hypercholesterolaemia is a major risk factor for the development of atherosclerosis and coronary heart disease ( chd ) .
reducing low - density lipoprotein cholesterol ( ldl - c ) with statins lowers the risk of chd events and all - cause mortality and there is a clear relation between the degree of absolute ldl - c lowering and the degree of cardiovascular event reduction .
comparative data of intensive vs. standard - dose statin treatment suggest that the lower the ldl - c concentration , the greater the benefit in high cardiovascular risk patients .
mmol / l ( < 100 mg / dl ) in patients at high risk and < 1.8 mmol / l ( < 70 mg / dl ) , or a 50% reduction from baseline , in those at very high risk . despite more widespread use of intensive statin therapy , a substantial proportion of high - risk hypercholesterolaemic patients do not achieve adequate ldl - c reduction .
while the latest us guidelines emphasize the use of intensive statin therapy , they call for evidence for new lipid - modifying agents to determine the incremental cardiovascular disease event - reduction benefits on top of statin therapy .
such therapies include fully human monoclonal antibodies against proprotein convertase subtilisin / kexin 9 ( pcsk9 ) , including alirocumab ( formerly sar236553/regn727 ) and evolocumab .
alirocumab reduces ldl - c concentrations by 4070% in combination with other lipid - lowering therapies ( llt ) or as monotherapy .
guided by these very large reductions , even in combination with concomitant llt , the combo ii study ( nct01644188 ) was designed to test the hypothesis of the superiority of alirocumab vs. ezetimibe in ldl - c reduction in patients at high risk for cardiovascular events and who require additional pharmacological management because their current statin therapy failed to achieve their ldl - c treatment goal .
the selection of doses , dosing frequency , and dose - increase approach was based on the ldl - c reduction needed to provide the best achievement of the target ldl - c level at the lowest dose .
combo ii is an ongoing double - blind , double - dummy , active - controlled , parallel - group , 104-week study of alirocumab vs. ezetimibe in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins .
the study was conducted at 126 sites ( europe , israel , north america , south africa , south korea ) ( supplementary material online , text s1 ) , with enrolment from august 2012 to may 2013 .
results are presented from a pre - specified analysis , including final efficacy results up to week 52 and safety data up to the date of the last patient week 52 visit .
patients were to have hypercholesterolaemia and established chd or chd risk - equivalents ( ischaemic stroke , peripheral artery disease , moderate chronic kidney disease , or diabetes mellitus plus 2 additional risk factors ) , and be treated with a maximally tolerated dose of statin therapy [ i.e. rosuvastatin 20/40 mg , atorvastatin 40/80 mg , or simvastatin 80 mg ( if on this dose for > 1 year ) ] or on a lower dose provided the reason for doing so was documented .
statin dose had to be stable for 4 weeks before the screening visit and use of other llt was not permitted . at screening , patients with documented cardiovascular disease ( cvd ) and ldl - c 1.8
mmol / l ( 70 mg / dl ) or no documented history of cvd but who were at high cardiovascular risk and had ldl - c 2.6 mmol / l ( 100 mg / dl ) were eligible to participate .
the study was performed in accordance with the principles of the declaration of helsinki and all applicable amendments by the world medical assemblies , and the international conference on harmonization guidelines for good clinical practice .
eligible patients entered a screening period of up to 3 weeks before randomization during which they were trained to self - inject using a prefilled pen ( autoinjector ) , vital signs were taken , a 12-lead electrocardiogram was performed , and fasting blood and urine samples were obtained .
whose triglycerides exceeded 4.5 mmol / l , the central laboratory automatically measured ldl - c using the beta - quantification method ( medpace reference laboratories ; cincinnati , oh , usa ; leuven , belgium ; singapore ) .
other lipid parameters [ total cholesterol , high - density lipoprotein cholesterol ( hdl - c ) , triglycerides , apolipoprotein b , and lipoprotein a ] were measured directly by the central laboratory ( medpace reference laboratories ) .
eligible patients were randomized to alirocumab or ezetimibe through an interactive voice response system ( almac company ) , using a permuted - block design with a 2:1 allocation ratio . to attain balance between arms for factors that may have influenced treatment response
, patients were stratified according to history of myocardial infarction or ischaemic stroke , intensity of statin treatment , and geographic region .
after randomization , patients entered a double - blind , double - dummy treatment period lasting 104 weeks .
patients were randomized to either subcutaneous ( sc ) alirocumab 75 mg ( in 1 ml volume ) every 2 weeks ( q2w ) ( plus oral placebo for ezetimibe daily ) or 10 mg oral ezetimibe daily ( plus placebo sc q2w for alirocumab ) and continued to receive their background statin therapy .
the dose in the alirocumab arm ( only ) was automatically increased , per protocol , at week 12 to 150 mg q2w ( 1 ml volume ) if the week-8 ldl - c value was 1.8
the study is ongoing at the time of writing , and randomized treatment will continue until week 104 , followed by an 8-week post - treatment observational period .
patients were instructed to remain on a stable diet [ national cholesterol education program adult treatment panel iii ( ncep atp iii ) therapeutic lifestyle changes diet or equivalent ] and to maintain the same daily statin dose throughout the study . the primary endpoint was percent change in calculated ldl - c from baseline to week 24 , using all ldl - c values from week 24 regardless of adherence to treatment [ intent - to - treat ( itt ) approach ] .
principal secondary efficacy endpoints included : percent change in calculated ldl - c from baseline to week 24 ( on - treatment analysis ) , and from baseline to weeks 12 ( itt / on - treatment analysis ) or 52 ( itt analysis ) ; percent change in apolipoprotein b , non - hdl - c , total cholesterol , lipoprotein a , hdl - c , fasting triglycerides , and apolipoprotein a-1 from baseline to week 24 ( itt analysis ) , and proportion of patients reaching calculated ldl - c < 1.8 mmol / l at week 24 ( itt / on - treatment analysis ) .
safety was assessed by analysing adverse - event reports ( including adjudicated cardiovascular events and serious adverse events ) and laboratory analyses from the time of signed informed consent until the end of the study .
laboratory analyses for all safety parameters , except lipids , were performed by a central laboratory ( covance laboratories ; indianapolis , in , usa ; geneva , switzerland ) . in this analysis
we estimated that a sample of 96 participants would have 95% power to detect a difference in mean percent change in ldl - c of 20% at a significance level of 0.05 for a 2-sided test , assuming a common standard deviation of 25% and all 96 patients having an evaluable primary endpoint .
however , the sample size was set at 660 ( 2:1 randomization ) to better assess the safety of alirocumab in the context of this study and in the overall integrated safety database of the odyssey program .
