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 Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies Prevalence of Dyslipidemia and Lipid Goal Attainment in Statin-Treated Subjects From 3 Data Sources: A Retrospective Analysis 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. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised 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. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. Effects of lovastatin on cognitive function and psychological well-being. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. Determinants of Residual Risk in Secondary Prevention Patients Treated With High- Versus Low-Dose Statin Therapy: The Treating to New Targets (TNT) Study Pravastatin and cognitive function in the elderly. Results of the PROSPER study Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin‐Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3) Trial 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. Randomized trial of the effects of simvastatin on cognitive functioning in hypercholesterolemic adults. 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. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. 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 Efficacy and Safety of Alirocumab in Japanese Subjects (Phase 1 and 2 Studies). Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. Low-Density Lipoprotein Cholesterol–Lowering Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia: The Reduction of LDL-C With PCSK9 Inhibition in Heterozygous Familial Hypercholesterole Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study
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 Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9 , which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol ( LDL-C ) levels in patients with hypercholesterolemia . In this 24-week , multicenter , double-blind , placebo-controlled , dose-ranging study ( NCT01592240 ) , subjects with LDL-C levels≥80 mg/dl on stable statin therapy were r and omized to Q14 days  subcutaneous placebo or bococizumab 50 , 100 , or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg . Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl . The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration . Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period . Of the 354 subjects r and omized , 351 received treatment  ( placebo [ n=100 ] or bococizumab [ n=251 ] ) . The most efficacious bococizumab doses were 150 mg Q14 days and 300 mg Q28 days . Compared with placebo , bococizumab 150 mg Q14 days reduced LDL-C at week 12 by 53.4 mg/dl and bococizumab 300 mg Q28 days reduced LDL-C by 44.9 mg/dl ; this was despite dose reductions in 32.5 % and 34.2 % of subjects at week 10 or 8 , respectively . Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted that bococizumab would lower LDL-C levels by 72.2 and 55.4 mg/dl , respectively . Adverse events were similar across placebo and bococizumab groups . Few subjects ( n=7 ; 2 % ) discontinued treatment because of treatment-related adverse events . In conclusion , bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects . Model-based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction . The Q14 days regimen is being evaluated in phase 3 clinical trials BACKGROUND Efficacy and safety of alirocumab were compared with ezetimibe in hypercholesterolemic patients at moderate cardiovascular risk not receiving statins or other lipid-lowering therapy . METHODS In a Phase 3 , r and omized , double-blind , double-dummy study ( NCT01644474 ) , patients ( low-density lipoprotein cholesterol [ LDL-C ] 100 - 190 mg/dL , 10-year risk of fatal cardiovascular events ≥ 1%-<5 % [ systemic coronary risk estimation ] ) were r and omized  to ezetimibe 10mg/day ( n=51 ) or alirocumab 75 mg subcutaneously ( via 1-mL autoinjector ) every 2 weeks ( Q2W ) ( n=52 ) , with dose up-titrated to 150 mg Q2W ( also 1 mL ) at week 12 if week 8 LDL-C was ≥ 70 mg/dL. Primary endpoint was mean LDL-C % change from baseline to 24 weeks , analyzed using all available data ( intent-to-treat approach , ITT ) . Analyses using on-treatment LDL-C values were also conducted . RESULTS Mean ( SD ) baseline LDL-C levels were 141.1 ( 27.1 ) mg/dL ( alirocumab ) and 138.3 ( 24.5 ) mg/dL ( ezetimibe ) . The 24-week treatment period was completed by 85 % of alirocumab and 86 % of ezetimibe patients . Least squares mean ( SE ) LDL-C reductions were 47 (3)% with alirocumab versus 16 (3)% with ezetimibe ( ITT ; p<0.0001 ) and 54 (2)% versus 17 (2)% ( on-treatment ; p<0.0001 ) . At week 12 , before up-titration , alirocumab 75 mg Q2W reduced LDL-C by 53 (2)% ( on-treatment ) . Injection site reactions were infrequent ( < 2 % and < 4 % of alirocumab and ezetimibe patients , respectively ) . CONCLUSIONS Alirocumab demonstrated significantly greater LDL-C lowering versus ezetimibe after 24 weeks with the lower 75 mg Q2W dose sufficient to provide ≥ 50 % LDL-C reduction in the majority of the patients . Adverse events were comparable between groups BACKGROUND AND AIMS In previous phase III studies , the PCSK9 monoclonal antibody alirocumab was administered at doses of 75 or 150 mg every 2 weeks ( Q2W ) . CHOICE I ( NCT01926782 ) evaluated 300 mg every 4 weeks ( Q4W ) in patients on either maximally  tolerated statin  or no statin , both ± other lipid-lowering therapies . METHODS CHOICE I included patients with hypercholesterolemia at moderate-to-very-high cardiovascular risk . Patients were r and omized to alirocumab 300 mg Q4W , 75 mg Q2W ( calibrator arm ) , or placebo for 48 weeks , with dose adjustment for either alirocumab arm to 150 mg Q2W at Week ( W ) 12 if at W8 LDL-C levels were > 70/100 mg/dL ( 1.8/2.6 mmol/L ) depending on cardiovascular risk or LDL-C reduction was < 30 % from baseline . Co- primary endpoints were percent LDL-C change from baseline to W24 , and to time-averaged LDL-C over W21 - 24 . RESULTS Approximately two-thirds of r and omized patients were receiving statins . At W12 , 14.7 % ( no statin ) and 19.3 % ( statin ) of patients receiving alirocumab 300 mg Q4W required dose adjustment . At W24 , significant LDL-C reductions from baseline were observed with alirocumab 300 mg Q4W : mean differences were -52.7 % ( no statin ; placebo : -0.3 % ) and -58.8 % ( statin ; placebo : -0.1 % ) . Average LDL-C reductions from baseline to W21 - 24 were also significantly greater with alirocumab 300 mg Q4W vs. placebo in patients not receiving ( -56.9 % vs. -1.6 % ) and receiving statin ( -65.8 % vs. -0.8 % ) . Treatment-emergent adverse event rates ranged from 61.1 to 75.0 % ( placebo ) and 71.5 to 78.1 % ( alirocumab 300 mg Q4W ) . CONCLUSIONS Alirocumab 300 mg Q4W is a viable additional treatment option in patients requiring LDL-C-lowering Aims Statins have modest adverse effects on glycaemic control .  