title: Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk--primary results from the phase 2 YUKAWA study. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab. Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins　- ODYSSEY JAPAN Randomized Controlled Trial. Efficacy and safety of alirocumab in insulin‐treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM‐INSULIN randomized trial Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Primary results of the BERSON clinical trial Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. Lipid‐Reduction Variability and Antidrug‐Antibody Formation with Bococizumab Cardiovascular Efficacy and Safety of Bococizumab in High‐Risk Patients A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes
abstract: BACKGROUND The ODYSSEY COMBO I study ( http:// clinical trials.gov/show/NCT01644175 ) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia . METHODS This multicenter , phase 3 , r and omized ( 2:1 alirocumab vs placebo ) , double-blind , 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia .  Alirocumab ( 75 mg every 2 weeks [ Q2W ] ) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen . The alirocumab dose was increased to 150 mg Q2W ( also 1 mL ) at week 12 if week 8 low-density lipoprotein cholesterol ( LDL-C ) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 ( intention-to-treat analysis ) . RESULTS At week 24 , estimated mean ( 95 % CI ) changes in LDL-C from baseline were -48.2 % ( -52.0 % to -44.4 % ) and -2.3 % ( -7.6 % to 3.1 % ) for alirocumab and placebo , respectively , an estimated mean ( 95 % CI ) difference of -45.9 % ( -52.5 % to -39.3 % ) ( P < .0001 ) . Low-density lipoprotein cholesterol < 70 mg/dL was achieved by 75 % alirocumab versus 9 % placebo patients at week 24 . At week 12 , 83.2 % of evaluable alirocumab-treated patients remained on 75-mg Q2W . Treatment-emergent adverse events were comparable between groups . CONCLUSIONS Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals , versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy . The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups Aims To 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 results COMBO 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 2012–May 2013 ) . This pre-specified analysis was conducted after the last patient completed 52 weeks . Patients were r and omized 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 . Conclusion In 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 registration clinical trials.gov Identifier : NCT01644188 Aim To evaluate the effect of alirocumab on frequency of st and ard apheresis treatments [ weekly or every 2 weeks ( Q2W ) ] in heterozygous familial hypercholesterolaemia ( HeFH ) . Methods and results ODYSSEY ESCAPE ( NCT02326220 ) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis .  Patients were r and omly assigned ( 2:1 , respectively ) to receive alirocumab 150 mg ( n = 41 ) or placebo ( n = 21 ) Q2W subcutaneously for 18 weeks . From day 1 to week 6 , apheresis rate was fixed according to the patient ’s established schedule ; from weeks 7 to 18 , apheresis rate was adjusted based on the patient ’s low-density lipoprotein cholesterol ( LDL-C ) response in a blinded fashion . Apheresis was not performed when the LDL-C value was ≥30 % lower than the baseline ( pre-apheresis ) value . The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks ( weeks 7–18 ) , st and ardized to number of planned treatments . In the alirocumab group the least square ( LS ) mean ± SE ( 95 % confidence interval [ CI ] ) per cent change in pre-apheresis LDL-C from baseline at week 6 was −53.7 ± 2.3 ( −58.2 to − 49.2 ) compared with 1.6 ± 3.1 ( –4.7 to 7.9 ) in the placebo group . The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab ( Hodges – Lehmann median estimate of treatment difference : 0.75 ; 95 % CI 0.67–0.83 ; P < 0.0001 ) . Therefore , alirocumab-treated patients had a 0.75 ( 75 % ) additional reduction in the st and ardized rate of apheresis treatments vs. placebo-treated patients . During this period , 63.4 % of patients on alirocumab avoided all and 92.7 % avoided at least half of the apheresis treatments . Adverse event rates were similar ( 75.6 % of patients on alirocumab vs. 76.2 % on placebo ) . Conclusions Lipoprotein apheresis was discontinued in 63.4 % of patients on alirocumab who were previously undergoing regular apheresis , and the rate was at least halved in 92.7 % of patients . Alirocumab was generally safe and well tolerated Purpose Even with statins and other lipid-lowering therapy ( LLT ) , many patients with heterozygous familial hypercholesterolemia ( heFH ) continue to have elevated low-density lipoprotein cholesterol ( LDL-C ) levels . ODYSSEY HIGH FH ( NCT01617655 ) assessed the efficacy and safety of alirocumab , a proprotein convertase subtilisin/kexin type 9 monoclonal antibody , versus placebo in patients with heFH and LDL-C ≥ 160 mg/dl despite maximally tolerated statin ± other LLT . Methods Patients were r and omized to subcutaneous alirocumab 150 mg or placebo every 2 weeks ( Q2W ) for 78 weeks . The primary endpoint was percent change in LDL-C from baseline to week 24 . Results Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab ( n = 71 ) and 201.0 mg/dl in the placebo groups ( n = 35 ) . Significant mean ( st and ard error [ SE ] ) reductions in LDL-C from baseline to week 24 were observed with alirocumab ( −45.7 [ 3.5 ] % ) versus placebo ( −6.6 [ 4.9 ] % ) , a difference of −39.1 ( 6.0 ) % ( P < 0.0001 ) . Absolute mean ( SE ) LDL-C levels were reduced from baseline by 90.8 ( 6.7 ) mg/dl with alirocumab at week 24 , with reductions maintained to week 78 . Treatment-emergent adverse events were generally comparable between groups . Injection-site reactions were more frequent in the alirocumab group ( 8.3 % ) versus placebo ( 5.7 % ) ; most were mild in severity and did not result in study medication discontinuation . Conclusions In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT , alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals . Alirocumab was generally well tolerated BACKGROUND YUKAWA is a 12-week , r and omized , double-blind , placebo-controlled , phase 2 study evaluating the efficacy and safety of evolocumab ( AMG 145 ) in statin-treated Japanese patients at high cardiovascular risk . METHODS AND RESULTS 310 eligible patients receiving stable statin ( ±ezetimibe ) therapy were r and omized to 1 of 6 treatments : placebo every 2 weeks ( Q2W ) or monthly ( QM ) , evolocumab 70 mg or 140 mg Q2W , or evolocumab 280 mg or 420 mg QM . The primary endpoint was the percentage change from baseline in low-density lipoprotein cholesterol ( LDL-C ) measured by preparative ultracentrifugation ( UC ) . Secondary endpoints included percentage changes in other lipid parameters and the proportion of patients with LDL-C < 1.8 mmol/L.  