the population for the primary efficacy analysis comprised randomized patients with a calculated ldl - c value at baseline and at least one of the planned time - points from weeks 4 to 24 , regardless of treatment adherence ( itt population ) .
the primary endpoint was analysed using a mixed effect model with a repeated measures ( mmrm ) approach to account for missing data .
all available post - baseline data at planned time - points from week 4 to 52 regardless of status on- or off - treatment were used in the mmrm for the itt analysis , with the model used to provide least - squares ( ls ) mean estimates and comparison between treatment arms of ldl - c reductions at week 24 .
the models included fixed categorical effects of treatment group , randomization strata , time - point , treatment - by - time - point interaction , and strata - by - time - point interaction , as well as the continuous fixed covariates of baseline ldl - c value and baseline value - by - time - point interaction .
a hierarchical procedure was used to control type i error and to handle multiple secondary endpoint analyses . because the primary endpoint analysis ( itt ) was significant at the 5% alpha level
on treatment in the pre - specified modified itt ( mitt ) population ( i.e. all patients in the itt population who had an evaluable primary efficacy endpoint while on treatment , defined as the period between first dose of study treatment up to 21 days after last injection , or 3 days after taking the last capsule , whichever came first ) .
for the on - treatment analysis , all available on - treatment measurements ( i.e. up to 21 days after last injection or 3 days after the last capsule , whichever came first ) at planned time - points from weeks 4 to 52 were used in the mmrm . a sensitivity analysis , based on a pattern mixture model ,
was conducted to evaluate the impact of missing data on the primary endpoint ; in this approach , missing calculated ldl - c values during the  on - treatment period were multiply imputed using a model assuming  missing at random and missing calculated ldl - c values during the post - treatment period were multiply imputed using random draws from a normal distribution where the mean was equal to subject 's own baseline value .
secondary endpoints comprising continuous variables with a normal distribution were analysed using the mmrm model .
those secondary endpoints with a non - normal distribution ( lipoprotein a and triglycerides ) and the binary ( non - continuous ) variable secondary endpoints were analysed using a multiple imputation approach for handling of missing values followed by robust regression ( for lipoprotein a and triglycerides ) or logistic regression ( for the binary endpoints ) .
safety analyses used a pre - specified cut - off corresponding to the last patient visit at week 52 and included all data collected between 52 and 104 weeks .
data are reported descriptively based on data from randomized patients who received at least one dose or partial ( in the event that < 1 ml was injected ) dose of study treatment .
the analysis was performed using sas version 9.2 software ( sas institute inc . , cary , nc , usa ) .
eligible patients entered a screening period of up to 3 weeks before randomization during which they were trained to self - inject using a prefilled pen ( autoinjector ) , vital signs were taken , a 12-lead electrocardiogram was performed , and fasting blood and urine samples were obtained .
whose triglycerides exceeded 4.5 mmol / l , the central laboratory automatically measured ldl - c using the beta - quantification method ( medpace reference laboratories ; cincinnati , oh , usa ; leuven , belgium ; singapore ) .
other lipid parameters [ total cholesterol , high - density lipoprotein cholesterol ( hdl - c ) , triglycerides , apolipoprotein b , and lipoprotein a ] were measured directly by the central laboratory ( medpace reference laboratories ) .
eligible patients were randomized to alirocumab or ezetimibe through an interactive voice response system ( almac company ) , using a permuted - block design with a 2:1 allocation ratio . to attain balance between arms for factors that may have influenced treatment response , patients were stratified according to history of myocardial infarction or ischaemic stroke , intensity of statin treatment , and geographic region .
after randomization , patients entered a double - blind , double - dummy treatment period lasting 104 weeks .
patients were randomized to either subcutaneous ( sc ) alirocumab 75 mg ( in 1 ml volume ) every 2 weeks ( q2w ) ( plus oral placebo for ezetimibe daily ) or 10 mg oral ezetimibe daily ( plus placebo sc q2w for alirocumab ) and continued to receive their background statin therapy .
the dose in the alirocumab arm ( only ) was automatically increased , per protocol , at week 12 to 150 mg q2w ( 1 ml volume ) if the week-8 ldl - c value was 1.8
the study is ongoing at the time of writing , and randomized treatment will continue until week 104 , followed by an 8-week post - treatment observational period .
patients were instructed to remain on a stable diet [ national cholesterol education program adult treatment panel iii ( ncep atp iii ) therapeutic lifestyle changes diet or equivalent ] and to maintain the same daily statin dose throughout the study .
the primary endpoint was percent change in calculated ldl - c from baseline to week 24 , using all ldl - c values from week 24 regardless of adherence to treatment [ intent - to - treat ( itt ) approach ] .
principal secondary efficacy endpoints included : percent change in calculated ldl - c from baseline to week 24 ( on - treatment analysis ) , and from baseline to weeks 12 ( itt / on - treatment analysis ) or 52 ( itt analysis ) ; percent change in apolipoprotein b , non - hdl - c , total cholesterol , lipoprotein a , hdl - c , fasting triglycerides , and apolipoprotein a-1 from baseline to week 24 ( itt analysis ) , and proportion of patients reaching calculated ldl - c < 1.8 mmol / l at week 24 ( itt / on - treatment analysis ) .
safety was assessed by analysing adverse - event reports ( including adjudicated cardiovascular events and serious adverse events ) and laboratory analyses from the time of signed informed consent until the end of the study .
laboratory analyses for all safety parameters , except lipids , were performed by a central laboratory ( covance laboratories ; indianapolis , in , usa ; geneva , switzerland ) . in this analysis
we estimated that a sample of 96 participants would have 95% power to detect a difference in mean percent change in ldl - c of 20% at a significance level of 0.05 for a 2-sided test , assuming a common standard deviation of 25% and all 96 patients having an evaluable primary endpoint .
however , the sample size was set at 660 ( 2:1 randomization ) to better assess the safety of alirocumab in the context of this study and in the overall integrated safety database of the odyssey program .
the population for the primary efficacy analysis comprised randomized patients with a calculated ldl - c value at baseline and at least one of the planned time - points from weeks 4 to 24 , regardless of treatment adherence ( itt population ) .
the primary endpoint was analysed using a mixed effect model with a repeated measures ( mmrm ) approach to account for missing data .
all available post - baseline data at planned time - points from week 4 to 52 regardless of status on- or off - treatment were used in the mmrm for the itt analysis , with the model used to provide least - squares ( ls ) mean estimates and comparison between treatment arms of ldl - c reductions at week 24 .
the models included fixed categorical effects of treatment group , randomization strata , time - point , treatment - by - time - point interaction , and strata - by - time - point interaction , as well as the continuous fixed covariates of baseline ldl - c value and baseline value - by - time - point interaction .
a hierarchical procedure was used to control type i error and to handle multiple secondary endpoint analyses .
