Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV). Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. Efficacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients With Hypercholesterolemia: 52-Week Results From the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) Randomized Trial Risk prediction with proprotein convertase subtilisin/kexin type 9 (PCSK9) in patients with stable coronary disease on statin treatment. Proprotein convertase subtilisin-kexin type 9 as a biomarker for the severity of coronary artery disease 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 Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). 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. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies 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. Effects of niacin, statin, and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 levels in patients with dyslipidemia. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. 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 Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. Proprotein convertase subtilisin-kexin type 9 is elevated in proteinuric subjects: relationship with lipoprotein response to antiproteinuric treatment. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial 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 and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia not Adequately Controlled with Current Lipid-Lowering Therapy: Design and Rationale of the ODYSSEY FH Studies A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). PCSK9 Inhibitors and Neurocognitive Adverse Events: Exploring the FDA Directive and a Proposal for N-of-1 Trials 2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. 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 Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population. Effect of Alirocumab on Lipoprotein(a) Over ≥1.5 Years (from the Phase 3 ODYSSEY Program). 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 Efficacy and Safety of Alirocumab as Add‐on Therapy in High–Cardiovascular‐Risk Patients With Hypercholesterolemia Not Adequately Controlled With Atorvastatin (20 or 40 mg) or Rosuvastatin (10 or 20 mg): Design and Rationale of the ODYSSEY OPTIONS Studies Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. 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 Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM - 2019 EXECUTIVE SUMMARY. 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. Cardiovascular Efficacy and Safety of Bococizumab in High‐Risk Patients NUtraceutical TReatment for hYpercholesterolemia in HIV-infected patients: The NU-TRY(HIV) randomized cross-over trial. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab.
BACKGROUND Statin-mediated low-density lipoprotein cholesterol ( LDL-C ) lowering fails to prevent more than half of cardiovascular events in clinical trials . Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering , with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels < 70 mg/dL. Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) inhibitors permit LDL-C-lowering by a further 54 % to 75 % in statin-treated patients . The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated . AIMS To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor , evolocumab , will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy . METHODS A phase 3 , multicenter , double-blind , r and omized , placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinical ly indicated coronary angiogram with angiographic evidence of coronary atheroma , and after 78 weeks of treatment . Subjects ( n = 968 ) were r and omized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections . CONCLUSIONS The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy . GLAGOV will provide important mechanistic , safety , and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis ( www . clinical trials.gov identifier NCT01813422 ) 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 ) 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 — Evolocumab ( AMG 145 ) , a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , significantly reduced low-density lipoprotein cholesterol ( LDL-C ) in phase 2 studies of 12 weeks ’ duration . The longer-term efficacy and safety of PCSK9 inhibition remain undefined . Methods and Results — Of 1359 r and omized and dosed patients in the 4 evolocumab phase 2 parent studies , 1104 ( 81 % ) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C ( OSLER ) study . Regardless of their treatment assignment in the parent study , patients were r and omized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with st and ard of care ( SOC ) ( evolocumab+SOC , n=736 ) or SOC alone ( n=368 ) . Ninety-two percent of patients in the evolocumab+SOC group and 89 % of patients in the SOC group completed 52 weeks of follow-up . Patients who first received evolocumab in OSLER experienced a mean 52.3 % [ SE , 1.8 % ] reduction in LDL-C at week 52 ( P<0.0001 ) . Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions ( mean reduction , 50.4 % [ SE , 0.8 % ] at the end of the parent study versus 52.1 % [ SE , 1.0 % ] at 52 weeks ; P=0.31 ) . In patients who discontinued evolocumab on entry into OSLER , LDL-C levels returned to near baseline levels . Adverse events and serious adverse events occurred in 81.4 % and 7.1 % of the evolocumab+SOC group patients and 73.1 % and 6.3 % of the SOC group patients , respectively . Conclusion — Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date . Clinical Trial Registration — URL : http:// clinical trials.gov . Unique identifier : NCT01439880 BACKGROUND Proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) is a regulator of LDL-cholesterol receptor homeostasis and emerges as a therapeutic target in the prevention of cardiovascular ( CV ) disease . This prospect i ve cohort study analyzes risk prediction with PCSK9 serum concentrations in patients with stable coronary artery disease ( CAD ) on statin treatment .  METHODS AND RESULTS Fasting PCSK9 concentrations were measured in 504 consecutive patients with stable CAD confirmed by angiography .  Oral glucose tolerance tests were performed in all patients without known diabetes . Patients were followed up for 48months . The primary outcome was the composite of cardiovascular death and unplanned cardiovascular hospitalization . Serum concentrations of PCSK9 predicted CV outcomes ( PCSK9>622 ng/ml vs. < 471 ng/ml : HR 1.55 , 95%-CI 1.11 - 2.16 , p=0.009 ) . Higher PCSK9 concentrations were associated with female gender , hypertension , statin treatment , C-reactive protein , HbA1c , insulin , total cholesterol and fasting triglycerides , but not with LDL- or HDL-cholesterol . The association of  PCSK9 levels with CV events was reduced after adjustment for fasting TG . CONCLUSION  PCSK9 concentrations predict cardiovascular events in patients with coronary artery disease on statin treatment . Serum triglycerides are correlated with PCSK9 and modify risk prediction by PCSK9 Abstract Aim . To evaluate the relation of proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) levels to coronary artery disease ( CAD ) . Methods . A total of 1031 consecutive individuals ( 552 CAD and 479 controls ) were prospect ively enrolled . The associations of plasma PCSK9 levels with the incidence and severity of CAD were investigated . Further , mediator analysis was performed to detect the potential mechanisms of the associations . Results . No difference in PCSK9 levels between CAD patients and controls was detected ( median 224.75 versus 224.64 ng/mL , P > 0.05 ) . However , the CAD group had higher PCSK9 levels than the control group when adjusting for the confounding factors ( 228.03 ± 1.01 versus 219.28 ± 1.02 ng/mL , P = 0.019 )  . PCSK9 levels were also associated with the severity of CAD assessed by the Gensini score ( GS ) system ( P for trend < 0.05 ) . Logistic regression analysis showed that PCSK9 levels were associated with an increased CAD risk ( OR 3.296 and 5.130 for the incidence and severity , respectively ) . Importantly , mediator analysis indicated that the effects of PCSK9 levels on CAD were mediated by lipid ( around 20 % ) and inflammation ( around 15 % ) . Conclusions . PCSK9 levels were positively associated with the severity of CAD ; the relatively important mechanisms including lipid and inflammation pathways were partly involved in this association 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 Lipoprotein(a ) [ Lp(a ) ] is an independent risk factor for cardiovascular disease , with limited treatment options . This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9 , alirocumab 150 mg every 2 weeks ( Q2W ) , on Lp(a ) levels in pooled data from 3 double-blind , r and omized , placebo-controlled , phase 2 studies of 8 or 12 weeks ' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy ( NCT01266876 , NCT01288469 , and NCT01288443 ) . Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo .  Alirocumab result ed in a significant reduction in Lp(a ) from baseline compared with placebo ( -30.3 % vs -0.3 % , p < 0.0001 ) . Median percentage Lp(a ) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a ) levels , result ing in greater absolute reductions in Lp(a ) in patients with higher baseline levels . Regression analysis indicated that < 5 % of the variance in the reduction of Lp(a ) was explained by the effect of alirocumab on low-density lipoprotein cholesterol . In conclusion , pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a ) with alirocumab 150 mg Q2W , including patients with baseline Lp(a ) > 50 mg/dl . Reductions in Lp(a ) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering 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 ) 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 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 Recent trials demonstrated substantial improvement in lipid parameters with inhibition of proprotein convertase subtilisin-like/kexin type 9 ( PCSK9 ) . Although statins and fibrates have been reported to increase plasma PCSK9 levels , the effect of niacin on PCSK9 is unknown . We investigated the impact of niacin , atorvastatin , and fenofibrate on PCSK9 levels in 3 distinct studies . A statin-only study r and omized 74 hypercholesterolemic patients to placebo , atorvastatin 10 mg/day , or atorvastatin 80 mg/day for 16 weeks . A dose-related increase in PCSK9 was noted such that atorvastatin 80 mg increased PCSK9 by a mean + 27 % ( 95 % confidence interval [ CI ] + 12 to + 42 ) , confirming the effect of statin therapy on raising PCSK9 . A second study r and omized 70 patients with carotid atherosclerosis to simvastatin 20 mg/day , simvastatin 80 mg/day , or simvastatin 20 mg/extended-release ( ER ) niacin 2 g/day . PCSK9 levels were