Alirocumab , a proprotein convertase subtilisin/kexin type 9 inhibitor , lowers low-density lipoprotein cholesterol . This study assessed the effects of alirocumab on  new-onset diabetes and pre-diabetes incidence in individuals without diabetes at baseline . Methods and results Pooled analysis of 10 ODYSSEY Phase 3 trials ( n = 4974 ) of 24–104 weeks duration . Six trials ( n = 4211 ) were ≥52 weeks in length . Most patients received background maximally tolerated statin . Alirocumab effect on the rate of diabetes-related treatment-emergent adverse events ( TEAEs ) , and /or fasting plasma glucose ( FPG ) and glycated haemoglobin A1C ( HbA1C ) was measured at baseline and every 12–24 weeks . Transition to diabetes analysis combined TEAE and FPG/HbA1C laboratory data . At baseline , 30.7 % of individuals had diabetes and were excluded from the current analysis . The remaining 3448 individuals without diabetes had pre-diabetes ( 39.6 % ) or were normoglycaemic ( 29.7 % ) . The hazard ratio ( HR ; 95 % confidence interval ) for diabetes-related TEAEs in alirocumab was 0.64 ( 0.36–1.14 ) vs. placebo and 0.55 ( 0.22–1.41 ) vs. ezetimibe . The HR associated for transition from pre-diabetes to new-onset diabetes for alirocumab was 0.90 ( 0.63–1.29 ) vs. placebo and 1.10 ( 0.57–2.12 ) vs. ezetimibe  . Mean change in FPG/HbA1C over time showed no difference between treatment groups in patients without diabetes . Conclusions There was no evidence of an effect of alirocumab  on transition to new-onset diabetes in 3448 individuals without diabetes at baseline with a follow-up period of 6–18 months , compared to either placebo or ezetimibe . Longer follow-up with larger number of individuals is needed to conclusively rule out an effect Background Evidence -based r and omized clinical trials have shown significant benefit of statin treatment with regard to cardiovascular disease . In anticipation of the National Cholesterol Education Program Adult Treatment Panel IV guidelines , we wanted to assess the current state of lipid goal attainment in the high-risk secondary prevention population in the United States . The objectives of the study were to estimate the proportion of high-risk patients treated with statin monotherapy  who achieved Adult Treatment Panel III – recommended low-density lipoprotein cholesterol ( LDL-C ) goals ( < 100 mg/dL ; optional < 70 mg/dL ) as well as non – high-density lipoprotein cholesterol goals ( < 130 mg/dL ; optional < 100 mg/dL ) . Methods and Results This is a cross-sectional , retrospective study of 3 data sources : electronic medical records ( 2003–September 2010 ) , administrative cl aims data ( 2003–2010 ) , and National Health and Nutrition Examination Survey data ( 2007–2008 ) . High-risk patients ( ≥18 years of age ) were defined as those with a history of coronary heart disease or coronary heart disease risk equivalent who had the latest complete lipid panel measurement and had been treated with statin monotherapy for > 90 days at the time of the lipid panel . Cardiovascular disease , coronary heart disease , and coronary heart disease risk equivalents were defined on the basis of availability , specific to each data source . Across the 3 data sources , 20 % to 26 % of high-risk patients treated with statin monotherapy for > 90 days had LDL-C < 70 mg/dL , and 67 % to 77 % had LDL-C < 100 mg/dL. The percentages of those attaining both LDL-C goals and non – high-density lipoprotein cholesterol goals were quantitatively smaller ( 13.5 % to 19.0 % and 46 % to 70 % ) . Conclusions Across the 3 data sources , there was consistency in the proportion of high-risk patients treated with statin monotherapy who were at LDL-C goal . A significant number of these statin-treated patients had additional dyslipidemias 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 Summary Background Lowering of LDL cholesterol reduces major vascular events , but whether more intensive therapy safely produces extra benefits is uncertain . We aim ed to establish efficacy and safety of more intensive statin treatment in patients at high cardiovascular risk . Methods We undertook a double-blind r and omised trial in 12 064 men and women aged 18–80 years with a history of myocardial infa rct ion . Participants were either currently on or had clear indication for statin therapy , and had a total cholesterol concentration of at least 3·5 mmol/L if already on a statin or 4·5 mmol/L if not . R and omisation to either 80 mg or 20 mg simvastatin daily was done central ly using a minimisation algorithm . Participants were assessed at 2 , 4 , 8 , and 12 months after r and omisation and then every 6 months until final follow-up . The primary endpoint was major vascular events , defined as coronary death , myocardial infa rct ion , stroke , or arterial revascularisation . Analysis was by intention to treat . This study is registered , number IS RCT N74348595 . Findings 6031 participants were allocated 80 mg simvastatin  daily , and 6033 allocated 20 mg simvastatin daily . During a mean follow-up of 6·7 ( SD 1·5 ) years , allocation to 80 mg simvastatin produced an average 0·35 ( SE 0·01 ) mmol/L greater reduction in LDL cholesterol compared with allocation to 20 mg . Major vascular events occurred in 1477 ( 24·5 % ) participants allocated 80 mg simvastatin versus 1553 ( 25·7 % ) of those allocated 20 mg , corresponding to a 6 % proportional reduction ( risk ratio 0·94 , 95 % CI 0·88–1·01 ; p=0·10 ) . There were no apparent differences in numbers of haemorrhagic strokes ( 24 [ 0·4 % ] vs 25 [ 0·4 % ] ) or deaths attributed to vascular ( 565 [ 9·4 % ] vs 572 [ 9·5 % ] ) or non-vascular ( 399 [ 6·6 % ] vs 398 [ 6·6 % ] ) causes . Compared with two ( 0·03 % ) cases of myopathy in patients taking 20 mg simvastatin daily , there were 53 ( 0·9 % ) cases in the 80 mg group . Interpretation The 6 % ( SE 3·5 % ) reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials . Myopathy was increased with 80 mg simvastatin daily , but intensive lowering of LDL cholesterol can be achieved safely with other regimens . Funding Merck ; The Clinical Trial Service Unit also receives funding from the UK Medical Research Council and the British Heart Foundation 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 CONTEXT An estimated 10 % to 20 % of patients can not tolerate statins or adequate doses to achieve treatment goals . Plasma proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) binds to low-density lipoprotein ( LDL ) receptors , promoting their degradation and increasing LDL cholesterol levels . In phase 1 studies , a human