because the primary endpoint analysis ( itt ) was significant at the 5% alpha level , key secondary efficacy endpoints were tested sequentially .
on treatment in the pre - specified modified itt ( mitt ) population ( i.e. all patients in the itt population who had an evaluable primary efficacy endpoint while on treatment , defined as the period between first dose of study treatment up to 21 days after last injection , or 3 days after taking the last capsule , whichever came first ) .
for the on - treatment analysis , all available on - treatment measurements ( i.e. up to 21 days after last injection or 3 days after the last capsule , whichever came first ) at planned time - points from weeks 4 to 52 were used in the mmrm . a sensitivity analysis , based on a pattern mixture model ,
was conducted to evaluate the impact of missing data on the primary endpoint ; in this approach , missing calculated ldl - c values during the  on - treatment period were multiply imputed using a model assuming  missing at random and missing calculated ldl - c values during the post - treatment period were multiply imputed using random draws from a normal distribution where the mean was equal to subject 's own baseline value .
secondary endpoints comprising continuous variables with a normal distribution were analysed using the mmrm model . those secondary endpoints with a non - normal distribution ( lipoprotein a and triglycerides ) and the binary ( non - continuous ) variable secondary endpoints were analysed using a multiple imputation approach for handling of missing values followed by robust regression ( for lipoprotein a and triglycerides ) or logistic regression ( for the binary endpoints ) .
safety analyses used a pre - specified cut - off corresponding to the last patient visit at week 52 and included all data collected between 52 and 104 weeks .
data are reported descriptively based on data from randomized patients who received at least one dose or partial ( in the event that < 1 ml was injected ) dose of study treatment .
the analysis was performed using sas version 9.2 software ( sas institute inc . , cary , nc , usa ) .
we screened 1112 high cardiovascular risk patients , 720 of whom were eligible and consented to participate ( figure  1 ) .
the mean  standard deviation ( sd ) age was 61.6  9.3 years , 73.6% of participants were men , 90.1% had chd , and 30.7% had type 2 diabetes mellitus .
mean  sd body mass index ( bmi ) was 30.3  5.1 kg / m and 113 ( n = 46.9% ) had a bmi 30 kg / m .
the mean  sd baseline calculated ldl - c concentration was 2.8  0.9 mmol / l ; 66.7% ( n = 480 ) were taking atorvastatin 40/80 mg / day or rosuvastatin 20/40 mg / day , and 2.1% ( n = 15 ) were on simvastatin 80 mg .
the reasons documented for taking a lower dose of statin are detailed in supplementary material online , table s2 .
table  1baseline characteristics ( all randomized patients)characteristicalirocumab ( n = 479)ezetimibe ( n = 241)age ( years)61.7  9.461.3  9.2men360 ( 75.2)170 ( 70.5)race  white404 ( 84.3)206 ( 85.5 )  black or african american21 ( 4.4)7 ( 2.9 )  other54 ( 11.3)28 ( 11.6)body mass index ( kg / m)30.0  5.430.3  5.1cardiovascular history and risk factors  any cardiovascular history / risk factor(s)477 ( 99.6)241 ( 100 )  coronary heart disease437 ( 91.2)212 ( 88.0 )  acute myocardial infarction277 ( 57.8)139 ( 57.7 )  silent myocardial infarction11 ( 2.3)4 ( 1.7 )  unstable angina106 ( 22.1)46 ( 19.1 )  coronary revascularization procedure330 ( 68.9)165 ( 68.5 )  other clinically significant chd184 ( 38.4)82 ( 34.0 )  chd associated with 1 comorbidity ( among hypertension , diabetes or moderate ckd ) and/or associated with other cvd ( ischaemic stroke , peripheral artery disease)366 ( 76.4)178 ( 73.9 )  coronary heart disease risk - equivalent151 ( 31.5)72 ( 29.9 )  ischaemic stroke40 ( 8.4)20 ( 8.3 )  peripheral artery disease24 ( 5.0)11 ( 4.6 )  moderate ckd61 ( 12.7)23 ( 9.5 )  diabetes mellitus plus 2 additional risk factors59 ( 12.3)31 ( 12.9 )  2 chd risk - equivalents or 1 chd risk - equivalent associated with hypertension or diabetes141 ( 29.4)67 ( 27.8 )  diabetes mellitus type 12 ( 0.4)0  diabetes mellitus type 2145 ( 30.3)76 ( 31.5)laboratory values  hba1c ( % ) 6.05  0.756.07  0.77  lipid parameters  ldl - c ( friedewald formula ) ( mmol / l)2.8  0.92.7  0.9  range0.67.91.06.3  apolipoprotein b ( g / l)0.9  0.20.9  0.2  total cholesterol ( mmol / l)4.8  1.14.8  1.1  non - hdl - c ( mmol / l)3.6  1.03.5  1.0  lipoprotein a ( mmol / l)1.0 ( 0.3 , 2.5)0.8 ( 0.3 , 2.0 )  triglycerides ( fasted ) ( mmol / l)1.5 ( 1.1 , 2.2)1.6 ( 1.2 , 2.3 )  hdl - c ( mmol / l)1.2  0.31.2  0.4  c - reactive protein ( nmol / l)34.1  74.134.6  51.1statin therapy at randomization478 ( 99.8)241 ( 100 )  taking high - intensity statin320 ( 66.8)160 ( 66.4 )  atorvastatin237 ( 49.5)118 ( 49.0 )  rosuvastatin137 ( 28.6)75 ( 31.1 )  simvastatin105 ( 21.9)49 ( 20.3)data are mean  sd , n ( % ) , or median ( interquartile range ) unless otherwise stated . to convert cholesterol measurements to mg / dl , divide by 0.02586 ; and to convert triglycerides measurements to mg / dl , divide by 0.01129.chd , coronary heart disease ; ckd , chronic kidney disease ; cvd , cardiovascular disease ; hba1c , glycated haemoglobin a1c ; hdl - c , high - density lipoprotein cholesterol ; ldl - c , low - density lipoprotein cholesterol ; sc , subcutaneous ; sd , standard deviation ; q2w , every 2 weeks.there were no clinically or statistically significant between - group differences.alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
mmol / l ( 70 mg / dl).10 mg / day oral ezetimibe.race was self-reported.asian , american indian , alaska native , other.high-intensity statin defined as 4080 mg / day atorvastatin or 2040 mg / day rosuvastatin . 