Mean ( SD ) age was 62 ( 10 ) years ; 37 % were female ; and the mean ( SD ) baseline LDL-C was 3.7 ( 0.5 ) mmol/L ( by UC ) . Mean ( SE ) changes vs. placebo in LDL-C were greatest in the high-dose groups : -68.6 ( 3.0 ) % and -63.9 ( 3.2 ) % with 140 mg Q2W and 420 mg QM dosing , respectively . Up to 96 % of evolocumab-treated patients achieved LDL-C < 1.8 mmol/L. Adverse events ( AEs ) were more frequent in evolocumab ( 51 % ) vs. placebo ( 38 % ) patients ; 4 patients taking evolocumab discontinued treatment because of an AE . There were no significant differences in AE rates based on dose or dose frequency . CONCLUSIONS In Japanese patients at high cardiovascular risk with hypercholesterolemia on stable statin therapy , evolocumab  significantly reduced LDL-C and was well tolerated during this 12-week study Aims To assess long-term ( 78 weeks ) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia ( HeFH ) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy ( LLT ) . Methods and results In two r and omized , double-blind studies ( ODYSSEY FH I , n = 486 ; FH II , n = 249 ) , patients were r and omized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks ( Q2W ) . Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L ( 70 mg/dL ) . Primary endpoint ( both studies ) was percentage change in calculated LDL-C from baseline to Week 24 . Mean LDL-C levels decreased from 3.7 mmol/L ( 144.7 mg/dL ) at baseline to 1.8 mmol/L ( 71.3 mg/dL ; −57.9 % vs. placebo ) at Week 24 in patients r and omized to alirocumab in FH I and from 3.5 mmol/L ( 134.6 mg/dL ) to 1.8 mmol/L ( 67.7 mg/dL ; −51.4 % vs. placebo ) in FH II ( P < 0.0001 ) . These reductions were maintained through Week 78 . LDL-C < 1.8 mmol/L ( regardless of cardiovascular risk ) was achieved at Week 24 by 59.8 and 68.2 % of alirocumab-treated patients in FH I and FH II , respectively . Adverse events result ed in discontinuation in 3.4 % of alirocumab-treated patients in FH I ( vs. 6.1 % placebo ) and 3.6 % ( vs. 1.2 % ) in FH II . Rate of injection site reactions  in alirocumab-treated patients was 12.4 % in FH I and 11.4 % in FH II ( vs. 11.0 and 7.4 % with placebo ) . Conclusion In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT , alirocumab treatment result ed in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated . Clinical trial registration Cinicaltrials.gov ( identifiers : NCT01623115 ; NCT01709500 ) CONTEXT Despite current st and ard of care , many patients at high risk of cardiovascular disease ( CVD ) still have elevated low-density lipoprotein cholesterol ( LDL-C ) levels . Alirocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 . OBJECTIVE The objective of the study was to compare the LDL-C-lowering efficacy of adding alirocumab vs other common lipid-lowering strategies . DESIGN , PATIENTS , AND INTERVENTIONS Patients ( n = 355 ) with very high CVD risk and LDL-C levels of 70 mg/dL or greater or high CVD risk and LDL-C of 100 mg/dL or greater on baseline atorvastatin 20 or 40 mg were r and omized to one of the following : 1 ) add-on alirocumab 75 mg every 2 weeks ( Q2W ) sc ; 2 ) add-on ezetimibe 10 mg/d ; 3 ) double atorvastatin dose ; or 4 ) for atorvastatin 40 mg regimen only , switch to rosuvastatin 40 mg . For patients not achieving protocol -defined LDL-C goals , the alirocumab dose was increased ( blinded ) at week 12 to 150 mg Q2W . MAIN OUTCOME MEASURE The primary end point was percentage change in calculated LDL-C from baseline to 24 weeks ( intent to treat ) . RESULTS Among atorvastatin 20 and 40 mg regimens , respectively , add-on alirocumab  reduced LDL-C levels by 44.1 % and 54.0 % ( P < .001 vs all comparators ) ; add-on ezetimibe , 20.5 % and 22.6 % ; doubling of atorvastatin dose , 5.0 % and 4.8 % ; and switching atorvastatin 40 mg to rosuvastatin 40 mg , 21.4 % . Most alirocumab-treated patients ( 87.2 % and 84.6 % ) achieved their LDL-C goals .  Most alirocumab-treated patients ( 86 % ) maintained their 75-mg Q2W regimen . Treatment-emergent adverse events occurred in 65.4 % of alirocumab patients vs 64.4 % ezetimibe and 63.8 % double atorvastatin/switch to rosuvastatin ( data were pooled ) . CONCLUSIONS Adding alirocumab to atorvastatin provided significantly greater LDL-C reductions vs adding ezetimibe , doubling atorvastatin dose , or switching to rosuvastatin and enabled greater LDL-C goal achievement BACKGROUND Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease ( PCSK9 ) result ed in large reductions of low-density lipoprotein cholesterol ( LDL-C ) in phase 1 trials . We assessed the efficacy and safety of various doses and dosing intervals of REGN727 , a monoclonal antibody to PCSK9 , added to statins , to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia . METHODS This multicentre , r and omised , placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada . Between Jan 18 , 2011 , and Nov 7 , 2011 , we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose , with or without ezetimibe . Patients were r and omly assigned to receive REGN727 150 mg , 200 mg , or 300 mg every 4 weeks , or 150 mg every 2 weeks , or placebo every 2 weeks ( ratio 1:1:1:1:1 ) . R and omisation was stratified by concomitant use of ezetimibe at baseline . Investigators , study staff , and patients were masked to treatment group . Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing . The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance ( ANCOVA ) model with treatment group . This trial is registered in Clinical Trials.gov , number NCT 01266876 . FINDINGS 77 patients were r and omly assigned to study groups ( 15 - 16 patients per group ) and all were analysed . Least-squares ( LS ) mean LDL-C reduction from baseline to week 12 was 28·9 % ( SE 5·08 ) for 150 mg every 4 weeks ( p=0·0113 ) , 31·54 % ( 4·91 ) for 200 mg every 4 weeks ( p=0·0035 ) , 42·53 % ( 5·09 ) for 300 mg every 4 weeks ( p<0·0001 ) , and 67·90 % ( 4·85 ) for 150 mg every 2 weeks ( p<0·0001 ) , compared with 10·65 % ( 5·04 ) with  placebo . One serious adverse event was reported with placebo and none with REGN727 . No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase . The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment . INTERPRETATION REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose  statins , with or without ezetimibe . REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder . FUNDING Sanofi US and Regeneron Pharmaceuticals Incorporated BACKGROUND Alirocumab , a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) , has been shown to reduce low-density lipoprotein ( LDL ) cholesterol levels in patients who are receiving statin therapy .  Larger and longer-term studies are needed to establish safety and efficacy . METHODS We conducted a r and omized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter ( 1.8 mmol per liter ) or more and were receiving treatment with statins at the maximum tolerated dose ( the highest dose associated with an acceptable side-effect profile ) , with or without other lipid-lowering therapy .  Patients were r and omly assigned in a 2:1 ratio to receive alirocumab ( 150 mg ) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks . The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24 . RESULTS At week 24 , the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points ( P<0.001 ) ; the treatment effect remained consistent over a period of 78 weeks . The alirocumab group , as compared with the placebo group , had higher rates of injection-site reactions ( 5.9 % vs. 4.2 % ) , myalgia ( 5.4 % vs. 2.9 % ) , neurocognitive events ( 1.2 % vs. 0.5 % ) , and ophthalmologic events ( 2.9 % vs. 1.9 % ) . In a post hoc analysis , the rate of major adverse cardiovascular events ( death from coronary heart disease , nonfatal myocardial infa rct ion , fatal or nonfatal ischemic stroke , or unstable angina requiring hospitalization ) was lower with alirocumab than with placebo ( 1.7 % vs. 3.3 % ; hazard ratio , 0.52 ; 95 % confidence interval , 0.31 to 0.90 ; nominal P=0.02 ) . CONCLUSIONS Over a period of 78 weeks , alirocumab , when added to statin therapy at the maximum tolerated dose , significantly reduced LDL cholesterol levels . In a post hoc analysis , there was evidence of a reduction in the rate of cardiovascular events with alirocumab . ( Funded by Sanofi and Regeneron Pharmaceuticals ; ODYSSEY LONG TERM Clinical Trials.gov number , NCT01507831 . ) BACKGROUND Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol ( LDL-C ) concentrations . Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies . METHODS ODYSSEY ALTERNATIVE ( NCT01709513 ) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance ( unable to tolerate ≥2 statins , including one at the lowest approved starting dose ) due to muscle symptoms . A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance . Patients ( n = 361 ) received single-blind subcutaneous ( SC ) and oral placebo for 4 weeks during placebo run-in . Patients reporting muscle-related symptoms during the run-in were to be withdrawn . Continuing patients were r and omized ( 2:2:1 ) to double-blind alirocumab 75 mg SC every 2 weeks ( Q2W ; plus oral placebo ) , ezetimibe 10 mg/d ( plus SC placebo Q2W ) , or atorvastatin 20 mg/d ( rechallenge ; plus SC placebo Q2W ) for 24 weeks . Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values . Primary end point was percent change in LDL-C from baseline to week 24 ( intent-to-treat ) for alirocumab vs ezetimibe . RESULTS Baseline mean ( st and ard deviation ) LDL-C was 191.3 ( 69.3 ) mg/dL ( 5.0 [ 1.8 ] mmol/L ) . Alirocumab reduced mean ( st and ard error ) LDL-C by 45.0 % ( 2.2 % ) vs 14.6 % ( 2.2 % ) with ezetimibe ( mean difference 30.4 % [ 3.1 % ] , P < .0001 ) . Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin ( hazard ratio 0.61 , 95 % confidence interval 0.38 - 0.99 , P = .042 ) . CONCLUSIONS Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients , with fewer skeletal-muscle adverse events vs atorvastatin BACKGROUND Familial hypercholesterolemia ( FH ) is a dominant genetic disorder associated with elevated low-density lipoprotein cholesterol ( LDL-C ) and premature atherosclerotic events . Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) are indicated for LDL-C reduction among adult patients with FH , placebo-controlled outcome data among FH patients are scant . OBJECTIVE Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction of vascular Events ( SPIRE ) program . METHODS We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular event rates among 1578 FH patients and 15,959 patients without FH who were selected for comparable lipid levels ( on-statin levels of LDL-C > 100 mg/dL or non-high-density lipoprotein cholesterol > 130 mg/dL ) . All patients were r and omized by computer generated codes to bococizumab 150 mg subcutaneously every 2 weeks or to matching placebo in the SPIRE clinical trials program and were followed over a median period of 11.2 months for major adverse cardiovascular events ( nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death ) . Analysis is by intention to treat . The SPIRE trials are closed and registered at Clinical Trials.gov : NCT01968954 , NCT01968967 , NCT02100514 , NCT01968980 , NCT01975376 , and NCT01975389 . RESULTS Compared to non-FH patients , FH patients enrolled in the SPIRE trials were on average younger ( 58 vs 63 years ) , more likely to be women ( 42 vs 35 % ) , more likely to be primary prevention patients ( 42 vs 23 % ) , had higher mean baseline LDL-C levels ( 151 vs 127 mg/dL ) , and lower rates of diabetes ( 25 vs 52 % ) and hypertension ( 59 vs 82 % ) . FH and