monoclonal antibody to PCSK9 , AMG145 , was well tolerated and reduced LDL cholesterol levels . OBJECTIVE To assess the efficacy and tolerability of AMG145 in patients with statin intolerance due to muscle-related side effects . DESIGN , SETTING , AND PATIENTS A 12-week , r and omized , double-blind , placebo- and ezetimibe-controlled , dose-ranging study conducted between July 2011 and May 2012 in statin-intolerant adult patients at 33 international sites . INTERVENTION Patients were r and omized equally to 1 of 5 groups : AMG145 alone at doses of 280 mg , 350 mg , or 420 mg ; AMG145 at 420 mg plus 10 mg of ezetimibe ; or 10 mg of ezetimibe plus placebo . AMG145 or placebo was administered subcutaneously every 4 weeks . MAIN OUTCOME MEASURES The primary end point was percentage change from baseline to week 12 in ultracentrifugation-measured LDL cholesterol . Other end points included measures of safety and tolerability of different doses of AMG145 and AMG145 plus ezetimibe . RESULTS Of 236 patients screened , 160 were r and omized ( mean age , 62 years ; 64 % female ; mean baseline LDL cholesterol , 193 mg/dL ) ; all patients had intolerance to 1 or more statins because of muscle-related events . At week 12 , mean changes in LDL cholesterol levels were -67 mg/dL ( -41 % ; 95 % CI , -49 % to -33 % ) for the AMG145 , 280-mg , group ; -70 mg/dL ( -43 % ; 95 % CI , -51 % to -35 % ) for the 350-mg group ; -91 mg/dL ( -51 % ; 95 % CI , -59 % to -43 % ) for the 420-mg group ; and -110 mg/dL ( -63 % ; 95 % CI , -71 % to -55 % ) for the 420-mg/ezetimibe group compared with -14 mg/dL ( -15 % ; 95 % CI , -23 % to -7.0 % ) for the placebo/ezetimibe group ( P < .001 ) . Four serious adverse events were reported with AMG145 ( coronary artery disease , acute pancreatitis , hip fracture , syncope ) . Myalgia was the most common treatment-emergent adverse event during the study , occurring in 5 patients ( 15.6 % ) in the 280-mg group ( n = 32 ) ; 1 patient ( 3.2 % ) in the 350-mg group ( n = 31 ) , 1 patient ( 3.1 % ) in the 420-mg group ( n = 32 ) , 6 patients ( 20.0 % ) receiving 420-mg AMG145/ezetimibe , and 1 patient ( 3.1 % ) receiving placebo/ezetimibe . CONCLUSION In this phase 2 study in statin-intolerant patients , subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01375764 PURPOSE Animal research and cross-sectional studies suggest that serum lipid concentrations may influence cognitive function , mood , and behavior , but few clinical trials have studied these effects . SUBJECTS AND METHODS In this double-blind investigation , 209 generally healthy adults with a serum low-density-lipoprotein ( LDL ) cholesterol level of 160 mg/dL or higher were r and omly assigned to 6-month treatment with lovastatin ( 20 mg ) or placebo . Assessment s of neuropsychological performance , depression , hostility , and quality of life were conducted at baseline and at the end of the treatment period . Summary effect sizes were estimated as z scores on a st and ard deviation ( SD ) scale . RESULTS Placebo-treated subjects improved between baseline and posttreatment periods on neuropsychological tests in all five performance domains , consistent with the effects of practice on test performance ( all P < 0.04 ) , whereas those treated with lovastatin improved only on tests of memory recall ( P = 0.03 ) . Comparisons of the changes in performance between placebo- and lovastatin-treated subjects revealed small , but statistically significant , differences for tests of attention ( z score = 0.18 ; 95 % confidence interval ( CI ) , 0.06 to 0.31 ; P = 0.005 ) and psychomotor speed ( z score = 0.17 ; 95 % CI , 0.05 to 0.28 ; P = 0 . 004 ) that were consistent with greater improvement in the placebo group . Psychological well-being , as measured several ways , was not affected by lovastatin . CONCLUSION Treatment of hypercholesterolemia with lovastatin did not cause psychological distress or substantially alter cognitive function . Treatment did result in small performance decrements on neuropsychological tests of attention and psychomotor speed , the clinical importance of which is uncertain BACKGROUND Statin therapy reduces low-density lipoprotein ( LDL ) cholesterol levels and the risk of cardiovascular events , but whether the addition of ezetimibe , a nonstatin drug that reduces intestinal cholesterol absorption , can reduce the rate of cardiovascular events further is not known . METHODS We conducted a double-blind , r and omized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter ( 1.3 to 2.6 mmol per liter ) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter ( 1.3 to 3.2 mmol per liter ) if they were not receiving lipid-lowering therapy .  The combination of simvastatin ( 40 mg ) and ezetimibe ( 10 mg ) ( simvastatin-ezetimibe ) was compared with simvastatin ( 40 mg ) and placebo ( simvastatin monotherapy ) . The primary end point was a composite of cardiovascular death , nonfatal myocardial infa rct ion , unstable angina requiring rehospitalization , coronary revascularization ( ≥30 days after r and omization ) , or nonfatal stroke . The median follow-up was 6 years . RESULTS The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter ( 1.4 mmol per liter ) in the simvastatin-ezetimibe group , as compared with 69.5 mg per deciliter ( 1.8 mmol per liter ) in the simvastatin-monotherapy group ( P<0.001 ) . The Kaplan-Meier event rate for the primary end point at 7 years was 32.7 % in the simvastatin-ezetimibe group , as compared with 34.7 % in the simvastatin-monotherapy group ( absolute risk difference , 2.0 percentage points ; hazard ratio , 0.936 ; 95 % confidence interval , 0.89 to 0.99 ; P=0.016 ) . Rates of prespecified muscle , gallbladder , and hepatic adverse effects and cancer were similar in the two groups . CONCLUSIONS When added to statin therapy , ezetimibe result ed in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes . Moreover , lowering LDL cholesterol to levels below previous targets provided additional benefit . ( Funded by Merck ; IMPROVE-IT Clinical Trials.gov number , NCT00202878 . ) Background — Cardiovascular events occur among  statin-treated patients , albeit at lower rates . Risk factors for this “ residual risk ” have not been studied comprehensively . We aim ed to identify determinants of this risk above and beyond lipid-related risk factors . Methods and Results — A total of 9251 coronary patients with low-density lipoprotein cholesterol < 130 mg/dL r and omized to double-blind atorvastatin 10 or 80 mg/d in the Treating to New Targets ( TNT ) study had complete on-treatment 1-year lipid data . Median follow-up was 4.9 years . The primary end point was major cardiovascular events ( n=729 ) : coronary death , nonfatal