increased with statin therapy , but decreased with the simvastatin 20 mg/ER niacin combination ( mean -13 % , CI -3 to -23 ) . A final study involved 19 dyslipidemic participants on atorvastatin 10 mg with serial addition of  fenofibric acid 135 mg followed by ER niacin 2 g/day . Fenofibric acid led to a + 23 % ( CI + 10 to + 36 , p = 0.001 ) increase in PCSK9 ; the addition of niacin result ed in a subsequent -17 % decrease ( CI -19 to -5 , p = 0.004 ) . A positive association was noted between change in PCSK9 and low-density lipoprotein cholesterol levels ( r = 0.62 , p = 0.006 ) with the addition of niacin . In conclusion , niacin therapy offsets the increase in PCSK9 levels noted with statin and fibrate therapy . A portion of the low-density lipoprotein cholesterol reduction seen with niacin therapy may be due to reduction in PCSK9 BACKGROUND Statin intolerance has been a major limitation in the use of statins , especially at higher doses . New effective treatments are needed for lowering low-density lipoprotein cholesterol ( LDL-C ) in patients who can not tolerate daily statin doses . OBJECTIVE ODYSSEY ALTERNATIVE ( NCT01709513 ) evaluates efficacy and safety of alirocumab , a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody , in patients with well-documented statin intolerance and moderate to very high cardiovascular risk . METHODS This is a phase 3 , multicenter , r and omized , double-blind , double-dummy study in statin-intolerant patients . Intolerance was defined as inability to take at least 2 different statins because of muscle-related adverse events ( AEs ) , 1 at the lowest approved starting dose . Patients first received single-blind subcutaneous and oral placebo for 4 weeks , and were withdrawn if they developed muscle-related AEs after the placebo treatment . Continuing patients were r and omized ( 2:2:1 ratio ) to alirocumab 75 mg self-administered via single 1 mL prefilled pen every 2 weeks or ezetimibe 10 mg/day or atorvastatin 20 mg/day ( statin rechallenge ) , for 24 weeks . Alirocumab dose was increased to 150 mg every 2 weeks ( also 1 mL ) at week 12 depending on week 8 LDL-C level . The primary endpoint is percent change in LDL-C from baseline to week 24 by intent-to-treat analysis . Muscle-related AEs were assessed by spontaneous patient reports and clinic queries . RESULTS A total of 314 patients have been r and omized . CONCLUSIONS This is the first and only study of a new class of LDL-C-lowering agents in patients selected with a rigorously documented intolerance to statins , using a placebo run-in and statin control arm 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 BACKGROUND Evolocumab , a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) , significantly reduced low-density lipoprotein ( LDL ) cholesterol levels in short-term studies . We conducted two extension studies to obtain longer-term data . METHODS In two open-label , r and omized trials , we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ( " parent trials " ) of evolocumab .  Regardless of study -group assignments in the parent trials , eligible patients were r and omly assigned in a 2:1 ratio to receive either evolocumab ( 140 mg every 2 weeks or 420 mg monthly ) plus st and ard therapy or st and ard therapy alone . Patients were followed for a median of 11.1 months with assessment of lipid levels , safety , and ( as a prespecified exploratory analysis ) adjudicated cardiovascular events including death , myocardial infa rct ion , unstable angina , coronary revascularization , stroke , transient ischemic attack , and heart failure . Data from the two trials were combined . RESULTS As compared with st and ard therapy alone , evolocumab reduced the level of LDL cholesterol by 61 % , from a median of 120 mg per deciliter to 48 mg per deciliter ( P<0.001 ) . Most adverse events occurred with similar frequency in the two groups , although neurocognitive events were reported more frequently in the evolocumab group . The risk of adverse events , including neurocognitive events , did not vary significantly according to the achieved level of LDL cholesterol . The rate of cardiovascular events at 1 year was reduced from 2.18 % in the st and ard-therapy group to 0.95 % in the evolocumab group ( hazard ratio in the evolocumab group , 0.47 ; 95 % confidence interval , 0.28 to 0.78 ; P=0.003 ) . CONCLUSIONS During approximately 1 year of therapy , the use of evolocumab plus st and ard therapy , as compared with st and ard therapy alone , significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis . ( Funded by Amgen ; OSLER-1 and OSLER-2 Clinical Trials.gov numbers , NCT01439880 and NCT01854918 . ) OBJECTIVE LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria . The proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation . We tested whether plasma PCSK9 is elevated in proteinuric states , and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction . METHODS Thirty-nine kidney patients ( e-GFR 61 ± 29 mL/min/1.73 m(2 ) , proteinuria 1.9 [ 0.9 - 3.3 ] g/day ; 19 on statin treatment ) were studied during 2 r and omized double-blind 6-week periods on either lisinopril ( 40 mg/day ) and a regular sodium diet ( 194 ± 49 mmol Na+/day ; baseline treatment ) or lisinopril plus valsartan ( 320 mg/day ) and a low sodium diet ( 102 ± 52 mmol Na(+)/day ; maximal treatment ) , and compared to age- and sex-matched controls . Maximal treatment decreased