non-FH patients both had 55 % reductions in LDL-C with bococizumab . Among FH patients , major adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and 22 of 797 allocated to placebo ( hazard ratio 0.83 ; 95 % confidence interval 0.44 - 1.54 , P = .55 ) . This best estimate of effect was similar in magnitude to that observed in the much larger group of patients without FH ( hazard ratio 0.79 , 95 % confidence interval 0.64 - 0.97 , P = .023 ) with no statistically significant evidence of heterogeneity between groups ( P = .87 ) . Incidence rate ratios comparing bococizumab to placebo for adverse events were similar among those with and without FH . The proportion of patients developing antidrug antibodies was higher among those with FH compared to those without FH ( 43 % vs 36 % , P < .001 ) . CONCLUSIONS In these r and omized placebo-controlled data , the subgroup of statin-treated FH patients had a similar magnitude of risk reduction for hard cardiovascular events with the PCSK9 inhibitor bococizumab as did patients without FH , with no evidence of statistical heterogeneity between groups BACKGROUND The ODYSSEY Japan study was design ed to demonstrate the reduction in low-density lipoprotein cholesterol ( LDL-C )  by alirocumab as add-on to existing lipid-lowering therapy in Japanese patients with heterozygous familial hypercholesterolemia ( heFH ) or non-FH at high cardiovascular risk who require additional pharmacological management to achieve their LDL-C treatment goal ( < 2.6 or < 3.1 mmol/L , depending on risk category ) . METHODS AND RESULTS This r and omized , double-blind , parallel-group , 52-week study was conducted in Japan . Patients ( n=216 ) with heFH , non-FH at high cardiovascular risk with coronary disease , or classified as category III were enrolled . The prespecified safety analysis was done after the last patient completed 52 weeks . Patients were r and omized ( 2:1 , alirocumab : placebo ) with stratification for heFH to s.c . alirocumab ( 75 mg every 2 weeks [ Q2 W ] with increase to 150 mg if week 8 LDL-C ≥2.6/3.1 mmol/L ) or placebo for 52 weeks plus stable statin therapy . At week 24 , mean±SE change in LDL-C from baseline was -62.5±1.3 % in the alirocumab group and 1.6±1.8 % in the placebo group ( difference , -64.1±2.2 % ; P<0.0001 ) ; the reduction was sustained to week 52 ( alirocumab , -62.5±1.4 % ; placebo , -3.6±1.9 % ) . No patterns were evident between treatment groups for adverse events at 52 weeks . CONCLUSIONS In high-risk Japanese patients with hypercholesterolemia on stable statin therapy , alirocumab markedly reduced LDL-C vs. placebo and was well tolerated over 52 weeks . ( Circ J 2016 ; 80 : 1980 - 1987 ) Aims To investigate the efficacy and safety of alirocumab in participants with type 2 ( T2D ) or type 1 diabetes ( T1D ) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy . Methods Participants at high cardiovascular risk with T2D ( n = 441 ) or T1D ( n = 76 ) and LDL cholesterol levels ≥1.8 mmol/L ( ≥70 mg/dL ) were r and omized 2:1  to alirocumab : placebo administered subcutaneously every 2 weeks , for 24 weeks ' double‐blind treatment . Alirocumab‐treated participants received 75 mg every 2 weeks , with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24 , and safety assessment s. Results Alirocumab  reduced LDL cholesterol from baseline to week 24 by a mean ± st and ard error of 49.0 % ± 2.7 % and 47.8 % ± 6.5 % vs placebo ( both P < .0001 ) in participants with T2D and T1D , respectively . Significant reductions were observed in non‐HDL cholesterol ( P < .0001 ) , apolipoprotein B ( P < .0001 ) and lipoprotein ( a ) ( P ≤ .0039 ) . At week 24 , 76.4 % and 70.2 % of the alirocumab group achieved LDL cholesterol < 1.8 mmol/L in the T2D and T1D population s ( P < .0001 ) , respectively . Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration . Treatment‐emergent adverse events were observed in 64.5 % of alirocumab‐ vs 64.1 % of placebo‐treated individuals ( overall population ) . Conclusions Alirocumab  produced significant LDL cholesterol reductions in participants with insulin‐treated diabetes regardless of diabetes type , and was generally well tolerated . Concomitant administration of alirocumab and insulin did not raise any safety concerns ( NCT02585778 ) OBJECTIVE To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies ( NCT01730053 ) . METHODS Patients receiving baseline rosuvastatin regimens ( 10 or 20 mg ) were r and omized to :  add-on alirocumab 75 mg every-2-weeks ( Q2W ) ( 1-mL subcutaneous injection via pre-filled pen ) ; add-on ezetimibe 10 mg/day ; or double-dose rosuvastatin .  Patients had cardiovascular disease ( CVD ) and low-density lipoprotein cholesterol ( LDL-C ) ≥70 mg/dL ( 1.8 mmol/L ) or CVD risk factors and LDL-C ≥100 mg/dL ( 2.6 mmol/L ) . In the alirocumab group , dose was blindly increased at Week 12 to 150 mg Q2W ( also 1-mL volume ) in patients not achieving their LDL-C target . Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks ( intent-to-treat ) . RESULTS 305 patients were r and omized . In the baseline rosuvastatin 10 mg group , significantly greater LDL-C reductions were observed with add-on alirocumab ( -50.6 % ) versus ezetimibe ( -14.4 % ; p < 0.0001 ) and double-dose rosuvastatin ( -16.3 % ; p < 0.0001 ) . In the baseline rosuvastatin 20 mg group , LDL-C reduction with add-on alirocumab was -36.3 % compared with -11.0 % with ezetimibe and -15.9 % with double-dose rosuvastatin ( p = 0.0136 and 0.0453 , respectively ; pre-specified threshold for significance p < 0.0125 ) . Overall , ∼80 % alirocumab patients were maintained on 75 mg Q2W . Of alirocumab-treated patients , 84.9 % and 66.7 % in the baseline rosuvastatin 10 and 20 mg groups , respectively , achieved risk-based LDL-C targets . Treatment-emergent adverse events occurred in 56.3 % of alirocumab patients versus 53.5 % ezetimibe and 67.3 % double-dose rosuvastatin ( pooled data ) . CONCLUSIONS The addition of alirocumab to rosuvastatin provided incremental LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose Evolocumab ( AMG 145 ) , a fully human monoclonal antibody against PCSK9 , significantly reduced low-density