myocardial infa rct ion , resuscitation after cardiac arrest , or fatal or nonfatal stroke . Multivariable determinants of increased risk were older age ( adjusted hazard ratio [ aHR ] , 1.13 per 1 SD [ 8.8 years ] ; 95 % confidence interval [ CI ] , 1.04–1.23 ) , increased body mass index ( aHR , 1.09 ; 95 % CI , 1.02–1.17 per 4.5 kg/m2 ) , male sex ( aHR , 1.33 ; 95 % CI , 1.07–1.65 ) , hypertension ( aHR , 1.38 ; 95 % CI , 1.17–1.63 ) , diabetes mellitus ( aHR , 1.33 ; 95 % CI , 1.11–1.60 ) , baseline apolipoprotein B ( aHR , 1.19 ; 95 % CI , 1.11–1.28 per 19 mg/dL ) , and blood urea nitrogen ( aHR , 1.10 ; 95 % CI , 1.03–1.17 per 4.9 mg/dL ) , in addition to current smoking , prior cardiovascular disease , and calcium channel blocker use . Determinants of decreased risk were high-dose statin ( aHR , 0.82 ; 95 % CI , 0.70–0.94 ) , aspirin use ( aHR , 0.67 ; 95 % CI , 0.56–0.81 ) , and baseline apolipoprotein A-I ( aHR , 0.91 ; 95 % CI , 0.84–0.99 per 25 mg/dL ) . On-treatment 1-year lipids or apolipoproteins were not additionally associated with risk in multivariable models . Known baseline variables performed moderately well in discriminating future cases from noncases ( Harrell c index=0.679 ) . Conclusions — Determinants of residual risk in statin-treated secondary prevention patients included lipid-related and nonlipid factors such as baseline apolipoproteins , increased body mass index , smoking , hypertension , and diabetes mellitus . A multifaceted prevention approach should be underscored to address this risk . Clinical Trial Registration — URL : http:// clinical trials.gov . Unique identifier : NCT00327691 Observational studies have given conflicting results about the effect of statins in preventing  dementia and cognitive decline . Moreover , observational studies are subject to prescription bias , making it hard to draw definite conclusions from them . R and omized controlled trials are therefore the preferred study design to investigate the association between statins and cognition . Here we present detailed cognitive outcomes from the r and omized placebo-controlled PROspect i ve Study of  Pravastatin in the Elderly at Risk ( PROSPER ) . Cognitive function was assessed repeatedly in all 5,804 PROSPER participants at six different time points during the study using four neuropsychological performance tests . After a mean follow-up period of 42 months , no difference in cognitive decline at any of the cognitive domains was found in subjects treated with pravastatin compared to placebo ( all p > 0.05 ) . Pravastatin treatment in old age did not affect cognitive decline during a 3 year follow-up period . Employing statin therapy in the elderly in an attempt to prevent cognitive decline therefore seems to be futile IMPORTANCE In phase 2 studies , evolocumab , a fully human monoclonal antibody to PCSK9 , reduced LDL-C levels in patients receiving statin therapy . OBJECTIVE To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin . DESIGN , SETTING , AND PATIENTS Phase 3 , 12-week , r and omized , double-blind , placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries . INTERVENTIONS Patients ( n = 2067 ) were r and omized to 1 of 24 treatment groups in 2 steps . Patients were initially r and omized to a daily , moderate-intensity ( atorvastatin [ 10 mg ] , simvastatin [ 40 mg ] , or rosuvastatin [ 5 mg ] ) or high-intensity ( atorvastatin [ 80 mg ] , rosuvastatin [ 40 mg ] ) statin . After a 4-week lipid-stabilization period , patients ( n = 1899 ) were r and omized to compare evolocumab ( 140 mg every 2 weeks or 420 mg monthly ) with placebo ( every 2 weeks or monthly ) or ezetimibe ( 10 mg or placebo daily ; atorvastatin patients only ) when added to statin therapies . MAIN OUTCOMES AND MEASURES Percent change from baseline in low-density lipoprotein cholesterol ( LDL-C ) level at the mean of weeks 10 and 12 and at week 12 . RESULTS Evolocumab  reduced LDL-C levels by 66 % ( 95 % CI , 58 % to 73 % ) to 75 % ( 95 % CI , 65 % to 84 % ) ( every 2 weeks ) and by 63 % ( 95 % CI , 54 % to 71 % ) to 75 % ( 95 % CI , 67 % to 83 % ) ( monthly ) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups ; the LDL-C reductions at week 12 were comparable . For moderate-intensity statin groups , evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL ; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups , evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL ; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36 % , 40 % , and 39 % of evolocumab- , ezetimibe- , and placebo-treated patients , respectively . The most common adverse events in evolocumab-treated patients were back pain , arthralgia , headache , muscle spasms , and pain in extremity ( all < 2 % ) . CONCLUSIONS AND RELEVANCE In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia , evolocumab added to moderate- or high-intensity statin therapy result ed in additional LDL-C lowering . Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01763866 BACKGROUND Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) are being evaluated in clinical trials for the treatment of cardiovascular disease . The effect of lowering low-density lipoprotein ( LDL ) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown . METHODS We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase ( HMGCR ; the target of statins ) as instruments to r and omly assign 112,772 participants from 14 studies , with 14,120 cardiovascular events and 10,635 cases of diabetes , to groups according to the number of LDL cholesterol-lowering alleles that they had inherited . We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9 , HMGCR , or both on the risk of cardiovascular events and the risk of diabetes . RESULTS Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter ( 0.26 mmol per liter ) in the LDL cholesterol level : odds ratio for cardiovascular events , 0.81 ( 95 % confidence interval [ CI ] , 0.74 to 0.89 ) for PCSK9 and 0.81 ( 95 % CI , 0.72 to 0.90 ) for HMGCR . Variants in these two genes were also associated with very similar effects on the risk of diabetes : odds ratio for each 10 mg per deciliter decrease in LDL cholesterol , 1.11 ( 95 % CI , 1.04 to 1.19 ) for PCSK9 and 1.13 ( 95 % CI , 1.06 to 1.20 ) for HMGCR . The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events . When present together , PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes . CONCLUSIONS In this study , variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level . The effects of these variants were independent and additive . ( Funded by the Medical Research Council and the National Heart , Lung , and Blood Institute . ) Background The PCSK9 antibody alirocumab ( 75 mg every 2 weeks ; Q2W ) as