proteinuria to 0.5 [ 0.3 - 1.1 ] g/day ( P < 0.001 ) . RESULTS Plasma PCSK9 was increased at baseline in proteinuric subjects ( 213 [ 161 - 314 ] vs. 143 [ 113 - 190 ] ug/L in controls , P ≤ 0.001 ) , irrespective of statin use , e-GFR and BMI . PCSK9 correlated with proteinuria at baseline ( R = 0.399 , P = 0.018 ) and at maximal antiproteinuric treatment ( R = 0.525 , P = 0.001 ) , but did not decrease during proteinuria reduction ( P = 0.84 ) . Individual changes in total cholesterol ( R = 0.365 , P = 0.024 ) , non-HDL cholesterol ( R = 0.333 , P = 0.041 ) , and LDL cholesterol ( R = 0.346 , P = 0.033 ) were correlated positively with individual PCSK9 responses . PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment ( P = 0.04 ) . CONCLUSION Plasma PCSK9 was elevated in proteinuria , predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction . Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects 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 : The PCSK9 ( proprotein convertase subtilisin/kexin type 9 ) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial ( Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk ) . We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease ( PAD ) as well as the effect on major adverse limb events . Methods : FOURIER was a r and omized trial of evolocumab versus placebo  in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years . Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of < 0.85 , or if they had a prior peripheral vascular procedure . The primary end point was a composite of cardiovascular death , myocardial infa rct ion , stroke , hospital admission for unstable angina , or coronary revascularization . The key secondary end point was a composite of cardiovascular death , myocardial infa rct ion , or stroke . An additional outcome of interest was major adverse limb events defined as acute limb ischemia , major amputation , or urgent peripheral revascularization for ischemia . Results : Three thous and six hundred forty-two patients ( 13.2 % ) had PAD ( 1505 with no prior myocardial infa rct ion or stroke ) . Evolocumab significantly reduced the primary end point consistently in patients with PAD ( hazard ratio [ HR ] 0.79 ; 95 % confidence interval [ CI ] , 0.66–0.94 ; P=0.0098 ) and without PAD ( HR 0.86 ; 95 % CI , 0.80–0.93 ; P=0.0003 ; Pinteraction=0.40 ) . For the key secondary end point , the HRs were 0.73 ( 0.59–0.91 ; P=0.0040 ) for those with PAD and 0.81 ( 0.73–0.90 ; P<0.0001 ) for those without PAD ( Pinteraction=0.41 ) . Because of their higher risk , patients with PAD had larger absolute risk reductions for the primary end point ( 3.5 % with PAD , 1.6 % without PAD ) and the key secondary end point ( 3.5 % with PAD , 1.4 % without PAD ) . Evolocumab reduced the risk of major adverse limb events in all patients ( HR , 0.58 ; 95 % CI , 0.38–0.88 ; P=0.0093 ) with consistent effects in those with and without known PAD . There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events ( P=0.026 for the beta coefficient ) that extended down to < 10 mg/dL. Conclusions : Patients with PAD are at high risk of cardiovascular events , and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions . Moreover , lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events . Clinical Trial Registration : URL : https://www . clinical trials.gov . Unique identifier : NCT01764633 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 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 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 Individuals with heterozygous familial hypercholesterolemia ( heFH ) have higher levels of low-density lipoprotein cholesterol ( LDL-C ) and are predisposed to premature cardiovascular disease . Alirocumab is a fully-human , monoclonal antibody targeted to proprotein convertase subtilisin/kexin type 9 currently in Phase 3 development for the treatment of hypercholesterolemia . Described here are three ODYSSEY Phase 3 trials , FH I ( NCT01623115 ) , FH II ( NCT01709500 ) and HIGH FH ( patients with heFH and LDL-C levels ≥160 mg/dL ) ( NCT01617655 ) , in which alirocumab is further evaluated in the heFH population . Methods Multicenter , multinational , r and omized , double-blind , placebo-controlled studies have been design ed to evaluate efficacy and safety  of alirocumab in more than 800 patients with heFH who are not adequately controlled with a maximally-tolerated stable daily dose of statin for ≥4 weeks prior to the screening visit , with or without other lipid-lowering therapy . Patients are r and omized ( 2:1 ) to receive alirocumab or placebo via a 1-mL subcutaneous auto-injection every 2 weeks ( Q2W ) for 78 weeks . In studies FH I and II , if their Week 8 LDL-C level is ≥70 mg/dL , patients will undergo a dose uptitration from 75 to 150 mg alirocumab Q2W at Week 12 . In HIGH FH , patients will receive alirocumab 150 mg Q2W throughout the entire treatment period . The primary efficacy endpoint in all three studies is the percent change in calculated LDL-C from baseline to Week 24 . Conclusions The ODYSSEY FH studies are three Phase 3 studies aim ing to further evaluate the efficacy and long-term safety of alirocumab as an effective therapeutic option for patients with heFH 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 Alirocumab , a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 , has been shown to provide significant reductions