baseline characteristics ( all randomized patients ) data are mean  sd , n ( % ) , or median ( interquartile range ) unless otherwise stated . to convert cholesterol measurements to mg / dl , divide by 0.02586 ; and to convert triglycerides measurements to mg / dl , divide by 0.01129 .
chd , coronary heart disease ; ckd , chronic kidney disease ; cvd , cardiovascular disease ; hba1c , glycated haemoglobin a1c ; hdl - c , high - density lipoprotein cholesterol ; ldl - c , low - density lipoprotein cholesterol ; sc , subcutaneous ; sd , standard deviation ; q2w , every 2 weeks .
alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
high - intensity statin defined as 4080 mg / day atorvastatin or 2040 mg / day rosuvastatin .
the mean  sd duration of injection exposure was 58.0  18.7 weeks ( 26.6  8.8 injections ) in the alirocumab arm and 57.7  19.0 weeks ( 26.6  9.0 injections ) in the ezetimibe arm .
at the time of this analysis , 84.8% of patients in the alirocumab arm and 85.5% in the ezetimibe arm were receiving ongoing treatment ( active or placebo ) ; 18.4% ( 82 patients ) of patients in the alirocumab arm had the dose increased at week 12 to the 150 mg q2w dosing regimen because their ldl - c at week 8 was 1.8 mmol / l .
for the primary endpoint , mean  standard error ( se ) reductions in ldl - c from baseline to week 24 were 50.6  1.4% in the alirocumab arm and 20.7  1.9% in the ezetimibe arm , both on a background of maximally tolerated statin therapy , with a statistically significant difference of the means  se between groups of 29.8 ( 95% ci 34.4 to 25.3 , p < 0.0001 ) ( table  2 ) .
the results for the on - treatment analysis ( table  2 and supplementary material online , table s3 ) and the sensitivity analysis ( supplementary material online , table s4 ) were consistent with the primary endpoint .
the proportion of patients who achieved the target ldl - c of < 1.8 mmol / l at week 24 ( itt analysis ) was 77.0% in the alirocumab arm and 45.6% in the ezetimibe arm ( p < 0.0001 ) .
the distribution of baseline and achieved ldl - c values at 24 weeks is shown in figure  2 .
table  2percent change from baseline to week 24 in ldl - c ( itt and on - treatment ) and in secondary lipid parameters ( itt)all patients on maximally tolerated statin therapyalirocumabezetimibealirocumab vs. ezetimibels mean difference  se ( % ) 95% cip - valueprimary endpoint : ldl - c  ittn = 467n = 240  ls mean  se change from baseline ( % ) 50.6  1.420.7  1.929.8  2.334.4 to 25.3<0.0001  on - treatmentn = 464n = 235  baseline ldl - c , mean  sd ( mmol / l)2.8  0.92.7  0.9 
range0.67.91.06.3  ls mean  se change from baseline ( % ) 52.4  1.321.8  1.830.6  2.234.9 to 26.2<0.0001secondary lipid parameters ( itt ) ,
ls mean  se change from baseline ( % ) n = 467n = 240  ldl - c ( beta - quantification method)47.7  1.618.0  2.229.7  2.735.0 to 24.4<0.0001  ldl - c ( baseline to week 12)51.2  1.321.8  1.829.4  2.233.7 to 25.1<0.0001  apolipoprotein b40.7  1.118.3  1.522.4  1.826.0 to 18.8<0.0001  non - hdl - c42.1  1.219.2  1.722.9  2.026.9 to 18.9<0.0001  total cholesterol29.3  0.914.6  1.214.7  1.517.7 to 11.7<0.0001  lipoprotein a27.8  1.46.1  2.021.7  2.426.4 to 17.0<0.0001  hdl - c8.6 
0.80.5  1.18.1  1.35.4 to 10.7<0.0001  triglycerides ( fasted)13.0  1.512.8  2.00.3  2.55.1 to 4.60.91  apolipoprotein a-15.0  0.61.3  0.86.3  1.04.3 to 8.3<0.0001ci , confidence interval ; hdl - c , high - density lipoprotein cholesterol ; itt , intention - to - treat ; ldl - c , low - density lipoprotein cholesterol ; ls , least squares ; q2w , every 2 weeks ; sc , subcutaneous ; se , standard error.one patient was not on maximally tolerated statin therapy.alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
mmol / l ( 70 mg / dl).10 mg / day oral ezetimibe.sensitivity analysis conducted in 180 patients in the ezetimibe group and 361 patients in the alirocumab group .
p - value for descriptive purposes only.combined estimate obtained by combining adjusted means  se from robust regression model analyses of the different imputed data sets ( multiple imputation).p - value for descriptive purposes only ( according to the hierarchical analysis , formal analysis was stopped after triglycerides , which were not statistically significant ) . 

figure  2distribution by 10 mg / dl increments of ldl - c concentration at baseline and at week 24 in patients on maximally tolerated statins and alirocumab or ezetimibe .
comparison between week 24 vs. baseline is descriptive and exploratory only , as data for all patients were not available at week 24 .
percent change from baseline to week 24 in ldl - c ( itt and on - treatment ) and in secondary lipid parameters ( itt ) ci , confidence interval ; hdl - c , high - density lipoprotein cholesterol ; itt , intention - to - treat ; ldl - c , low - density lipoprotein cholesterol ; ls , least squares ; q2w , every 2 weeks ; sc , subcutaneous ; se , standard error .
alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
sensitivity analysis conducted in 180 patients in the ezetimibe group and 361 patients in the alirocumab group .
combined estimate obtained by combining adjusted means  se from robust regression model analyses of the different imputed data sets ( multiple imputation ) .
p - value for descriptive purposes only ( according to the hierarchical analysis , formal analysis was stopped after triglycerides , which were not statistically significant ) .
distribution by 10 mg / dl increments of ldl - c concentration at baseline and at week 24 in patients on maximally tolerated statins and alirocumab or ezetimibe .
comparison between week 24 vs. baseline is descriptive and exploratory only , as data for all patients were not available at week 24 .
the time - course of changes in ldl - c concentrations in the alirocumab and ezetimibe arms from baseline to 52 weeks is shown in figure  3 .
mean ldl - c concentrations dropped rapidly in the first 4 weeks , but to a greater degree in the alirocumab arm .
figure  3ldl - c values achieved vs. study time - points ( itt analysis ) .
percentages above weeks 12 and 24 data points indicate ls mean ( se ) percent change from baseline .
percentages above weeks 12 and 24 data points indicate ls mean ( se ) percent change from baseline .
the time - course of changes in ldl - c concentrations according to dose - increase status in the alirocumab arm is shown in supplementary material online , figure s1 .
percent changes in other lipid measures are shown in table  2 and supplementary material online , table s3 .
statistically significant mean  se reductions were observed for apolipoprotein b ( 22.4  1.8% ) , lipoprotein a ( 21.7  2.4% ) , and non - hdl - c ( 22.9  2.0% ) ( all p < 0.0001 ) , and there was an 8.1  1.3% increase in hdl - c at week 24 in the alirocumab arm compared with ezetimibe ( p < 0.0001 ) . triglycerides were reduced from baseline to week 24 by 13.0  1.5% in the alirocumab group and by 12.8  2.0% in the ezetimibe group , but the difference between treatment arms was not statistically significant .