monotherapy reduced low‐density lipoprotein‐cholesterol ( LDL‐C ) levels by 47 % . Because the option of a monthly dosing regimen is convenient , ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin ( majority with statin‐associated muscle symptoms ) , receiving treatment with fenofibrate , ezetimibe , or diet alone . Methods and Results Patients were r and omly assigned to placebo , alirocumab 150 mg Q4W or 75 mg Q2W ( calibrator arm ) , with dose adjustment to 150 mg Q2W at week ( W ) 12 if W8 predefined LDL‐C target levels were not met . The primary efficacy endpoint was LDL‐C percentage change from baseline to W24 . Mean baseline LDL‐C levels were 163.9 mg/dL ( alirocumab 150 mg Q4W , n=59 ) , 154.5 mg/dL ( alirocumab 75 mg Q2W , n=116 ) , and 158.5 mg/dL ( placebo , n=58 ) . In the alirocumab 150 mg Q4W and 75 mg Q2W groups ( 49.1 % and 36.0 % of patients received dose adjustment , respectively ) , least‐squares mean LDL‐C changes from baseline to W24 were −51.7 % and −53.5 % , respectively ( placebo [ + 4.7 % ] ; both groups P<0.0001 versus placebo ) . In total , 63.9 % and 70.3 % of alirocumab‐treated patients achieved their LDL‐C targets at W24 . Treatment‐emergent adverse events occurred in 77.6 % ( alirocumab 150 mg Q4W ) , 73.0 % ( alirocumab 75 mg Q2W ) , and 63.8 % ( placebo ) of patients , with injection‐site reactions among the most common treatment‐emergent adverse events . Conclusions Alirocumab 150 mg Q4W can be considered in patients not on statin with inadequately controlled hypercholesterolemia as a convenient option for lowering LDL‐C. Clinical Trial Registration URL : http://www . clinical trials.gov . Unique identifier : NCT02023879 BACKGROUND Evolocumab , a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , significantly reduced low-density lipoprotein ( LDL ) cholesterol levels in phase 2 studies . We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab . METHODS We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program . On the basis of this classification , patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily , atorvastatin at a dose of 80 mg daily , or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily , for a run-in period of 4 to 12 weeks . Patients with an LDL cholesterol level of 75 mg per deciliter ( 1.9 mmol per liter ) or higher were then r and omly assigned in a 2:1 ratio to receive either evolocumab ( 420 mg ) or placebo every 4 weeks . The primary end point was the percent change from baseline in LDL cholesterol , as measured by means of ultracentrifugation , at week 52 . RESULTS Among the 901 patients included in the primary analysis , the overall least-squares mean ( ±SE ) reduction in LDL cholesterol from baseline in the evolocumab group , taking into account the change in the placebo group , was 57.0±2.1 % ( P<0.001 ) . The mean reduction was 55.7±4.2 % among patients who underwent background therapy with diet alone , 61.6±2.6 % among those who received 10 mg of atorvastatin , 56.8±5.3 % among those who received 80 mg of atorvastatin , and 48.5±5.2 % among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe ( P<0.001 for all comparisons ) . Evolocumab treatment also significantly reduced levels of apolipoprotein B , non-high-density lipoprotein cholesterol , lipoprotein(a ) , and triglycerides . The most common adverse events were nasopharyngitis , upper respiratory tract infection , influenza , and back pain . CONCLUSIONS At 52 weeks , evolocumab added to diet alone , to low-dose atorvastatin , or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of  cardiovascular risks . ( Funded by Amgen ; DESCARTES Clinical Trials.gov number , NCT01516879 . ) BACKGROUND Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) increases serum LDL-cholesterol ( LDL-C ) concentrations . We assessed the effects of AMG 145 , a human monoclonal antibody against PCSK9 , in patients with hypercholesterolaemia in the absence of concurrent lipid-lowering treatment . METHODS In a phase 2 trial done at 52 centres in Europe , the USA , Canada , and Australia , patients ( aged 18 - 75 years ) with serum LDL-C concentrations of 2·6 mmol/L or greater but less than 4·9 mmol/L were r and omly assigned equally through an interactive voice response system to subcutaneous injections of AMG 145 70 mg , 105 mg , or 140 mg , or placebo every 2 weeks ; subcutaneous AMG 145 280 mg , 350 mg , or 420 mg or placebo every 4 weeks ; or oral ezetimibe 10 mg/day . The primary endpoint was percentage change from baseline in LDL-C concentration at week 12 . Analysis was by modified intention to treat . Study personnel and patients were masked to treatment assignment of AMG 145 or placebo . Ezetimibe assignment was open label . This trial is registered with Clinical Trials.gov , number NCT01375777 . FINDINGS 406 patients were assigned to AMG 145 70 mg ( n=45 ) , 105 mg ( n=46 ) , or 140 mg ( n=45 ) every 2 weeks ; AMG 145 280 mg ( n=45 ) , 350 mg ( n=45 ) , or 420 mg ( n=45 ) every 4 weeks ; placebo every 2 weeks ( n=45 ) or every 4 weeks ( n=45 ) ; or ezetimibe ( n=45 ) . AMG 145 significantly reduced LDL-C concentrations in all dose groups ( mean baseline LDL-C concentration 3·7 mmol/L [ SD 0·6 ] ; changes from baseline with every 2 weeks AMG 145 70 mg -41·0 % [ 95 % CI -46·2 to -35·8 ] ; 105 mg -43·9 % [ -49·0 to -38·7 ] ; 140 mg -50·9 % [ -56·2 to -45·7 ] ; every 4 weeks AMG 145 280 mg -39·0 % [ -44·1 to -34·0 ] ; 350 mg -43·2 % [ -48·3 to -38·1 ] ; 420 mg -48·0 % [ -53·1 to -42·9 ] ; placebo every 2 weeks -3·7 % [ -9·0 to 1·6 ] ; placebo every 4 weeks 4·5 % [ -0·7 to 9·8 ] ; and ezetimibe -14·7 % [ -18·6 to -10·8 ] ; p<0·0001 for all doses vs placebo or ezetimibe ) . Treatment-emergent adverse events occurred in 136 ( 50 % ) of 271 patients in the AMG 145 groups , 41 ( 46 % ) of 90 patients in the placebo groups , and 26 ( 58 % ) of 45 patients in the ezetimibe  group ; no deaths or serious treatment-related adverse events were reported . INTERPRETATION The results of our study support the further assessment of AMG 145 in long-term studies with larger and more diverse population s including patients with documented statin intolerance . FUNDING Amgen Statins are the accepted st and ard for lowering low‐density lipoprotein cholesterol ( LDL‐C ) . However , 5 % to 10 % of statin‐treated patients report intolerance , mostly due to muscle‐related adverse effects . Challenges exist to objective identification of statin‐intolerant patients . Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , result ing in marked LDL‐C reduction . We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 ( GAUSS‐3 ) , a phase 3 , multicenter , r and omized , double‐blind , ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose . The study incorporates a novel atorvastatin‐controlled , double‐blind , crossover phase to objective ly identify statin intolerance . Eligible patients had LDL‐C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins ( one of which was atorvastatin ≤10 mg/d ) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin . This trial has 2 co‐ primary endpoints : mean percent change from baseline in LDL‐C at weeks 22 and 24 and percent change from baseline in LDL‐C at week 24 . Key secondary efficacy endpoints include change from baseline in LDL‐C , percent of patients attaining LDL‐C < 70 mg/dL ( 1.81 mmol/L ) , and percent change from baseline in total cholesterol , non – high‐density lipoprotein cholesterol , and apolipoprotein B. Recruitment of 511 patients was completed on November 28 , 2014 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 ) PURPOSE In our initial study of the potential effects of cholesterol-lowering interventions on cognitive functioning , treatment with lovastatin as compared with placebo caused performance decrements on several neuropsychological tests , whereas scores on other tests were unaffected . The current study was design ed to confirm and extend those findings . METHODS The study comprised 308 hypercholesterolemic adults between 35 and 70 years of age . Employing a r and omized double-blind design , we assigned participants to daily treatment with placebo , 10 mg of simvastatin , or 40 mg of simvastatin for 6 months . A neuropsychological test battery was administered to assess cognitive functioning at baseline and at the end of the treatment period . RESULTS A total of 283 subjects completed the study : 94 subjects on placebo , 96 taking 10 mg of simvastatin , and 93 taking 40 mg of simvastatin . Compared with placebo , decremental effects of simvastatin treatment were found on tests previously observed to be sensitive to statins ( P = 0.008 ; difference in summary z scores = 0.18 ; 95 % confidence interval [ CI ] : 0.07 to 0.29 ) and on tests not previously administered ( P = 0.04 ; difference in summary z scores = 0.17 ; 95 % CI : 0.05 to 0.29 ) , but not on tests previously observed to be insensitive to statins ( P = 0.84 ; difference in summary z scores = 0.02 ; 95 % CI : -0.07 to 0.10 ) . For the three tests specifically affected by simvastatin , effects on cognitive performance were small , manifest only as failure to improve during the 6 months of treatment ( compared with placebo ) , and were confounded by baseline differences on one test . CONCLUSION This study provides partial support for minor decrements in cognitive functioning with statins . Whether such effects have any long-term sequelae or occur with other cholesterol-lowering interventions is not known 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 OBJECTIVES The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 ( SAR236553 ) dosing regimens versus placebo at week 12 in patients with LDL-C ≥100 mg/dl on stable atorvastatin therapy . Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of < 100 mg/dl ( 2.59 mmol/l ) and < 70 mg/dl ( 1.81 mmol/l ) . BACKGROUND Serum proprotein convertase subtilisin kexin 9 ( PCSK9 ) binds to low-density lipoprotein receptors , increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9 . METHODS This double-blind , parallel-group , placebo-controlled trial r and omized 183 patients with LDL-C ≥100 mg/dl ( 2.59 mmol/l ) on stable-dose atorvastatin 10 , 20 , or 40 mg for ≥6 weeks to : subcutaneous placebo every 2 weeks ( Q2W ) ; SAR236553 50 , 100 , or 150 mg Q2W ; or SAR236553 200 or 300 mg every 4 weeks ( Q4W ) , alternating with placebo for a total treatment period of 12 weeks . RESULTS SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration : 40 % , 64 % , and 72 % with 50 , 100 , and 150 mg Q2W , respectively , and 43 % and 48 % with 200 and 300 mg Q4W . LDL-C reduction with placebo at week 12 was 5 % . SAR236553 also substantially reduced non-high-density lipoprotein cholesterol , apolipoprotein B , and lipoprotein(a ) . SAR236553 was generally well tolerated . One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis . CONCLUSIONS When added to atorvastatin , PCSK9 inhibition with SAR236553  further reduces LDL-C by 40 % to 72 % . These additional reductions are both dose- and dosing frequency-dependent . ( Efficacy and Safety Evaluation of SAR236553 [ REGN727 ] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy ; NCT01288443 ) BACKGROUND In view of evidence that statin therapy increases risk of diabetes , the balance of benefit and risk of these drugs in primary prevention has become controversial . We undertook an analysis of participants from the JUPITER trial to address the balance of vascular benefits and diabetes hazard of statin use . METHODS In the r and omised , double-blind JUPITER trial , 17,603 men and women without previous cardiovascular disease or diabetes were r and omly assigned to rosuvastatin 20 mg or placebo and followed up for up to 5 years for the primary endpoint ( myocardial infa rct ion , stroke , admission to hospital for unstable angina , arterial revascularisation , or cardiovascular death ) and the protocol -prespecified secondary endpoints of venous thromboembolism , all-cause mortality , and incident physician-reported diabetes . In this analysis , participants were stratified on the basis of having none or at least one of four major risk factors for developing diabetes : metabolic syndrome , impaired fasting glucose , body-mass index 30 kg/m(2 ) or higher , or glycated haemoglobin A(1c ) greater than 6 % . The trial is registered at Clinical Trials.gov , NCT00239681 . FINDINGS Trial participants with one or more major diabetes risk factor ( n=11,508 ) were at higher risk of developing diabetes than were those without a major risk factor ( n=6095 ) . In individuals with one or more risk factors , statin allocation was associated with a 39 % reduction in the primary endpoint ( hazard ratio [ HR ] 0·61 , 95 % CI 0·47 - 0·79 , p=0·0001 ) , a 36 % reduction in venous thromboembolism ( 0·64 , 0·39 - 1·06 , p=0·08 ) , a 17 % reduction in total mortality ( 0·83 , 0·64 - 1·07 , p=0·15 ) , and a 28 % increase in diabetes ( 1·28 , 1·07 - 1·54 , p=0·01 ) . Thus , for those with diabetes risk factors , a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed . For trial participants with no major diabetes risk factors  , statin allocation was associated with a 52 % reduction in the primary endpoint ( HR 0·48 , 95 % CI 0·33 - 0·68 , p=0·0001 ) , a 53 % reduction in venous thromboembolism ( 0·47 , 0·21 - 1·03 , p=0·05 ) , a 22 % reduction in total mortality ( 0·78 , 0·59 - 1·03 , p=0·08 ) , and no increase in diabetes ( 0·99 , 0·45 - 2·21 , p=0·99 ) . For such