in low-density lipoprotein cholesterol ( LDL-C ) . Data about its efficacy and safety in patients from South Korea and Taiwan are limited . OBJECTIVE ODYSSEY KT assessed the efficacy and safety of alirocumab in patients from South Korea and Taiwan . METHODS Patients with hypercholesterolemia at high cardiovascular risk who were on maximally tolerated statin were r and omized ( 1:1 ) to alirocumab ( 75 mg every 2 weeks , with dose increase to 150 mg every 2 weeks at week 12 if LDL-C ≥70 mg/dL at week 8) or placebo for 24 weeks . The primary efficacy endpoint was percentage change in LDL-C from baseline to week 24 . Safety was assessed throughout . RESULTS At week 24 , alirocumab  changed LDL-C levels by -57.1 % ( placebo : + 6.3 % ) . In the alirocumab group , 9 patients ( 9.5 % ) received dose increase at week 12 . At week 24 , 85.8 % of patients in the alirocumab group reached LDL-C < 70 mg/dL ( placebo : 14.2 % ; P ≤ .0001 vs placebo ) . Alirocumab significantly improved non-high-density lipoprotein cholesterol ( non-HDL-C ) , apolipoprotein B , total cholesterol , lipoprotein ( a ) , and HDL-C vs placebo ( P ≤ .05 ) . Two consecutive calculated LDL-C values < 25 mg/dL were recorded in 27.8 % of alirocumab-treated patients . Overall , 58.8 % ( alirocumab ) and 61.8 % ( placebo ) of patients experienced treatment-emergent adverse events ; 2.1 % and 1.0 % discontinued treatment due to treatment-emergent adverse events , respectively . CONCLUSION Alirocumab  significantly improved LDL-C , apolipoprotein B , non-HDL-C , lipoprotein ( a ) , HDL-C , and total cholesterol  in Asian patients . Alirocumab was generally well tolerated . These findings are consistent with ODYSSEY findings to date Proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) inhibitors are a novel class of medications that greatly lower low-density lipoprotein cholesterol ( LDL-C ) by upregulating LDL receptor availability . In early 2014 , the US Food and Drug Administration ( FDA ) directed developers of PCSK9 inhibitors to monitor neurocognitive adverse effects and consider neurocognitive testing in at least a subset of participants in ongoing late-stage trials . Available trial evidence indicates that neurocognitive adverse events may occur more commonly in individuals receiving an antibody to PCSK9 , but these events are uncommon and have not been associated with on-treatment LDL-C levels . Moreover , it is unclear to what extent closer monitoring of trial participants allocated to PCSK9 inhibitors has led to an ascertainment bias . Regardless , further trial data are needed , and long-term outcomes trials are ongoing , with at least one including a neurocognitive sub study . Considering lessons learned from the statin experience , high- quality prospect i ve cohort studies and r and omized trials may not be enough to allay concerns or settle debate since the focus of effect in these studies is the group average . Therefore , we suggest that n-of-1 trials could be considered to bring the focus to the individual while retaining the benefits of blinding and r and omization in evidence generation . Ultimately , any neurocognitive adverse effects that might exist with PCSK9 inhibition and lipid lowering must be weighed against potential benefits of therapy , including avoidance of myocardial infa rct ion and stroke , and a reduced risk of dementia due to neurovascular benefits from long-term lipid lowering In 2016 , the American College of Cardiology published the first expert consensus decision pathway ( ECDP ) on the role of non-statin therapies for low-density lipoprotein (LDL)-cholesterol lowering in the management of atherosclerotic cardiovascular disease ( ASCVD ) risk . Since the publication of that document , additional evidence and perspectives have emerged from r and omized clinical trials and other sources , particularly considering the longer-term efficacy and safety of proprotein convertase subtilisin/kexin 9 ( PCSK9 ) inhibitors in secondary prevention of ASCVD . Most notably , the FOURIER ( Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk ) trial and SPIRE-1 and -2 ( Studies of PCSK9 Inhibition and the Reduction of Vascular Events ) , assessing evolocumab and bococizumab , respectively , have published final results of cardiovascular outcomes trials in patients with clinical ASCVD and in a smaller number of high-risk primary prevention patients . In addition , further evidence on the types of patients most likely to benefit from the use of ezetimibe in addition to statin therapy after acute coronary syndrome has been published . Based on results from these important analyses , the ECDP writing committee judged that it would be desirable to provide a focused up date to help guide clinicians more clearly on decision making regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities . In the following summary table , changes from the 2016 ECDP to the 2017 ECDP Focused Up date are highlighted , and a brief rationale is provided . The content of the full document has been changed accordingly , with more extensive and detailed guidance regarding decision making provided both in the text and in the up date d algorithms . Revised recommendations are provided for patients with clinical ASCVD with or without comorbidities  on statin therapy for secondary prevention . The ECDP writing committee judged that these new data did not warrant changes to the decision pathways