apolipoprotein a-1 concentrations increased in the alirocumab group and decreased in the ezetimibe group , but according to the hierarchical analysis rules , formal analysis was stopped following the non - significant difference for triglyceride reduction .
c - reactive protein levels did not change over time with alirocumab and were slightly lower with ezetimibe ( supplementary material online , table s5 and figure s2 ) .
the results did not differ qualitatively as a function of demographics , region , medical history , baseline total / free pcsk9 concentration , diabetes ( personal history ) , intensity of statin treatment , or baseline lipid values ( supplementary material online , figure s3 ) .
rates of treatment - emergent adverse events ( teaes ) over a mean of 58  19 weeks ' follow - up are shown in table  3 .
the overall percentages of patients who experienced at least one teae were 71.2% in the alirocumab arm and 67.2% in the ezetimibe arm .
a teae leading to death occurred in 0.4% ( n = 2 ) of patients in the alirocumab arm ( both of cardiac origin ) and in 1.7% ( n = 4 ) of patients in the ezetimibe arm ( two of cardiac origin )
. similar percentages of subjects in both groups experienced a serious adverse event ( 18.8% alirocumab vs. 17.8% ezetimibe ) . a higher proportion of patients in the alirocumab group experienced teaes leading to treatment discontinuation ( 7.5 vs. 5.4% ) , with no specific pattern in type of adverse event . 

table  3teaes and laboratory parameters ( safety population ) at 52 weeksall patients on maximally tolerated statin therapyalirocumab ( n = 479)ezetimibe ( n = 241)any teae341 ( 71.2)162 ( 67.2)treatment - emergent sae90 ( 18.8)43 ( 17.8)teae leading to death2 ( 0.4)4 ( 1.7)teae leading to treatment discontinuation36 ( 7.5)13 ( 5.4)teaes occurring in 5% of patients in either group or teaes of interest  accidental overdose30 ( 6.3)16 ( 6.6 )  upper respiratory tract infection31 ( 6.5)14 ( 5.8 )  dizziness23 ( 4.8)13 ( 5.4 )  myalgia21 ( 4.4)12 ( 5.0 )  injection - site reaction12 ( 2.5)2 ( 0.8 )  neurocognitive disorder4 ( 0.8)3 ( 1.2)adjudicated cardiovascular events23 ( 4.8)9 ( 3.7 )  chd death ( including undetermined cause)2 ( 0.4)2 ( 0.8 )  non - fatal myocardial infarction12 ( 2.5)3 ( 1.2 )  fatal / non - fatal ischaemic stroke ( including stroke not otherwise specified)1 ( 0.2)1 ( 0.4 )  unstable angina requiring hospitalization1 ( 0.2)0  congestive heart failure requiring hospitalization1 ( 0.2)1 ( 0.4 )  ischaemia - driven coronary revascularization procedure16 ( 3.3)4 ( 1.7)laboratory parameters  alanine aminotransferase > 3  uln8/470 ( 1.7)1/240 ( 0.4 )  creatine kinase > 3  uln13/467 ( 2.8)6/236 ( 2.5)data are n ( % ) or n / n ( % ) .
chd , coronary heart disease ; q2w , every 2 weeks ; sae , serious adverse event ; sc , subcutaneous ; teae , treatment - emergent adverse event ; uln , upper limit of normal.teaes are adverse events that developed or worsened or became serious during the teae period [ defined as the time from the first dose of double - blind study treatment to the last injection plus 70 days ( 10 weeks ) , as the residual effect of alirocumab was expected until 10 weeks after the last injection].one patient was not on maximally tolerated statin therapy.alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
mmol / l ( 70 mg / dl).10 mg / day oral ezetimibe.both deaths in the alirocumab arm were due to cardiovascular events ( cardiac arrest and sudden cardiac death ) .
of the four deaths in the ezetimibe arm ( malignant lung neoplasm , suicide , defect conduction intraventricular plus sudden cardiac death , and sudden death 
one patient was counted in two categories ) , two were due to cardiovascular events.accidental overdose was an event suspected by the investigator or spontaneously notified by the patient ( not based on systematic injection / capsule counts ) and defined as at least twice the intended dose within the intended therapeutic interval ( i.e. 2 injections from the double - blind treatment kit administered in < 7 calendar days or 2 capsules from the double - blind treatment kit were administered within 1 calendar day ) .
teaes and laboratory parameters ( safety population ) at 52 weeks data are n ( % ) or n / n ( % ) .
chd , coronary heart disease ; q2w , every 2 weeks ; sae , serious adverse event ; sc , subcutaneous ; teae , treatment - emergent adverse event ; uln , upper limit of normal .
teaes are adverse events that developed or worsened or became serious during the teae period [ defined as the time from the first dose of double - blind study treatment to the last injection plus 70 days ( 10 weeks ) , as the residual effect of alirocumab was expected until 10 weeks after the last injection ] .
alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
of the four deaths in the ezetimibe arm ( malignant lung neoplasm , suicide , defect conduction intraventricular plus sudden cardiac death , and sudden death 
one patient was counted in two categories ) , two were due to cardiovascular events .
accidental overdose was an event suspected by the investigator or spontaneously notified by the patient ( not based on systematic injection / capsule counts ) and defined as at least twice the intended dose within the intended therapeutic interval ( i.e. 2 injections from the double - blind treatment kit administered in < 7 calendar days or 2 capsules from the double - blind treatment kit were administered within 1 calendar day ) .
there was no imbalance in teaes at the system organ class level ( supplementary material online , table s6 ) .
the most common teaes ( occurring in 5% of patients from either treatment arm ) were upper respiratory tract infection , accidental overdose , dizziness , and myalgia ( table  3 ) .
adjudicated cardiovascular events were infrequent , occurring in 4.8% ( n = 23 ) of the alirocumab group vs. 3.7% ( n = 9 ) in the ezetimibe group .
treatment - emergent local injection site reactions occurred in 2.5% of patients in the alirocumab arm vs. 0.8% for ezetimibe / placebo injections ( table  3 ) .
reactions were of mild intensity , except for one of moderate intensity , and none were serious ; two events led to discontinuation in the alirocumab group .
exceptions were the incidence of elevated alanine aminotransaminase , which was more frequent in the alirocumab group , and impaired glucose control , which was less frequent in the alirocumab group ( table  3 and supplementary material online , table s6 ) .