individuals , a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed . In analysis limited to the 486 participants who developed diabetes during follow-up ( 270 on rosuvastatin vs 216 on placebo ; HR 1·25 , 95 % CI 1·05 - 1·49 , p=0·01 ) , the point estimate of cardiovascular risk reduction  associated with statin therapy ( HR 0·63 , 95 % CI 0·25 - 1·60 ) was consistent with that for the trial as a whole ( 0·56 , 0·46 - 0·69 ) . By comparison with placebo , statins  accelerated the average time to diagnosis of diabetes by 5·4 weeks ( 84·3 [ SD 47·8 ] weeks on rosuvastatin vs 89·7 [ 50·4 ] weeks on placebo ) . INTERPRETATION In the JUPITER primary prevention trial , the cardiovascular and mortality benefits  of statin therapy exceed the diabetes hazard , including in participants at high risk of developing diabetes . FUNDING AstraZeneca OBJECTIVES The aim of this study was to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in patients with hypercholesterolemia in a phase III trial . BACKGROUND Evolocumab , a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , significantly reduced LDL-C in phase II trials . METHODS Patients 18 to 80 years of age with fasting low-density lipoprotein cholesterol ( LDL-C ) ≥100 and < 190 mg/dl and Framingham risk scores ≤10 % were r and omized ( 1:1:1:1:2:2 ) to oral placebo and subcutaneous ( SC ) placebo biweekly ; oral placebo and SC placebo monthly ; ezetimibe and SC placebo biweekly ; ezetimibe and SC placebo monthly ; oral placebo and evolocumab 140 mg biweekly ; or oral placebo and evolocumab 420 mg monthly . RESULTS A total of 614 patients were r and omized and administered  doses . Evolocumab treatment reduced LDL-C from baseline , on average , by 55 % to 57 % more than placebo and 38 % to 40 % more than ezetimibe ( p < 0.001 for all comparisons ) . Evolocumab treatment also favorably altered other lipoprotein levels . Treatment-emergent adverse events ( AEs ) , muscle-related AEs , and laboratory abnormalities were comparable across treatment groups . CONCLUSIONS In the largest monotherapy trial using a PCSK9 inhibitor to date , evolocumab yielded significant LDL-C reductions compared with placebo or ezetimibe and was well tolerated in patients with hypercholesterolemia . ( Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2 [ MENDEL-2 ] ; NCT01763827 ) 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 We assessed the safety and tolerability of ascending single doses of alirocumab in healthy Japanese subjects and evaluated the effect of alirocumab at 3 doses ( 50 , 75 , 150 mg ) on low-density lipoprotein cholesterol ( LDL-C ) reduction in patients with primary hypercholesterolemia on atorvastatin . A r and omized , single ascending-dose study of alirocumab ( 100 , 150 , 250 , or 300 mg ) or placebo ( 3:1 ratio ) , administered subcutaneously , was conducted in 32 healthy Japanese men . The phase 2 , r and omized , double-blind , placebo-controlled , parallel-group study was performed in patients with primary hypercholesterolemia ( defined as calculated LDL-C ≥100 mg/dl [ 2.6 mmol/l ] ) who were on a stable dose of atorvastatin ( 5 to 20 mg ) . Patients were r and omized to alirocumab ( 50 , 75 , or 150 mg ) or placebo ( in single 1.0-ml injection volumes ) administered every 2 weeks ( Q2W ) for 12 weeks ; the primary outcome was the mean percent change in calculated LDL-C from baseline to week 12 . Single subcutaneous administration of alirocumab in healthy subjects was well tolerated over 15 weeks and result ed in highest mean percent reductions in LDL-C from baseline of approximately 40 % to 60 % . In the multiple-dose study , least-square mean ( SE ) changes in calculated LDL-C concentrations from baseline to week 12 were -54.8 % ( 3.1 % ) for alirocumab 50 mg , -62.3 % ( 3.1 % ) for alirocumab 75 mg , and -71.7 % ( 3.1 % ) for alirocumab 150 mg , with a least-square mean ( SE ) difference versus placebo of -52.2 % ( 4.3 % ) , -59.6 % ( 4.3 % ) , and -69.1 % ( 4.3 % ) , respectively ( all p < 0.0001 ) . In conclusion , alirocumab was well tolerated and significantly reduced LDL-C concentrations in Japanese patients with primary hypercholesterolemia on atorvastatin 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 Serum proprotein convertase subtilisin/kexin 9 ( PCSK9 ) binds to low-density lipoprotein ( LDL ) receptors , increasing the degradation of LDL receptors and reducing the rate at which LDL cholesterol is removed from the circulation . REGN727/SAR236553 ( design ated here as SAR236553 ) , a fully human PCSK9 monoclonal antibody , increases the recycling of LDL receptors and reduces LDL cholesterol levels . METHODS We performed a phase 2 , multicenter , double-blind , placebo-controlled trial involving 92 patients who had LDL cholesterol levels of 100 mg per deciliter ( 2.6 mmol per liter ) or higher after treatment with 10 mg of atorvastatin for at least 7 weeks . Patients were r and omly assigned to receive 8 weeks of treatment with 80 mg of atorvastatin daily plus SAR236553 once every 2 weeks , 10 mg of atorvastatin daily plus SAR236553 once every 2 weeks , or 80 mg of atorvastatin daily plus placebo once every 2 weeks and were followed for an additional 8 weeks after treatment . RESULTS The least-squares mean ( ±SE ) percent reduction from baseline in LDL cholesterol was 73.2±3.5 with 80 mg of atorvastatin plus SAR236553 , as compared with 17.3±3.5 with 80 mg of atorvastatin plus placebo ( P<0.001 ) and 66.2±3.5 with 10 mg of atorvastatin plus SAR236553 . All the patients who received SAR236553 , as compared with 52 % of those who received 80 mg of atorvastatin plus placebo , attained an LDL cholesterol level of less than 100 mg per deciliter , and at least 90 % of the patients who received SAR236553 , as compared with 17 % who received 80 mg of atorvastatin plus placebo , attained LDL cholesterol levels of less than 70 mg per deciliter ( 1.8 mmol per liter ) . CONCLUSIONS In a r and omized trial involving patients with primary hypercholesterolemia , adding SAR236553 to either 10 mg of atorvastatin or 80 mg of atorvastatin result ed in a significantly greater reduction in LDL cholesterol than that attained with 80 mg of atorvastatin alone . ( Funded by Sanofi and Regeneron Pharmaceuticals ; Clinical Trials.gov number , NCT01288469 . ) BACKGROUND Following acute coronary syndrome ( ACS ) , the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol ( LDL-C ) even within the setting of intensive statin treatment . Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab , a fully human monoclonal antibody to PCSK9 , improves cardiovascular outcomes after ACS . DESIGN This Phase 3 study will r and omize approximately 18,000 patients to receive biweekly injections of alirocumab ( 75 - 150 mg ) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infa rct ion or unstable angina . Qualifying patients are treated with atorvastatin 40 or 80 mg daily , rosuvastatin 20 or 40 mg daily , or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria : LDL-C ≥ 70 mg/dL , non-high-density lipoprotein cholesterol ≥ 100 mg/dL , or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death , acute myocardial infa rct ion , hospitalization for unstable angina , or ischemic stroke . The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years , providing 90 % power to detect a 15 % hazard reduction . Adverse events of special interest include allergic events and injection site reactions . Interim analyses are planned when approximately 50 % and 75 % of the targeted number of primary end points have occurred . SUMMARY ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS OBJECTIVES This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses . BACKGROUND Statin intolerance , which is predominantly due to muscle-related side effects , is reported in up to 10 % to 20 % of patients . Evolocumab , a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , demonstrated marked reductions in plasma low-density lipoprotein cholesterol ( LDL-C ) in a phase 2 study in statin-intolerant patients . METHODS The GAUSS-2 ( Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects ) trial was a 12-week , double-blind study of r and omized patients ( 2:2:1:1 ) to evolocumab 140 mg every two weeks ( Q2W ) or evolocumab 420 mg once monthly ( QM ) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg . Co- primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12 , and at week 12 . RESULTS Three hundred seven patients ( age 62 ± 10 years ; LDL-C 193 ± 59 mg/dl ) were r and omized . Evolocumab  reduced LDL-C from baseline by 53 % to 56 % , corresponding to treatment differences versus ezetimibe of 37 % to 39 % ( p < 0.001 ) . Muscle adverse events occurred in 12 % of evolocumab-treated patients and 23 % of ezetimibe-treated  patients . Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups . CONCLUSIONS Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant . ( Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2 ; NCT01763905 ) Background — Despite statin treatment , many patients with heterozygous familial hypercholesterolemia do not reach desired low-density lipoprotein cholesterol ( LDL-C ) targets . AMG 145 , a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) serine protease , demonstrated significant reductions in LDL-C in phase 1 studies . This phase 2 , multicenter , double-blind , r and omized , placebo-controlled , dose-ranging study evaluated the efficacy and safety of AMG 145 in heterozygous familial hypercholesterolemia patients . Methods and Results — Patients with heterozygous familial hypercholesterolemia diagnosed by Simon Broome criteria with LDL-C ≥2.6 mmol/L ( 100 mg/dL ) despite statin therapy with or without ezetimibe  were r and omized 1:1:1 to AMG 145 350 mg , AMG 145 420 mg , or placebo-administered subcutaneously every 4 weeks . The primary end point was percentage change from baseline in LDL-C at week 12 . Of 168 patients r and omized , 167 received investigational product and were included in the full analysis set ( mean [ SD ] age , 50 [ 13 ] years ; 47 % female ; 89 % white ; mean [ SD ] baseline LDL-C , 4.0 [ 1.1 ] mmol/L ( 156 [ 42 ] mg/dL ) ) . At week 12 , LDL-C reduction measured by preparative ultracentrifugation ( least squares mean [ st and ard error ( SE ) ] ) was 43 (3)% and 55 (3)% with AMG 145 350 mg and 420 mg , respectively , compared with 1 (3)% increase with placebo ( P<0.001 for both dose groups ) . Serious adverse events ( not considered treatment-related ) occurred in 2 patients on AMG 145 . Conclusions — AMG 145 administered every 4 weeks yielded rapid and substantial reductions in LDL-C in heterozygous familial hypercholesterolemia patients despite intensive statin use , with or without ezetimibe , with minimal adverse events and good tolerability . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01375751 BACKGROUND LDL cholesterol ( LDL-C ) is a well established risk factor for cardiovascular disease . Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) binds LDL receptors , targeting them for degradation . We therefore assessed the efficacy , safety , and tolerability of AMG 145 , a human monoclonal IgG2 antibody against PCSK9 , in stable patients with hypercholesterolemia on a statin . METHODS In a phase 2 , dose-ranging study done in 78 centres in the USA , Canada , Denmark , Hungary , and Czech Republic , patients ( aged 18 - 80 years ) with LDL-C greater than 2·2 mmol/L on a stable dose of statin ( with or without ezetimibe )  , were r and omly assigned equally , through an interactive voice response system , to subcutaneous injections of AMG 145 70 mg , 105 mg , or 140 mg , or matching placebo every 2 weeks ; or subcutaneous injections of AMG 145 280 mg , 350 mg , or 420 mg , or matching placebo every 4 weeks . Everyone was masked to treatment assignment within the every 2 weeks and every 4 weeks schedules . The primary endpoint was the percentage change in LDL-C concentration from baseline after 12 weeks . Analysis was by modified intention to treat . This study is registered with Clinical Trials.gov , number NCT01380730 . FINDINGS 631 patients with hypercholesterolaemia were r and omly assigned to AMG 145 70 mg ( n=79 ) , 105 mg ( n=79 ) , or 140 mg ( n=78 ) , or matching placebo ( n=78 ) every 2 weeks ; or AMG 145 280 mg ( n=79 ) , 350 mg ( n=79 ) , and 420 mg ( n=80 ) , and matching placebo ( n=79 ) every 4 weeks . At the end of the dosing interval at week 12 , the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks ( ranging from 41·8 % to 66·1 % ; p<0·0001 for each dose vs placebo ) and AMG 145 every 4 weeks ( ranging from 41·8 % to 50·3 % ; p<0·0001 ) . No treatment-related serious adverse events occurred . The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups ( 39 [ 8 % ] of 474 vs 11 [ 7 % ] of 155 ) ; none of these events were severe or life-threatening . INTERPRETATION The results suggest that PCSK9 inhibition could be a new model in lipid management . Inhibition of PCSK9 warrants assessment in phase 3 clinical trials . FUNDING Amgen
target: Treatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes .
  Although no overall benefit was noted in all-cause or cardiovascular mortality , such benefit may be achievable in patients with higher baseline low-density lipoprotein cholesterol
background: BACKGROUND We sought to examine the efficacy and safety of 2 PCSK9 ( proprotein convertase subtilisin/kexin type 9 ) inhibitors : alirocumab and evolocumab .