and algorithms regarding the use of ezetimibe or PCSK9 inhibitors in primary prevention patients with LDL-C < 190 mg/dL with or without diabetes mellitus or patients without ASCVD and LDL-C ≥190 mg/dL not due to secondary causes . Based on feedback and further deliberation , the ECDP writing committee down- grade d recommendations regarding bile acid sequestrant use , recommending bile acid sequestrants only as optional secondary agents for consideration in patients intolerant to ezetimibe . For clarification , the writing committee has also included new information on diagnostic categories of heterozygous and homozygous familial hypercholesterolemia , based on clinical criteria with and without genetic testing . Other changes to the original document were kept to a minimum to provide consistent guidance to clinicians , unless there was a compelling reason or new evidence , in which case justification is provided 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 Purpose Even with statins and other lipid-lowering therapy ( LLT ) , many patients with heterozygous familial hypercholesterolemia ( heFH ) continue to have elevated low-density lipoprotein cholesterol ( LDL-C ) levels . ODYSSEY HIGH FH ( NCT01617655 ) assessed the efficacy and safety of alirocumab , a proprotein convertase subtilisin/kexin type 9 monoclonal antibody , versus placebo in patients with heFH and LDL-C ≥ 160 mg/dl despite maximally tolerated statin ± other LLT . Methods Patients were r and omized to subcutaneous alirocumab 150 mg or placebo every 2 weeks ( Q2W ) for 78 weeks . The primary endpoint was percent change in LDL-C from baseline to week 24 . Results Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab ( n = 71 ) and 201.0 mg/dl in the placebo groups ( n = 35 ) . Significant mean ( st and ard error [ SE ] ) reductions in LDL-C from baseline to week 24 were observed with alirocumab ( −45.7 [ 3.5 ] % ) versus placebo ( −6.6 [ 4.9 ] % ) , a difference of −39.1 ( 6.0 ) % ( P < 0.0001 ) . Absolute mean ( SE ) LDL-C levels were reduced from baseline by 90.8 ( 6.7 ) mg/dl with alirocumab at week 24 , with reductions maintained to week 78 . Treatment-emergent adverse events were generally comparable between groups . Injection-site reactions were more frequent in the alirocumab group ( 8.3 % ) versus placebo ( 5.7 % ) ; most were mild in severity and did not result in study medication discontinuation . Conclusions In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT , alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals . Alirocumab was generally well tolerated BACKGROUND Although statin therapy is known to increase concentrations of PCSK9 , whether this effect is related to the magnitude of LDL reduction is uncertain . This study was undertaken to underst and the extent of this effect and examine the relationship between PCSK9 and LDL cholesterol ( LDL-C ) reduction . METHODS We measured plasma PCSK9 concentrations by ELISA at baseline and at 1 year in 500 men and 500 women participating in the Justification for Use of Statins in Prevention : an Intervention Trial Evaluating Rosuvastatin ( JUPITER ) trial that r and omly allocated participants to rosuvastatin 20 mg daily or placebo . We also evaluated rs11591147 , a single nucleotide polymorphism known to have an impact on plasma PCSK9 concentrations . RESULTS At baseline , median ( interquartile range ) PCSK9 concentrations were higher in women [ 73 ( 62 - 90 ) ] ng/mL than in men [ 69 ( 57 - 81 ) ng/mL ] ( P<0.005 ) . During 1 year , there was no change in PCSK9 concentrations in the placebo arm , suggesting stability in time . In contrast , the rosuvastatin increased PCSK9 by 35 % in women [ 101 ( 82 - 117 ) ng/mL ] and 28 % in men [ 89 ( 71 - 109 ) ng/mL ] ( P<0.0001 ) . Among those allocated to rosuvastatin , greater reductions in LDL-C were associated with greater increases in PCSK9 on both absolute and relative scales ( r=-0.15 , P<0.0005 ) . Furthermore PCSK9 ( rs11591147 ) did not alter the magnitude of LDL-C reduction associated with rosuvastatin use . CONCLUSIONS In this r and omized trial , rosuvastatin increased plasma concentration of PCSK9 in proportion to the magnitude of LDL-C reduction ; the LDL-C response to statin could not be inferred by PCSK9 concentrations Caucasian carriers of the T allele at R46L in the proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) locus have been reported to have 15 % lower low-density lipoprotein ( LDL ) cholesterol ( C ) levels and 47 % lower coronary heart disease ( CHD ) risk . Our objective was to examine two PCSK9 single nucleotide polymorphisms ( SNPs ) , R46L and E670 G , in 5783 elderly participants in Prospect i ve Study of Pravastatin in the Elderly at Risk ( PROSPER ) , of whom 43 % had a history of vascular disease at baseline , and who were r and omized to pravastatin or placebo with followup . In this population 3.5 % were carriers of the T allele at R46L , and these subjects had significantly ( p<0.001 ) lower levels of LDL C ( mean , -10 % ) , no difference in LDL C lowering response to pravastatin , and a non-significant 19 % unadjusted and 9 % adjusted decreased risk of vascular disease at baseline , with no on trial effect . Moreover , 6.0 % were carriers of the G allele at E670 G with no significant relationships with baseline LDL C , response to pravastatin , or vascular disease risk being observed . Our data support the concept that the rare