one - hundred and five ( 22.8% of 460 ) patients in the alirocumab arm and none in the ezetimibe arm had two consecutive ldl - c values <
rates of teaes in this group were similar to those in the ezetimibe group , with the exception of nasopharyngitis , which was more frequent in the alirocumab group ( supplementary material online , table s6 ) .
for the primary endpoint , mean  standard error ( se ) reductions in ldl - c from baseline to week 24 were 50.6  1.4% in the alirocumab arm and 20.7  1.9% in the ezetimibe arm , both on a background of maximally tolerated statin therapy , with a statistically significant difference of the means  se between groups of 29.8 ( 95% ci 34.4 to 25.3 , p < 0.0001 ) ( table  2 ) .
the results for the on - treatment analysis ( table  2 and supplementary material online , table s3 ) and the sensitivity analysis ( supplementary material online , table s4 ) were consistent with the primary endpoint .
the proportion of patients who achieved the target ldl - c of < 1.8 mmol / l at week 24 ( itt analysis ) was 77.0% in the alirocumab arm and 45.6% in the ezetimibe arm ( p < 0.0001 ) .
the distribution of baseline and achieved ldl - c values at 24 weeks is shown in figure  2 .
table  2percent change from baseline to week 24 in ldl - c ( itt and on - treatment ) and in secondary lipid parameters ( itt)all patients on maximally tolerated statin therapyalirocumabezetimibealirocumab vs. ezetimibels mean difference  se ( % ) 95% cip - valueprimary endpoint : ldl - c  ittn = 467n = 240  ls mean  se change from baseline ( % ) 50.6  1.420.7  1.929.8  2.334.4 to 25.3<0.0001  on - treatmentn = 464n = 235  baseline ldl - c , mean  sd ( mmol / l)2.8  0.92.7  0.9 
range0.67.91.06.3  ls mean  se change from baseline ( % ) 52.4  1.321.8  1.830.6  2.234.9 to 26.2<0.0001secondary lipid parameters ( itt ) ,
ls mean  se change from baseline ( % ) n = 467n = 240  ldl - c ( beta - quantification method)47.7  1.618.0  2.229.7  2.735.0 to 24.4<0.0001  ldl - c ( baseline to week 12)51.2  1.321.8  1.829.4  2.233.7 to 25.1<0.0001  apolipoprotein b40.7  1.118.3  1.522.4  1.826.0 to 18.8<0.0001  non - hdl - c42.1 
1.219.2  1.722.9  2.026.9 to 18.9<0.0001  total cholesterol29.3  0.914.6  1.214.7  1.517.7 to 11.7<0.0001  lipoprotein a27.8  1.46.1  2.021.7  2.426.4 to 17.0<0.0001  hdl - c8.6 
0.80.5  1.18.1  1.35.4 to 10.7<0.0001  triglycerides ( fasted)13.0  1.512.8  2.00.3  2.55.1 to 4.60.91  apolipoprotein a-15.0  0.61.3  0.86.3  1.04.3 to 8.3<0.0001ci , confidence interval ; hdl - c , high - density lipoprotein cholesterol ; itt , intention - to - treat ; ldl - c , low - density lipoprotein cholesterol ; ls , least squares ; q2w , every 2 weeks ; sc , subcutaneous ; se , standard error.one patient was not on maximally tolerated statin therapy.alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
mmol / l ( 70 mg / dl).10 mg / day oral ezetimibe.sensitivity analysis conducted in 180 patients in the ezetimibe group and 361 patients in the alirocumab group .
p - value for descriptive purposes only.combined estimate obtained by combining adjusted means  se from robust regression model analyses of the different imputed data sets ( multiple imputation).p - value for descriptive purposes only ( according to the hierarchical analysis , formal analysis was stopped after triglycerides , which were not statistically significant ) . 
 figure  2distribution by 10 mg / dl increments of ldl - c concentration at baseline and at week 24 in patients on maximally tolerated statins and alirocumab or ezetimibe . comparison between week 24 vs. baseline
is descriptive and exploratory only , as data for all patients were not available at week 24 .
percent change from baseline to week 24 in ldl - c ( itt and on - treatment ) and in secondary lipid parameters ( itt ) ci , confidence interval ; hdl - c , high - density lipoprotein cholesterol ; itt , intention - to - treat ; ldl - c , low - density lipoprotein cholesterol ; ls , least squares ; q2w , every 2 weeks ; sc , subcutaneous ; se , standard error .
alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
10 mg / day oral ezetimibe . sensitivity analysis conducted in 180 patients in the ezetimibe group and 361 patients in the alirocumab group .
combined estimate obtained by combining adjusted means  se from robust regression model analyses of the different imputed data sets ( multiple imputation ) .
p - value for descriptive purposes only ( according to the hierarchical analysis , formal analysis was stopped after triglycerides , which were not statistically significant ) .
distribution by 10 mg / dl increments of ldl - c concentration at baseline and at week 24 in patients on maximally tolerated statins and alirocumab or ezetimibe .
comparison between week 24 vs. baseline is descriptive and exploratory only , as data for all patients were not available at week 24 .
the time - course of changes in ldl - c concentrations in the alirocumab and ezetimibe arms from baseline to 52 weeks is shown in figure  3 .
mean ldl - c concentrations dropped rapidly in the first 4 weeks , but to a greater degree in the alirocumab arm .
figure  3ldl - c values achieved vs. study time - points ( itt analysis ) . percentages above weeks 12 and 24 data points indicate ls mean ( se ) percent change from baseline .
percentages above weeks 12 and 24 data points indicate ls mean ( se ) percent change from baseline .
the time - course of changes in ldl - c concentrations according to dose - increase status in the alirocumab arm is shown in supplementary material online , figure s1 .
percent changes in other lipid measures are shown in table  2 and supplementary material online , table s3 .
statistically significant mean  se reductions were observed for apolipoprotein b ( 22.4  1.8% ) , lipoprotein a ( 21.7  2.4% ) , and non - hdl - c ( 22.9  2.0% ) ( all p < 0.0001 ) , and there was an 8.1  1.3% increase in hdl - c at week 24 in the alirocumab arm compared with ezetimibe ( p < 0.0001 ) . triglycerides were reduced from baseline to week 24 by 13.0  1.5% in the alirocumab group and by 12.8  2.0% in the ezetimibe group , but the difference between treatment arms was not statistically significant .
apolipoprotein a-1 concentrations increased in the alirocumab group and decreased in the ezetimibe group , but according to the hierarchical analysis rules , formal analysis was stopped following the non - significant difference for triglyceride reduction .
c - reactive protein levels did not change over time with alirocumab and were slightly lower with ezetimibe ( supplementary material online , table s5 and figure s2 ) .
the results did not differ qualitatively as a function of demographics , region , medical history , baseline total / free pcsk9 concentration , diabetes ( personal history ) , intensity of statin treatment , or baseline lipid values ( supplementary material online , figure s3 ) .
rates of treatment - emergent adverse events ( teaes ) over a mean of 58  19 weeks ' follow - up are shown in table  3 .
the overall percentages of patients who experienced at least one teae were 71.2% in the alirocumab arm and 67.2% in the ezetimibe arm .
a teae leading to death occurred in 0.4% ( n = 2 ) of patients in the alirocumab arm ( both of cardiac origin ) and in 1.7% ( n = 4 ) of patients in the ezetimibe arm ( two of cardiac origin )
. similar percentages of subjects in both groups experienced a serious adverse event ( 18.8% alirocumab vs. 17.8% ezetimibe ) . a higher proportion of patients in the alirocumab group experienced teaes leading to treatment discontinuation ( 7.5 vs. 5.4% ) , with no specific pattern in type of adverse event . 

