2:1 , stratified by background therapy , to double-blind anacetrapib 100 mg ( n = 204 ) or placebo ( n = 103 ) for 24 weeks , followed by a 28-week open-label extension phase ( anacetrapib 100 mg ) and a 12-week off-drug safety follow-up phase . The primary endpoint was percent change from baseline in LDL-C ( beta-quantification method ) , as well as the safety profile  of anacetrapib at Week 24 ; HDL-C was a key secondary endpoint . RESULTS Anacetrapib 100 mg further reduced LDL-C ( 38.0 % ) , non-HDL-C ( 35.1 % ) , ApoB ( 28.7 % ) , and Lp(a ) ( 48.3 % ) and increased HDL-C ( 148.9 % ) and ApoAI ( 50.7 % ) versus placebo ( p < 0.001 for all ) . There were no meaningful differences between the groups in the proportion of patients with liver enzymes elevations ( 2.0 % vs. 0 % ) , creatine kinase elevations overall ( 0.5 % vs. 0 % ) or with muscle symptoms ( 0.5 % vs. 0 % ) , blood pressure , electrolytes or adjudicated cardiovascular events ( 0.5 % vs. 0 % ) . In the open-label period , sustained effects on lipid parameters were observed with anacetrapib and the treatment was generally well tolerated . CONCLUSIONS Long-term treatment with anacetrapib 100 mg substantially reduced LDL-C , increased HDL-C and was well tolerated in Japanese patients with dyslipidemia ( Clinical Trials.gov number NCT01760460 ) 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 Present guidelines emphasise the importance of low concentrations of LDL cholesterol ( LDL-C ) in patients with familial hypercholesterolaemia . In most patients with the disease , however , these concentrations are not achieved with present treatments , so additional treatment is therefore warranted . Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease . We aim ed to investigate the safety and efficacy of anacetrapib , a cholesteryl ester transfer protein inhibitor , in patients with heterozygous familial hypercholesterolaemia . METHODS In this multicentre , r and omised , double-blind , placebo-controlled , phase 3 study , patients aged 18 - 80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia , on optimum lipid-lowering treatment for at least 6 weeks , and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible . We r and omly allocated participants with a computer-generated allocation schedule ( 2:1 ; block size of six ; no stratification ) to oral anacetrapib 100 mg or placebo for 52 weeks , with a 12 week post-treatment follow-up afterwards . We masked patients , care providers , and those assessing outcomes to treatment groups throughout the study . The primary outcome was percentage change from baseline in LDL-C concentration . We did analysis using a constrained longitudinal repeated measures model . This trial is registered with Clinical Trials.gov , number NCT01524289 . FINDINGS Between Feb 10 , 2012 , and Feb 12 , 2014 , we r and omly allocated 204 patients to anacetrapib and 102 to placebo . One patient in the anacetrapib group did not receive the drug . At week 52 , anacetrapib  reduced mean LDL-C concentration from 3·3 mmol/L ( SD 0·8 ) to 2·1 mmol/L ( 0·8 ; percentage change 36·0 % [ 95 % CI -39·5 to -32·5 ] compared with an increase with placebo from 3·4 mmol/L ( 1·2 ) to 3·5 mmol/L ( 1·6 ; percentage change 3·7 % [ -1·2 to 8·6 ] , with a difference in percentage change between anacetrapib and placebo of -39·7 % ( 95 % CI -45·7 to -33·7 ; p<0·0001 ) . The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo ( 4 [ 2 % ] of 203 vs none [ 0 % ] of 102 ; p=0·1544 ) , but the proportion with adverse events leading to discontinuation was similar ( 12 [ 6 % ] of 203 vs five [ 5 % ] of 102 ) . INTERPRETATION In patients with heterozygous familial hypercholesterolaemia , treatment with anacetrapib for 1 year was well tolerated and result ed in substantial reductions in LDL-C concentration . Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study . FUNDING Merck & Co , BACKGROUND Dyslipidaemia remains a significant risk factor for cardiovascular disease and additional lipid-modifying treatments are warranted to further decrease the cardiovascular disease burden . We assessed the safety , tolerability and efficacy of a novel cholesterol esterase transfer protein ( CETP ) inhibitor TA-8995 in patients with mild dyslipidaemia . METHODS In this r and omised , double-blind , placebo-controlled , parallel-group phase 2 trial , we recruited patients ( aged 18 - 75 years ) from 17 sites ( hospitals and independent clinical research organisations ) in the Netherl and s and Denmark with fasting LDL cholesterol levels between 2·5 mmol/L and 4·5 mmol/L , HDL cholesterol levels between 0·8 and 1·8 mmol/L and triglyceride levels below 4·5 mmol/L after washout of lipid-lowering treatments . Patients were r and omly allocated ( 1:1 ) by a computer-generated r and omisation schedule to receive one of the following nine treatments : a once a day dose of 1 mg , 2·5 mg , 5 mg , or 10 mg TA-8995 or matching placebo ; 10 mg TA-8995 plus 20 mg atorvastatin ; 10 mg TA-8995 plus 10 mg rosuvastatin or 20 mg atorvastatin or 10 mg rosuvastatin alone . We overencapsulated statins to achieve masking . The primary outcome was percentage change in LDL cholesterol and HDL cholesterol from baseline at week 12 , analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT01970215 . FINDINGS Between Aug 15 , 2013 , and Jan 10 , 2014 , 364 patients were enrolled . At week 12 , LDL cholesterol levels were reduced by 27·4 % in patients assigned to the 1 mg dose , 32·7 % in patients given the 2·5 mg dose , 45·3 % in those given the 5 mg dose , and 45·3 % in those given the 10 mg dose ( p<0·0001 ) . LDL cholesterol levels were reduced by 68·2 % in patients given 10 mg TA-8995 plus atorvastatin , and by 63·3 % in patients given rosuvastatin plus 10 mg TA-8995 ( p<0·0001 ) . A daily dose of 1 mg TA-8995  increased HDL cholesterol levels by 75·8 % , 2·5 mg by 124·3 % , 5 mg by 157·1 % , and 10 mg dose by 179·0 % ( p<0·0001 ) . In patients receiving 10 mg TA-8995 and 20 mg  atorvastatin HDL cholesterol levels increased by 152·1 % and in patients receiving 10 mg TA-8995 and 10 mg rosuvastatin by 157·5 % . We recorded no serious adverse events or signs of liver or muscle toxic effects . INTERPRETATION TA-8995 , a novel CETP inhibitor , is well tolerated and has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidaemia . A cardiovascular disease outcome trial is needed to translate these effects into a reduction of cardiovascular disease events . FUNDING Dezima AIMS High-density lipoprotein cholesterol ( HDL-C ) is inversely associated with cardiovascular ( CV ) events and thus an attractive therapeutic target . However , in spite of marked elevations in HDL-C , the first cholesterol transport protein ( CETP ) inhibitor torcetrapib raised blood pressure ( BP ) , impaired endothelial function , and increased CV mortality and morbidity . Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib . As HDL stimulates nitric oxide ( NO ) , suppresses inflammation , and exerts protective CV effects , we investigated the effects of dalcetrapib on endothelial function , blood pressure , inflammatory markers , and lipids in patients with , or at risk of , coronary heart disease ( CHD ) in a double-blind r and omized placebo-controlled trial ( clinical trials.gov number NCT00655538 ) . METHODS AND RESULTS Patients with target low-density lipoprotein cholesterol ( LDL-C ) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of st and ard therapy ( including statins ) . The primary outcome measures were the change from baseline of flow-mediated dilatation ( % FMD ) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring ( ABPM ) at week 4 . Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks , changes in HDL-C , LDL-C , triglycerides , CETP activity , as well as st and ard safety parameters . Four hundred seventy-six patients were r and omized . Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4 % with placebo or dalcetrapib , respectively and did not change significantly from placebo after 12 and 36 weeks ( P = 0.1764 and 0.9515 , respectively ) . After 4 , 24 , and 36 weeks of treatment with dalcetrapib , CETP activity decreased by 51 , 53 , and 56 % ( placebo corrected , all P < 0.0001 ) , while at weeks 4 , 12 , and 36 HDL-C increased by 25 , 27 , and 31 % ( placebo corrected , all P < 0.0001 ) . Low-density lipoprotein cholesterol levels did not change . At baseline , ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group ( P = 0.3372 and 0.1248 , respectively , placebo-corrected change from baseline ) and did not change for up to 36 weeks . Biomarkers of inflammation , oxidative stress , and coagulation did not change during follow-up except for Lp-PLA(2 ) mass levels which increased by 17 % ( placebo corrected ) . Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event ( 11 events with dalcetrapib and 12 events with placebo ) . CONCLUSION The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD . Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function , blood pressure , or markers of inflammation and oxidative stress . The dal- OUTCOMES trial ( NCT00658515 ) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function 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 . ) Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Dalcetrapib modulates cholesteryl ester transfer protein ( CETP ) activity to raise high-density lipoprotein cholesterol ( HDL-C ) . After the failure of torcetrapib it was unknown if HDL produced by interaction with CETP had pro-atherogenic or pro-inflammatory properties . dal-PLAQUE is the first multicentre study using novel non-invasive multimodality imaging to assess structural and inflammatory indices of atherosclerosis as primary endpoints . METHODS In this phase 2b , double-blind , multicentre trial , patients ( aged 18 - 75 years ) with , or with high risk of , coronary heart disease were r and omly assigned ( 1:1 ) to dalcetrapib 600 mg/day or placebo for 24 months . R and omisation was done with a computer-generated r and omisation code and was stratified by centre . Patients and investigators were masked to treatment . Co primary endpoints were MRI-assessed indices ( total vessel area , wall area , wall thickness , and normalised wall index [ average carotid ] ) after 24 months and (18)F-fluorodeoxyglucose ( (18)F-FDG ) PET/CT assessment of arterial inflammation within an index vessel ( right carotid , left carotid , or ascending thoracic aorta ) after 6 months , with no-harm boundaries established before unblinding of the trial . Analysis was by intention to treat . This trial is registered at Clinical Trials.gov , NCT00655473 . FINDINGS 189 patients were screened and 130 r and omly assigned to placebo ( 66 patients ) or dalcetrapib ( 64 patients ) . For the co primary MRI and PET/CT endpoints , CIs were below the no-harm boundary or the adverse change was numerically lower in the dalcetrapib group than in the placebo group . MRI-derived change in total vessel area was reduced in patients given dalcetrapib compared with those given placebo after 24 months ; absolute change from baseline relative to placebo was -4·01 mm(2 ) ( 90 % CI -7·23 to -0·80 ; nominal p=0·04 ) . The PET/CT measure of index vessel most-diseased-segment target-to- background ratio ( TBR ) was not different between groups , but carotid artery analysis showed a 7 % reduction in most-diseased-segment TBR in the dalcetrapib group compared with the placebo group ( -7·3 [ 90 % CI -13·5 to -0·8 ] ; nominal p=0·07 ) . Dalcetrapib did not increase office blood pressure and the frequency of adverse events was similar between groups . INTERPRETATION Dalcetrapib showed no evidence of a pathological effect related to the arterial wall over 24 months . Moreover , this trial suggests possible beneficial vascular effects of dalcetrapib , including the reduction in total vessel enlargement over 24 months , but long-term safety and clinical outcomes efficacy of dalcetrapib need to be analysed . FUNDING F Hoffmann-La Roche Aims Co- primary objectives were to evaluate dalcetrapib ( JTT-705/RO4607381 ) , which targets cholesteryl ester transfer protein ( CETP ) , effects on high-density lipoprotein cholesterol ( HDL-C ) in participants with coronary heart disease or risk equivalents and to evaluate potential changes in mesenteric lymph nodes . Methods and results Double-blind trial with participants r and omized ( 2:1 ) to dalcetrapib 900 mg/day ( higher than 600 mg phase III dose ) or placebo , both with atorvastatin  , for 24 weeks ( n = 135 ; one without post-baseline efficacy data was excluded from intent-to-treat population ) ; a subset continued for 24-week extension ( n = 77 ) . Lipid changes and safety parameters were assessed . Mesenteric lymph nodes were evaluated by magnetic resonance imaging . Dalcetrapib  increased HDL-C ( 33.4 % , Week 24 ; 33.8 % , Week 48 ) , decreased CETP activity ( –53.5 % , Week 24 ; –56.5 % , Week 48 ) , and increased apolipoprotein A-I ( 11.4 % , Week 24 ; 16.4 % , Week 48 ) . Dalcetrapib showed no clinical ly relevant differences vs. placebo  in adverse events , laboratory parameters including aldosterone , electrocardiograms , and vital signs including blood pressure ( BP ) .  