allele of the R46L SNP at the PCSK9 locus significantly lowers LDL C , but does not greatly reduce CHD risk in an elderly population with a high prevalence of cardiovascular disease Elevated lipoprotein(a ) [ Lp(a ) ] is independently associated with increased cardiovascular risk . However , treatment options for elevated Lp(a ) are limited . Alirocumab , a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 , reduced low-density lipoprotein cholesterol ( LDL-C ) by up to 62 % from baseline in phase 3 studies , with adverse event rates similar between alirocumab and controls . We evaluated the effect of alirocumab on serum Lp(a ) using pooled data from the phase 3 ODYSSEY program : 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included . Eight studies evaluated alirocumab 75 mg every 2 weeks ( Q2W ) , with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 ( 75/150 mg Q2W ) ; the other 2 studies evaluated alirocumab 150-mg Q2W from the outset . Comparators were placebo or ezetimibe . Eight studies were conducted on a background of statins , and 2 studies were carried out with no statins . Alirocumab was associated with significant reductions in Lp(a ) , regardless of starting dose and use of concomitant statins . At week 24 , reductions from baseline were 23 % to 27 % with alirocumab 75/150-mg Q2W and 29 % with alirocumab 150-mg Q2W ( all comparisons p < 0.0001 vs controls ) . Reductions were sustained over 78 to 104 weeks . Lp(a ) reductions with alirocumab were independent of race , gender , presence of familial hypercholesterolemia , baseline Lp(a ) , and LDL-C concentrations , or use of statins . In conclusion , in addition to marked reduction in LDL-C , alirocumab leads to a significant and sustained lowering of Lp(a ) 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 The phase 3 ODYSSEY OPTIONS studies ( OPTIONS I , NCT01730040 ; OPTIONS II , NCT01730053 ) are multicenter , multinational , r and omized , double‐blind , active‐comparator , 24‐week studies evaluating the efficacy and safety of alirocumab , a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 , as add‐on therapy in ∼ 650 high‐cardiovascular (CV)‐risk patients whose low‐density lipoprotein cholesterol ( LDL‐C ) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV‐risk category , high and very high CV risk , respectively , with atorvastatin ( 20–40 mg/d ) or rosuvastatin ( 10–20 mg/d ) . Patients are r and omized to receive alirocumab 75 mg via a single , subcutaneous , 1‐mL injection by prefilled pen every 2 weeks ( Q2W ) as add‐on therapy to atorvastatin ( 20–40 mg ) or rosuvastatin ( 10–20 mg ) ; or to receive ezetimibe 10 mg/d as add‐on therapy to statin ; or to receive statin up‐titration ; or to switch from atorvastatin to rosuvastatin ( OPTIONS I only ) . At week 12 , based on week 8 LDL‐C levels , the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL‐C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk , respectively . The primary efficacy endpoint in both studies is difference in percent change in calculated LDL‐C from baseline to week 24 in the alirocumab vs control arms . The studies may provide guidance to inform clinical decision‐making when patients with CV risk require additional lipid‐lowering therapy to further reduce LDL‐C levels . The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL‐C reduction required to achieve the desired LDL‐C level CONTEXT Despite current st and ard of care , many patients at high risk of cardiovascular disease ( CVD ) still have elevated low-density lipoprotein cholesterol ( LDL-C ) levels . Alirocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 . OBJECTIVE The objective of the study was to compare the LDL-C-lowering efficacy of adding alirocumab vs other common lipid-lowering strategies . DESIGN , PATIENTS , AND INTERVENTIONS Patients ( n = 355 ) with very high CVD risk and LDL-C levels of 70 mg/dL or greater or high CVD risk and LDL-C of 100 mg/dL or greater on baseline atorvastatin 20 or 40 mg were r and omized to one of the following : 1 ) add-on alirocumab 75 mg every 2 weeks ( Q2W ) sc ; 2 ) add-on ezetimibe 10 mg/d ; 3 ) double atorvastatin dose ; or 4 ) for atorvastatin 40 mg regimen only , switch to rosuvastatin 40 mg . For patients not achieving protocol -defined LDL-C goals , the alirocumab dose was increased ( blinded ) at week 12 to 150 mg Q2W . MAIN OUTCOME MEASURE The primary end point was percentage change in calculated LDL-C from baseline to 24 weeks ( intent to treat ) . RESULTS Among atorvastatin 20 and 40 mg regimens , respectively , add-on alirocumab  reduced LDL-C levels by 44.1 % and 54.0 % ( P < .001 vs all comparators ) ; add-on ezetimibe , 20.5 % and 22.6 % ; doubling of atorvastatin dose , 5.0 % and 4.8 % ; and switching atorvastatin 40 mg to rosuvastatin 40 mg , 21.4 % . Most alirocumab-treated patients ( 87.2 % and 84.6 % ) achieved their LDL-C goals .  