table  3teaes and laboratory parameters ( safety population ) at 52 weeksall patients on maximally tolerated statin therapyalirocumab ( n = 479)ezetimibe ( n = 241)any teae341 ( 71.2)162 ( 67.2)treatment - emergent sae90 ( 18.8)43 ( 17.8)teae leading to death2 ( 0.4)4 ( 1.7)teae leading to treatment discontinuation36 ( 7.5)13 ( 5.4)teaes occurring in 5% of patients in either group or teaes of interest  accidental overdose30 ( 6.3)16 ( 6.6 )  upper respiratory tract infection31 ( 6.5)14 ( 5.8 )  dizziness23 ( 4.8)13 ( 5.4 )  myalgia21 ( 4.4)12 ( 5.0 )  injection - site reaction12 ( 2.5)2 ( 0.8 )  neurocognitive disorder4 ( 0.8)3 ( 1.2)adjudicated cardiovascular events23 ( 4.8)9 ( 3.7 )  chd death ( including undetermined cause)2 ( 0.4)2 ( 0.8 )  non - fatal myocardial infarction12 ( 2.5)3 ( 1.2 )  fatal / non - fatal ischaemic stroke ( including stroke not otherwise specified)1 ( 0.2)1 ( 0.4 )  unstable angina requiring hospitalization1 ( 0.2)0  congestive heart failure requiring hospitalization1 ( 0.2)1 ( 0.4 )  ischaemia - driven coronary revascularization procedure16 ( 3.3)4 ( 1.7)laboratory parameters  alanine aminotransferase > 3  uln8/470 ( 1.7)1/240 ( 0.4 )  creatine kinase > 3  uln13/467 ( 2.8)6/236 ( 2.5)data are n ( % ) or n / n ( % ) .
chd , coronary heart disease ; q2w , every 2 weeks ; sae , serious adverse event ; sc , subcutaneous ; teae , treatment - emergent adverse event ; uln , upper limit of normal.teaes are adverse events that developed or worsened or became serious during the teae period [ defined as the time from the first dose of double - blind study treatment to the last injection plus 70 days ( 10 weeks ) , as the residual effect of alirocumab was expected until 10 weeks after the last injection].one patient was not on maximally tolerated statin therapy.alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
mmol / l ( 70 mg / dl).10 mg / day oral ezetimibe.both deaths in the alirocumab arm were due to cardiovascular events ( cardiac arrest and sudden cardiac death ) .
of the four deaths in the ezetimibe arm ( malignant lung neoplasm , suicide , defect conduction intraventricular plus sudden cardiac death , and sudden death  one patient was counted in two categories ) , two were due to cardiovascular events.accidental overdose was an event suspected by the investigator or spontaneously notified by the patient ( not based on systematic injection / capsule counts ) and defined as at least twice the intended dose within the intended therapeutic interval ( i.e. 2 injections from the double - blind treatment kit administered in < 7 calendar days or 2 capsules from the double - blind treatment kit were administered within 1 calendar day ) .
teaes and laboratory parameters ( safety population ) at 52 weeks data are n ( % ) or n / n ( % ) .
chd , coronary heart disease ; q2w , every 2 weeks ; sae , serious adverse event ; sc , subcutaneous ; teae , treatment - emergent adverse event ; uln , upper limit of normal .
teaes are adverse events that developed or worsened or became serious during the teae period [ defined as the time from the first dose of double - blind study treatment to the last injection plus 70 days ( 10 weeks ) , as the residual effect of alirocumab was expected until 10 weeks after the last injection ] .
alirocumab 75 mg sc q2w with a dose increase to 150 mg q2w at week 12 if week 8 ldl - c was 1.8
both deaths in the alirocumab arm were due to cardiovascular events ( cardiac arrest and sudden cardiac death ) .
of the four deaths in the ezetimibe arm ( malignant lung neoplasm , suicide , defect conduction intraventricular plus sudden cardiac death , and sudden death  one patient was counted in two categories ) , two were due to cardiovascular events .
accidental overdose was an event suspected by the investigator or spontaneously notified by the patient ( not based on systematic injection / capsule counts ) and defined as at least twice the intended dose within the intended therapeutic interval ( i.e. 2 injections from the double - blind treatment kit administered in < 7 calendar days or 2 capsules from the double - blind treatment kit were administered within 1 calendar day ) .
there was no imbalance in teaes at the system organ class level ( supplementary material online , table s6 ) .
the most common teaes ( occurring in 5% of patients from either treatment arm ) were upper respiratory tract infection , accidental overdose , dizziness , and myalgia ( table  3 ) .
adjudicated cardiovascular events were infrequent , occurring in 4.8% ( n = 23 ) of the alirocumab group vs. 3.7% ( n = 9 ) in the ezetimibe group .
treatment - emergent local injection site reactions occurred in 2.5% of patients in the alirocumab arm vs. 0.8% for ezetimibe / placebo injections
reactions were of mild intensity , except for one of moderate intensity , and none were serious ; two events led to discontinuation in the alirocumab group .
exceptions were the incidence of elevated alanine aminotransaminase , which was more frequent in the alirocumab group , and impaired glucose control , which was less frequent in the alirocumab group ( table  3 and supplementary material online , table s6 ) .
one - hundred and five ( 22.8% of 460 ) patients in the alirocumab arm and none in the ezetimibe arm had two consecutive ldl - c values
rates of teaes in this group were similar to those in the ezetimibe group , with the exception of nasopharyngitis , which was more frequent in the alirocumab group ( supplementary material online , table s6 ) .
in this active - controlled , double - blind trial , alirocumab demonstrated superior efficacy in reducing ldl - c concentrations compared with ezetimibe in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia over and above that seen with maximally tolerated doses of potent statins . a 50.6% reduction in ldl - c
this degree of efficacy translated to mean ( se ) on - treatment ldl - c values of 1.3  0.04 and 2.1
 0.05 mmol / l at week 24 , respectively , and a greater proportion of participants reached the treatment target of < 1.8 mmol / l [ or the even lower potential target of < 1.3 mmol / l ( < 50 mg / dl ) ] .