lipoprotein cholesterol ( LDL-C ) levels in phase 2 and 3 studies . This phase 3 study evaluated the efficacy and safety of evolocumab plus atorvastatin in Japanese patients with hyperlipidemia or mixed dyslipidemia and high cardiovascular risk . Patients were r and omized to atorvastatin 5 or 20 mg/day for 4 weeks . Subsequently , patients underwent second r and omization to evolocumab 140 mg biweekly ( Q2W ) or 420 mg monthly ( QM ) or placebo Q2W or QM . Co primary end points were % change from baseline in LDL-C at week 12 and mean of weeks 10 and 12 . Secondary end points included change and % change in other lipids and proportion of patients reaching LDL-C < 70 mg/dl . Adverse events and laboratory values were recorded . Four hundred four patients were r and omized to study drug . At baseline , the mean ( SD ) age was 61 ( 10 ) years ( placebo ) and 62 ( 11 ) years ( evolocumab ) ; 39 % and 40 % were women ; 14 % and 12 % had cerebrovascular or peripheral arterial disease ; and 51 % and 47 % had diabetes . At entry , mean ( SD ) calculated LDL-C was 128 ( 23 ) mg/dL ; after stabilization on atorvastatin 5 and 20 mg/day , baseline LDL-C levels were 118 ( 35 ) and 94 ( 24 ) mg/dL , respectively . Mean LDL-C reductions at week 12 for evolocumab versus placebo ranged from 67 % to 76 % . No imbalances were observed in adverse events between treatment groups . Efficacy and safety for Q2W or QM evolocumab dosing were similar . In conclusion , in high-risk Japanese patients receiving stable statin therapy  , evolocumab markedly reduced LDL-C and was well tolerated BACKGROUND Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol , increased plasma LDL cholesterol concentrations , and premature cardiovascular disease . Despite intensive statin therapy , with or without ezetimibe , many patients are unable to achieve recommended target levels of LDL cholesterol . We investigated the effect of PCSK9 inhibition with evolocumab ( AMG 145 ) on LDL cholesterol in patients with this disorder . METHODS This multicentre , r and omised , double-blind , placebo-controlled trial was undertaken at 39 sites ( most of which were specialised lipid clinics , mainly attached to academic institutions ) in Australia , Asia , Europe , New Zeal and , North America , and South Africa between Feb 7 and Dec 19 , 2013 . 331 eligible patients ( 18 - 80 years of age ) , who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks , with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher , were r and omly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks , evolocumab 420 mg monthly , or subcutaneous placebo every 2 weeks or monthly for 12 weeks . R and omisation was computer generated by the study sponsor , implemented by a computerised voice interactive system , and stratified by LDL cholesterol concentration at screening ( higher or lower than 4·1 mmol/L ) and by baseline ezetimibe use ( yes/no ) . Patients , study personnel , investigators , and Amgen study staff were masked to treatment assignments within dosing frequency groups . The co primary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12 , analysed by intention-to-treat . This trial is registered with Clinical Trials.gov , number NCT01763918 . FINDINGS Of 415 screened patients , 331 were eligible and were r and omly assigned to the four treatment groups : evolocumab 140 mg every 2 weeks ( n=111 ) , evolocumab 420 mg monthly ( n=110 ) , placebo every 2 weeks ( n=55 ) , or placebo monthly ( n=55 ) . 329 patients received at least one dose of study drug . Compared with placebo , evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 ( every-2-weeks dose : 59·2 % reduction [ 95 % CI 53·4 - 65·1 ] , monthly dose : 61·3 % reduction [ 53·6 - 69·0 ] ; both p<0·0001 ) and at the mean of weeks 10 and 12 ( 60·2 % reduction [ 95 % CI 54·5 - 65·8 ] and 65·6 % reduction [ 59·8 - 71·3 ] ; both p<0·0001 ) . Evolocumab was well tolerated , with rates of adverse events similar to placebo . The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis ( in 19 patients [ 9 % ] vs five [ 5 % ] in the placebo group ) and muscle-related adverse events ( ten patients [ 5 % ] vs 1 [ 1 % ] ) . INTERPRETATION In patients with heterozygous familial hypercholesterolaemia  , evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60 % reductions in LDL cholesterol compared with placebo . FUNDING Amgen BACKGROUND Homozygous familial hypercholesterolaemia is a rare , serious disorder caused by very low or absent plasma clearance of LDL , substantially raised LDL cholesterol , and accelerated development of cardiovascular disease . Conventional lipid-lowering treatments are modestly effective . Evolocumab , a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , reduced LDL cholesterol by 16 % in a pilot study . We now report results with evolocumab in a r and omised , double-blind , placebo-controlled phase 3 trial . METHODS This r and omised , double-blind , placebo-controlled phase 3 trial was undertaken at 17 sites in ten countries in North America , Europe , the Middle East , and South Africa . 50 eligible patients ( aged ≥12 years ) with homozygous familial hypercholesterolaemia , on stable lipid-regulating therapy for at least 4 weeks , and not receiving lipoprotein apheresis  , were r and omly allocated by a computer-generated r and omisation sequence in a 2:1 ratio to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks . R and omisation was stratified by LDL cholesterol at screening ( < 11 mmol/L or ≥11 mmol/L ) and implemented by a computerised interactive voice-response system . Patients , study personnel , and the funder were masked to treatment and to the efficacy results by the central laboratory not returning LDL cholesterol or any lipid results to the clinical sites after the baseline visit . The primary endpoint was percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo , analysed by intention-to-treat . This trial is registered with Clinical Trials.gov , number NCT01588496 . FINDINGS Of the 50 eligible patients r and omly assigned to the two treatment groups , 49 actually received the study drug and completed the study ( 16 in the placebo group