Dalcetrapib had no measurable , clinical ly relevant effect on lymph node size . Conclusion Dalcetrapib 900 mg administered for up to 48 weeks showed no clinical ly relevant changes in lymph nodes , BP , or other safety parameters . Dalcetrapib effectively increased HDL-C over 48 weeks of treatment To assess the effects of anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol ( LDL-C ) goal ( as per National Cholesterol Education Program Adult Treatment Panel III [ NCEP ATP III ] guidelines ) and in those with low high-density lipoprotein cholesterol ( HDL-C ) . Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70 , ≥100 , ≥130 , or ≥160 mg/dl for very high , high , moderate , and low coronary heart disease risk , respectively , or at LDL-C goal with HDL-C ≤40 mg/dl , were r and omized 1:1:1 , stratified by background therapy use ,  to anacetrapib  100 mg ( n = 153 ) , anacetrapib 25 mg ( n = 152 ) , or placebo ( n = 154 ) for 24 weeks , followed by a 12-week off-drug reversal phase . The primary end points were percent change from baseline in LDL-C ( beta-quantification method ) and HDL-C , as well as the safety profile  of anacetrapib . Both doses of anacetrapib  reduced LDL-C , non-HDL-C , apolipoprotein ( Apo ) B , and lipoprotein a and increased HDL-C and Apo AI versus placebo ( p < 0.001 for all ) . There were no meaningful differences between the anacetrapib 25 mg , 100 mg , and placebo groups in the proportions of discontinuations due to drug-related adverse events ( 0.7 % , 1.3 % vs 1.3 % ) or in abnormalities in liver enzymes ( 0 % , 0 % vs 0.7 % ) , creatine kinase elevations overall ( 0 % , 0.7 % vs 0 % ) or with muscle symptoms ( none seen ) , blood pressure , electrolytes , or adjudicated cardiovascular events ( 0.7 % , 0.7 % vs 1.3 % ) . In conclusion , treatment with anacetrapib result ed in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated 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 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 ] . ) The cholesteryl ester transfer protein ( CETP ) inhibitor evacetrapib has been previously shown to increase high-density lipoprotein cholesterol ( HDL-C ) and decrease low-density lipoprotein cholesterol ( LDL-C ) levels , as monotherapy or in combination with statins . In this study , 165 Japanese patients with elevated LDL-C or low HDL-C levels were r and omly assigned to receive placebo , evacetrapib monotherapy 30 mg , 100 mg , or 500 mg , atorvastatin 10 mg , or evacetrapib 100 mg in combination with atorvastatin 10 mg . After 12 weeks , evacetrapib monotherapy increased HDL-C levels by 74 % , 115 % , and 136 % and decreased LDL-C levels by 15 % , 23 % , and 22 % and CETP activity by 50 % , 83 % , and 95 % ( for the 30-mg , 100-mg , and 500-mg dose groups , respectively ) versus placebo . In combination with atorvastatin 10 mg , evacetrapib 100 mg increased HDL-C levels by 103 % and decreased LDL-C levels by 15 % and CETP activity by 68 % versus atorvastatin alone . After a 4- to 6-week washout , HDL-C , LDL-C , and CETP mass and activity returned to baseline levels in the evacetrapib-treated groups , and most patients had evacetrapib concentrations below the quantitation limit . Evacetrapib monotherapy or in combination with atorvastatin was not likely to be associated with any significant change in blood pressure and did not have any adverse effects on mineralocorticoid or glucocorticoid measures . Notably , plasma evacetrapib concentrations were mostly undetectable , and all pharmacodynamic biomarkers ( HDL-C and LDL-C levels and CETP mass and activity ) returned to baseline after a 4- to 6-week washout . In conclusion , evacetrapib as monotherapy or in combination with atorvastatin effectively decreased CETP activity and LDL-C levels and increased HDL-C levels after 12 weeks in Japanese patients with dyslipidemia
target: 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: 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 .