the substantial difference between arms in ldl - c lowering after 24 weeks was sustained through follow - up to 52 weeks . with the recent preliminary data from the
improve it trial just presented , the control arm of this study could potentially now be considered the appropriate reference for any new therapy . in current practice ,
4560% of patients on llt fail to achieve the ldl - c goal ( < 1.8
the proportion is even lower ( 18% ) for those on non - statin therapies . even in randomized trials using high - dose statins with high treatment adherence ,
> 40% of patients fail to achieve the target , leaving them at substantially increased risk of a major cardiovascular event .
initial data from the improve it trial suggest that further lowering of ldl - c with the non - statin agent ezetimibe reduces cardiovascular events , but this is being studied in several large outcomes trials with other agents , including with alirocumab .
the data presented here suggest that addition of alirocumab to a treatment regimen with maximally tolerated statins will provide substantial lowering of ldl - c so that many more patients can achieve ldl - c goals than by adding ezetimibe .
furthermore , the maximum ldl - c response to a pcsk9 inhibitor is greater with combination therapy , as in combo ii , vs. monotherapy ( i.e. with no background lipid - lowering therapies ) , indicating a possible additive effect , or synergy , with these two classes of drugs , as also suggested in studies involving evolocumab .
the combo ii study included a strategy of individualized goal attainment , with a pre - planned dose - increase in patients who failed to reach the ldl - c target by week 8 .
we hypothesized that most patients would gain substantial lipid lowering ( 50% ) even with the starting dose , and this proved correct .
approximately 80% of patients treated with alirocumab did not require a dose increase . of note ,
the 18% alirocumab - treated patients who required a dose increase had much higher mean baseline ldl - c values vs. patients who did not require an increase .
the dose increase at 12 weeks led to an additional mean reduction of 10.5% in ldl - c . furthermore , the absolute reduction in ldl - c by week 24 was slightly greater in the dose - increase group ( 1.6 vs. 1.5
alirocumab was generally well tolerated , with no evidence of an excess of teaes , serious adverse events , or deaths in this ongoing study .
injection site reactions occurred more frequently in the alirocumab arm ; these were mild in intensity in all but one case with moderate intensity .
the rate of adjudicated cardiovascular events was slightly higher with alirocumab ( 4.8% ) vs. ezetimibe ( 3.7% ) .
cardiovascular outcomes will be assessed in an ongoing study ( http://clinicaltrials.gov/show/nct01663402 ) and in a pooled analysis from overall odyssey program .
this study was limited to high cardiovascular risk patients with inadequately controlled hypercholesterolaemia , but will complement the range of data emerging from the odyssey program .
further research is needed to evaluate the efficacy of alirocumab in different racial groups . while the primary endpoint in this study was ldl - c reduction at 24 weeks , the study will continue up to 104 weeks to maximize available safety data and generate information on the durability of alirocumab lipid - lowering effects .
in this population of high cardiovascular risk patients with inadequately controlled ldl - c on maximally tolerated doses of potent statins , alirocumab produced significantly greater reductions in ldl - c vs. ezetimibe using a dose - increase approach , with a comparable safety profile .
conflict of interest : c.p.c . reports personal fees from sanofi , personal fees from regeneron pharmaceuticals , inc .
, during the conduct of the study ; grants from accumetrics , grants from arisaph , grants from astra zeneca , grants from boehringer - ingelheim , personal fees from csl behring , personal fees from essentialis , grants and personal fees from glaxosmithkline , grants from janssen , grants and personal fees from merck , grants and personal fees from takeda , personal fees from lipimedix , personal fees from bms , personal fees from pfizer , outside the submitted work . b.c .
reports personal fees from sanofi / regeneron pharmaceuticals , inc . , personal fees from amgen , outside the submitted work .
, during the conduct of the study ; personal fees from amgen , personal fees from sanofi / regeneron pharmaceuticals , inc . , personal fees from aegerion , personal fees from astra zeneca , personal fees from msd , personal fees from pfizer , personal fees from servier , personal fees from unilever , grants from amgen , grants from sanofi / regeneron pharmaceuticals , inc . , grants from eli lilly , grants from novartis , grants from aegerion , outside the submitted work .
reports grants , personal fees and non - financial support from sanofi / regeneron pharmaceuticals , inc .
, during the conduct of the study ; grants , personal fees , non - financial support , and other from pfizer inc . , grants , personal fees , and non - financial support from sanofi aventis , grants and non - financial support from novartis pharmaceuticals , grants and other from eli lilly & company , grants and other from roche pharmaceuticals , grants from boehringer ingelheim , grants from astrazeneca lp , grants and other from regeneron pharmaceuticals , inc . , outside the submitted work
 aimsto compare the efficacy [ low - density lipoprotein cholesterol ( ldl - c ) lowering ] and safety of alirocumab , a fully human monoclonal antibody to proprotein convertase subtilisin / kexin 9 , compared with ezetimibe , as add - on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia.methods and resultscombo ii is a double - blind , double - dummy , active - controlled , parallel - group , 104-week study of alirocumab vs. ezetimibe . 
 patients ( n = 720 ) with high cardiovascular risk and elevated ldl - c despite maximal doses of statins were enrolled ( august 2012may 2013 ) . 
 this pre - specified analysis was conducted after the last patient completed 52 weeks . 
 patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks ( plus oral placebo ) or oral ezetimibe 10 mg daily ( plus subcutaneous placebo ) on a background of statin therapy . at week 24 
 , mean  se reductions in ldl - c from baseline were 50.6  1.4% for alirocumab vs. 20.7  1.9% for ezetimibe ( difference 29.8  2.3% ; p < 0.0001 ) ; 77.0% of alirocumab and 45.6% of ezetimibe patients achieved ldl - c 
 < 1.8 mmol / l ( p < 0.0001 ) . mean achieved ldl - c at week 24 was 1.3  0.04 
 mmol / l with alirocumab and 2.1  0.05 mmol / l with ezetimibe , and were maintained to week 52 . 
 alirocumab was generally well tolerated , with no evidence of an excess of treatment - emergent adverse events.conclusionin patients at high cardiovascular risk with inadequately controlled ldl - c , alirocumab achieved significantly greater reductions in ldl - c compared with ezetimibe , with a similar safety profile.trial registrationclinicaltrials.gov identifier : nct01644188 . 
Trial registration
Introduction
Methods
Intervention
Outcome measures
Statistical analyses
Results
Efficacy
Safety
Discussion
Conclusions
Supplementary material
Funding