and 33 in the evolocumab group ) . Compared with placebo , evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9 % ( 95 % CI -43·9 % to -18·0 % ; p<0·0001 ) . Treatment-emergent adverse events occurred in ten ( 63 % ) of 16 patients in the placebo group and 12 ( 36 % ) of 33 in the evolocumab group . No serious clinical or laboratory adverse events occurred , and no anti-evolocumab antibody development was detected during the study . INTERPRETATION In patients with homozygous familial hypercholesterolaemia receiving stable background lipid-lowering treatment and not on apheresis , evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo . FUNDING Amgen Aim To evaluate the lipid‐lowering efficacy and safety of evolocumab combined with background atorvastatin in patients with type 2 diabetes mellitus ( T2DM ) and hyperlipidaemia or mixed dyslipidaemia . Material s and methods BERSON was a double‐blind , 12‐week , phase 3 study ( NCT02662569 ) conducted in 10 countries . Patients ≥18 to ≤80 years with type T2DM received atorvastatin 20 mg/d and were r and omised 2:2:1:1 to evolocumab 140 mg every 2 weeks ( Q2W ) or 420 mg monthly ( QM ) or placebo Q2W or QM . Co‐ primary endpoints were the percentage change in low‐density lipoprotein cholesterol ( LDL‐C ) from baseline to week 12 and from baseline to the mean of weeks 10 and 12 . Additional endpoints included atherogenic lipids , glycaemic measures , and adverse events ( AEs ) . Results Overall , 981 patients were r and omised and received ≥1 dose of study drug . Evolocumab significantly reduced LDL‐C  versus placebo at week 12 ( Q2W , −71.8 % ; QM , −74.9 % ) and at the mean of weeks 10 and 12 ( Q2W , −70.3 % ; QM , −70.0 % ; adjusted P < 0.0001 for all ) when administered with atorvastatin . Non‐high‐density lipoprotein cholesterol , apolipoprotein B100 , total cholesterol , lipoprotein ( a ) , triglycerides , high‐density lipoprotein cholesterol , and very low‐density lipoprotein cholesterol improved significantly with evolocumab versus placebo . The overall incidence of AEs was similar between evolocumab and placebo‐treated patients , and there were no clinical ly meaningful differences in changes over time in glycaemic variables ( fasting serum glucose and HbA1c ) between the two groups . Conclusions In patients with T2DM and hyperlipidaemia or mixed dyslipidaemia on statin , evolocumab  significantly reduced LDL‐C and other atherogenic lipids , was well tolerated , and had no notable impact on glycaemic measures Aims /hypothesisThe study aim ed to examine the efficacy of 12 weeks of monthly evolocumab or placebo in lowering LDL-cholesterol ( LDL-C ) in individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia and on a maximum-tolerated statin of at least moderate intensity . Methods For this r and omised , placebo-controlled outpatient study , eligible individuals were ≥18 years old with type 2 diabetes , HbA1c < 10 % ( 86 mmol/mol ) , had been on stable pharmacological therapy for diabetes for ≥6 months and were taking a maximum-tolerated statin dose of at least moderate intensity . Lipid eligibility criteria varied by history of clinical cardiovascular disease . Participants were r and omised 2:1 to evolocumab 420 mg s.c . or placebo .  R and omisation was performed central ly via an interactive web-based or voice recognition system . Allocation was concealed using the central ised r and omisation process . Treatment assignment was blinded to the sponsor study team , investigators , site staff and patients throughout the study . Co- primary endpoints were mean percentage change in LDL-C from baseline to week 12 and to the mean of weeks 10 and 12 . Additional endpoints included LDL-C < 1.81 mmol/l , LDL-C reduction ≥50 % and other lipids . Exploratory analyses included percentage changes in fasting and post mixed-meal tolerance test ( MMTT ) lipoproteins and lipids , glucose metabolism variables and inflammatory biomarkers . Results In total , 421 individuals were r and omised and analysed , having received evolocumab ( 280 participants ) or placebo ( 141 participants ) ( mean [ SD ] age 62 [ 8 ] years ; 44 % women ; 77 % white ) . Evolocumab decreased LDL-C by 54.3 % ( 1.4 % ) at week 12 ( vs 1.1 % [ 1.9 % ] decrease with placebo ; p < 0.0001 ) and by 65.0 % ( 1.3 % ) at the mean of weeks 10 and 12 ( vs 0.8 % [ 1.8 % ] decrease with placebo ; p < 0.0001 ) ; it also decreased non-HDL-cholesterol ( HDL-C ) by 46.9 % ( 1.3 % ) at week 12 ( vs 0.6 % [ 1.8 % ] decrease with placebo ) and by 56.6 % ( 1.2 % ) at the mean of weeks 10 and 12 ( vs 0.1 % [ 1.6 % ] decrease with placebo ) . Evolocumab significantly improved levels of other lipids and allowed more participants to reach LDL-C < 1.81 mmol/l or a reduction in LDL-C levels ≥50 % . After an MMTT ( 120 min ) , there were favourable changes ( p < 0.05 ; nominal , post hoc , no multiplicity adjustment ) in chylomicron triacylglycerol ( triglycerides ) , chylomicron cholesterol , VLDL-C and LDL-C. Evolocumab had no effect on glycaemic variables and was well tolerated . Conclusions /interpretationIn statin-treated individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia , evolocumab significantly reduced LDL-C and non-HDL-C. Favourable changes ( p < 0.05 ) were observed in postpr and ial levels of chylomicrons , VLDL-C and LDL-C.Trial registration Clinical Trials.gov NCT02739984 Funding This study was funded by Amgen Inc. Data availabilityQualified research ers may request data from Amgen clinical studies . Complete details are available at www.amgen.com/ data sharing Importance Reducing levels of low-density lipoprotein cholesterol ( LDL-C ) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels . Proprotein convertase subtilisin kexin type 9 ( PCSK9 ) inhibitors produce incremental LDL-C lowering in statin-treated patients ; however , the effects of these drugs on coronary atherosclerosis have not been evaluated . Objective To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients . Design , Setting , and Participants The GLAGOV multicenter , double-blind , placebo-controlled , r and omized clinical trial ( enrollment May 3 , 2013 , to January 12 , 2015 ) conducted