human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
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
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    