at 197 academic and community hospitals in North America , Europe , South America , Asia , Australia , and South Africa and enrolling 968 patients presenting for coronary angiography . Interventions Participants with angiographic coronary disease were r and omized to receive monthly evolocumab ( 420 mg ) ( n = 484 ) or placebo ( n = 484 ) via subcutaneous injection for 76 weeks , in addition to statins . Main Outcomes and Measures The primary efficacy measure was the nominal change in percent atheroma volume ( PAV ) from baseline to week 78 , measured by serial intravascular ultrasonography ( IVUS ) imaging . Secondary efficacy measures were nominal change in normalized total atheroma volume ( TAV ) and percentage of patients demonstrating plaque regression . Safety and tolerability were also evaluated . Results Among the 968 treated patients ( mean age , 59.8 years [ SD , 9.2 ] ; 269 [ 27.8 % ] women ; mean LDL-C level , 92.5 mg/dL [ SD , 27.2 ] ) , 846 had evaluable imaging at follow-up . Compared with placebo , the evolocumab group achieved lower mean , time-weighted LDL-C levels ( 93.0 vs 36.6 mg/dL ; difference , -56.5 mg/dL [ 95 % CI , -59.7 to -53.4 ] ; P < .001 ) . The primary efficacy parameter , PAV , increased 0.05 % with placebo and decreased 0.95 % with evolocumab ( difference , -1.0 % [ 95 % CI , -1.8 % to -0.64 % ] ; P < .001 ) . The secondary efficacy parameter , normalized TAV , decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab ( difference , -4.9 mm3 [ 95 % CI , -7.3 to -2.5 ] ; P < .001 ) . Evolocumab  induced plaque regression in a greater percentage of patients than placebo ( 64.3 % vs 47.3 % ; difference , 17.0 % [ 95 % CI , 10.4 % to 23.6 % ] ; P < .001 for PAV and 61.5 % vs 48.9 % ; difference , 12.5 % [ 95 % CI , 5.9 % to 19.2 % ] ; P < .001 for TAV ) . Conclusions and Relevance Among patients with angiographic coronary disease treated with statins , addition of evolocumab , compared with placebo , result ed in a greater decrease in PAV after 76 weeks of treatment . Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes . Trial Registration clinical trials.gov Identifier : NCT01813422 BACKGROUND Bococizumab , a humanized monoclonal antibody targeting proprotein convertase subtilisin – kexin type 9 ( PCSK9 ) , reduces levels of low‐density lipoprotein ( LDL ) cholesterol . However , the variability and durability of this effect are uncertain . METHODS We conducted six parallel , multinational lipid‐lowering trials enrolling 4300 patients with hyperlipidemia who were r and omly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months ; 96 % were receiving statin therapy at the time of enrollment . The patients were assessed for lipid changes over time , stratified according to the presence or absence of antidrug antibodies detected during the treatment period . RESULTS At 12 weeks , patients who received bococizumab had a reduction of 54.2 % in the LDL cholesterol level from baseline , as compared with an increase of 1.0 % among those who received placebo ( absolute between‐group difference , ‐55.2 percentage points ) . Significant between‐group differences were also observed in total cholesterol , non – high‐density lipoprotein cholesterol , apolipoprotein B , and lipoprotein(a ) ( P<0.001 for all comparisons ) . However , high‐titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab , which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels . In addition , among patients with no antidrug antibodies , there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks . Major cardiovascular events occurred in 57 patients ( 2.5 % ) who received bococizumab and in 55 ( 2.7 % ) who received placebo ( hazard ratio , 0.96 ; 95 % confidence interval , 0.66 to 1.39 ; P=0.83 ) . The most common adverse event among patients who received bococizumab was injection‐site reaction ( 12.7 per 100 person‐years ) . CONCLUSIONS In six multinational trials evaluating bococizumab , antidrug antibodies developed in a large proportion of the patients and significantly attenuated the lowering of LDL cholesterol levels . Wide variation in the relative reduction in cholesterol levels was also observed among patients in whom antidrug antibodies did not develop . ( Funded by Pfizer ; SPIRE Clinical Trials.gov numbers , NCT01968954 , NCT01968967 , NCT01968980 , NCT02100514 , NCT02135029 , and NCT02458287 . BACKGROUND Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin – kexin type 9 ( PCSK9 ) and reduces levels of low‐density lipoprotein ( LDL ) cholesterol . We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk . METHODS In two parallel , multinational trials with different entry criteria for LDL cholesterol levels , we r and omly assigned the 27,438 patients in the combined trials to receive bococizumab ( at a dose of 150 mg ) subcutaneously every 2 weeks or placebo . The primary end point was nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for unstable angina requiring urgent revascularization , or cardiovascular death ; 93 % of the patients were receiving statin therapy at baseline . The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies , as seen in data from other studies in the program . The median follow‐up was 10 months . RESULTS At 14 weeks , patients in the combined trials had a mean change from baseline in LDL cholesterol levels of ‐56.0 % in the bococizumab group and + 2.9 % in the placebo group , for a between‐group difference of –59.0 percentage points ( P<0.001 ) and a median reduction from baseline of 64.2 % ( P<0.001 ) . In the lower‐risk , shorter‐ duration trial ( in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [ 1.8 mmol per liter ] and the median follow‐up was 7 months ) , major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group ( hazard ratio , 0.99 ; 95 % confidence interval [ CI ] , 0.80 to 1.22 ; P=0.94 ) . In the higher‐risk , longer‐ duration trial ( in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [ 2.6 mmol per liter ] and the median follow‐up was 12 months ) , major cardiovascular events occurred in 179 and 224 patients , respectively ( hazard ratio , 0.79 ; 95 % CI , 0.65 to 0.97 ; P=0.02 ) . The hazard ratio for the primary end point in the combined trials was 0.88 ( 95 % CI , 0.76 to 1.02 ; P=0.08 ) . Injection‐site reactions were more common in the bococizumab group than in the placebo group ( 10.4 % vs. 1.3 % , P<0.001 ) . CONCLUSIONS In two r and omized trials comparing the PCSK9 inhibitor bococizumab with placebo , bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower‐risk patients but did have a significant benefit in the trial involving higher‐risk patients . ( Funded by Pfizer ; SPIRE‐1 and SPIRE‐2 Clinical Trials.gov numbers , NCT01975376 and NCT01975389 . BACKGROUND Alirocumab , a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 , has been shown to provide significant reductions in low-density lipoprotein cholesterol ( LDL-C ) . Data about its efficacy and safety in patients from South Korea and Taiwan are limited . OBJECTIVE ODYSSEY KT assessed the efficacy and safety of alirocumab in patients from South Korea and Taiwan . METHODS Patients with hypercholesterolemia at high cardiovascular risk who were on maximally tolerated statin were r and omized ( 1:1 ) to alirocumab ( 75 mg every 2 weeks , with dose increase to 150 mg every 2 weeks at week 12 if LDL-C ≥70 mg/dL at week 8) or placebo for 24 weeks . The primary efficacy endpoint was percentage change in LDL-C from baseline to week 24 . Safety was assessed throughout . RESULTS At week 24 , alirocumab  changed LDL-C levels by -57.1 % ( placebo : + 6.3 % ) . In the alirocumab group , 9 patients ( 9.5 % ) received dose increase at week 12 . At week 24 , 85.8 % of patients in the alirocumab group reached LDL-C < 70 mg/dL ( placebo : 14.2 % ; P ≤ .0001 vs placebo ) . Alirocumab significantly improved non-high-density lipoprotein cholesterol ( non-HDL-C ) , apolipoprotein B , total cholesterol , lipoprotein ( a ) , and HDL-C vs placebo ( P ≤ .05 ) . Two consecutive calculated LDL-C values < 25 mg/dL were recorded in 27.8 % of alirocumab-treated patients . Overall , 58.8 % ( alirocumab ) and 61.8 % ( placebo ) of patients experienced treatment-emergent adverse events ; 2.1 % and 1.0 % discontinued treatment due to treatment-emergent adverse events , respectively . CONCLUSION Alirocumab  significantly improved LDL-C , apolipoprotein B , non-HDL-C , lipoprotein ( a ) , HDL-C , and total cholesterol  in Asian patients . Alirocumab was generally well tolerated . These findings are consistent with ODYSSEY findings to date BACKGROUND : Patients with heterozygous familial hypercholesterolemia ( FH ) and coronary heart disease have high mortality rates . However , in an era of high-dose statin prescription after acute coronary syndrome ( ACS ) , the risk of recurrent coronary and cardiovascular events associated with FH might be mitigated . We compared coronary event rates between patients with and without FH after ACS . METHODS : We studied 4534 patients with ACS enrolled in a multicenter , prospect i ve cohort study in Switzerl and between 2009 and 2013 who were individually screened for FH on the basis of clinical criteria according to 3 definitions : the American Heart Association definition , the Simon Broome definition , and the Dutch Lipid Clinic definition . We used Cox proportional models to assess the 1-year risk of first recurrent coronary events defined as coronary death or myocardial infa rct ion and adjusted for age , sex , body mass index , smoking , hypertension , diabetes mellitus , existing cardiovascular disease , high-dose statin at discharge , attendance at cardiac rehabilitation , and the GRACE ( Global Registry of Acute Coronary Events ) risk score for severity of ACS . RESULTS : At the 1-year follow-up , 153 patients ( 3.4 % ) had died , including 104 ( 2.3 % ) of fatal myocardial infa rct ion . A further 113 patients ( 2.5 % ) experienced nonfatal myocardial infa rct ion . The prevalence of FH was 2.5 % with the American Heart Association definition , 5.5 % with the Simon Broome definition , and 1.6 % with the Dutch Lipid Clinic definition . Compared with patients without FH , the risk of coronary event recurrence after ACS was similar in patients with FH in unadjusted analyses , although patients with FH were > 10 years younger . However , after multivariable adjustment including age , the risk was greater in patients with FH than without , with an adjusted hazard ratio of 2.46 ( 95 % confidence interval , 1.07–5.65 ; P=0.034 ) for the American Heart Association definition , 2.73 ( 95 % confidence interval , 1.46–5.11 ; P=0.002 ) for the Simon Broome definition , and 3.53 ( 95 % confidence interval , 1.26–9.94 ; P=0.017 ) for the Dutch Lipid Clinic definition . Depending on which clinical definition of FH was used , between 94.5 % and 99.1 % of patients with FH were discharged on statins and between 74.0 % and 82.3 % on high-dose statins  . CONCLUSIONS : Patients with FH and ACS have a > 2-fold adjusted risk of coronary event recurrence within the first year after discharge than patients without FH despite the widespread use of high-intensity statins
target: The reduction in MACEs was observed in White but not in Asian subjects .
  Both alirocumab and evolocumab are well tolerated and can greatly improve lipid profiles for patients at high cardiovascular risk .
  Both PCSK9 monoclonal antibodies significantly reduce the risk of nonfatal MACEs in patients with previous cardiovascular events , but the effect on all-cause mortality remains uncertain
background: Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) monoclonal antibodies are powerful lipid-lowering drugs which have been shown to improve clinical endpoints in patients with hypercholesterolemia .
  However , it is not clear how effective PCSK9 monoclonal antibodies are for patients at high cardiovascular risk .
  Also , whether the effectiveness of PCSK9 monoclonal antibodies varies between different drug types , dosages , race , and indications for PCSK9 monoclonal antibodies remains unclear .
  Therefore , we used recently published studies to systematic ally evaluate the efficacy and safety of PCSK9 monoclonal antibodies by analyzing the lipid profiles , adverse events , and clinical endpoints in patients at high cardiovascular risk .