Most alirocumab-treated patients ( 86 % ) maintained their 75-mg Q2W regimen . Treatment-emergent adverse events occurred in 65.4 % of alirocumab patients vs 64.4 % ezetimibe and 63.8 % double atorvastatin/switch to rosuvastatin ( data were pooled ) . CONCLUSIONS Adding alirocumab to atorvastatin provided significantly greater LDL-C reductions vs adding ezetimibe , doubling atorvastatin dose , or switching to rosuvastatin and enabled greater LDL-C goal achievement BACKGROUND 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 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 Homozygous familial hypercholesterolaemia is a genetic disorder characterised by substantially raised LDL cholesterol , reduced LDL receptor function , xanthomas , and cardiovascular disease before age 20 years . Conventional therapy is with statins , ezetimibe , and apheresis . We aim ed to assess the long-term safety and efficacy of the proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) inhibitor evolocumab in a subset of patients with homozygous familial hypercholesterolaemia enrolled in an open-label , non-r and omised phase 3 trial . METHODS In this interim subset analysis of the TAUSSIG study , which was undertaken at 35 sites in 17 countries , we included patients aged 12 years or older with homozygous familial hypercholesterolaemia who were on stable LDL cholesterol-lowering therapy for at least 4 weeks ; all patients received evolocumab 420 mg subcutaneously monthly , or if on apheresis every 2 weeks . Dosing could be increased to every 2 weeks after 12 weeks in patients not on apheresis . The primary outcome of the TAUSSIG study was treatment-emergent adverse events ; secondary outcomes were the effects of evolocumab on LDL cholesterol and other lipids . We analysed patients on an intention-to-treat basis , and all statistical comparisons were done post hoc in this interim analysis . The TAUSSIG study is registered with Clinical Trials.gov , number NCT01624142 , and is ongoing . FINDINGS 106 patients were included in this analysis , 34 receiving apheresis at study entry and 14 younger than 18 years . The first patient was enrolled on June 28 , 2012 , and the cutoff date for the analysis was Aug 13 , 2015 ; mean follow-up was 1·7 years ( SD 0·63 ) . After 12 weeks , mean LDL cholesterol decreased from baseline by 20·6 % ( SD 24·4 ; mean absolute decrease 1·50 mmol/L [ SD 1·92 ] ) ; these reductions were maintained at week 48 . 47 of 72 patients not on apheresis at study entry increased evolocumab dosing to every 2 weeks , with an additional mean reduction in LDL cholesterol of 8·3 % ( SD 13·0 ; mean absolute decrease 0·77 mmol/L [ SD 1·38 ] ; p=0·0001 ) . In a post-hoc analysis , mean reductions in LDL cholesterol in patients on apheresis were significant at week 12 ( p=0·0012 ) and week 48 ( p=0·0032 ) , and did not differ from reductions achieved in patients not on apheresis ( p=0·38 at week 12 and p=0·09 at week 48 ) . We noted a small reduction ( median -7·7 % [ IQR -21·6 to 6·8 ] ) in lipoprotein(a ) at week 12 ( p=0·0015 ) , with some additional reduction at week 48 ( -11·9 % [ -28·0 to 0·0 ] ; p<0·0001 ) . HDL cholesterol was increased by a mean of 7·6 % ( SD 18·1 ) at week 12 ( p<0·0001 ) and 7·6 % ( SD 20·6 ) at week 48 ( p=0·0007 ) . Evolocumab was well tolerated ; 82 ( 77 % ) patients reported treatment-emergent adverse events , which were mostly minor . The most common were nasopharyngitis ( 14 patients [ 13 % ] ) , influenza ( 13 [ 12 % ] ) , headache ( 11 [ 10 % ] ) , and upper respiratory tract infection ( 11 [ 10 % ] ) . Serious adverse events occurred in 18 ( 17 % ) patients , with the most common being cardiovascular events ( four patients [ 4 % ] ) . There were no deaths and four positively adjudicated cardiovascular events , one ( 3 % ) among patients on apheresis and three ( 4 % ) among patients who did not receive apheresis . INTERPRETATION Our interim results suggest that evolocumab is an effective additional option to reduce LDL cholesterol in patients with homozygous familial hypercholesterolaemia , with or without apheresis . FUNDING Amgen ABBREVIATIONS A1C = hemoglobin A1C ; AACE = American Association of Clinical Endocrinologists ; ACCORD = Action to Control Cardiovascular Risk in Diabetes ; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ; ACE = American College of Endocrinology ; ACEI = angiotensin-converting enzyme inhibitor ; AGI = alpha-glucosidase inhibitor ; apo B = apolipoprotein B ; ARB = angiotensin II receptor blocker ; ASCVD = atherosclerotic cardiovascular disease ; BAS = bile acid sequestrant ; BMI = body mass index ; BP = blood pressure ; CCB = calcium channel blocker ; CGM = continuous glucose monitoring ; CHD = coronary heart disease ; CKD = chronic kidney disease ; DKA = diabetic ketoacidosis ; DPP4 = dipeptidyl peptidase 4 ; eGFR = estimated glomerular filtration rate ; EPA = eicosapentaenoic acid ; ER = extended release ; FDA = Food and Drug Administration ; GLP1 = glucagon-like peptide 1 ;  HDL-C = high-density-lipoprotein cholesterol ; HeFH = heterozygous familial hypercholesterolemia ; LDL-C = low-density-lipoprotein cholesterol ; LDL-P = low-density-lipoprotein particle ; Look AHEAD = Look Action for Health in Diabetes ; NPH = neutral protamine Hagedorn ; OSA = obstructive sleep apnea ; PCSK9 = proprotein convertase subtilisin-kexin type 9 serine protease ; RCT = r and omized controlled trial ; SU = sulfonylurea ; SGLT2 = sodium-glucose cotransporter 2 ; SMBG = self-monitoring of blood glucose ; T2D = type 2 diabetes ; TZD = thiazolidinedione 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 Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin – kexin type 9 ( PCSK9 ) and reduces levels of low‐density lipoprotein ( LDL ) cholesterol . We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk . METHODS In two parallel , multinational trials with different entry criteria for LDL cholesterol levels , we r and omly assigned the 27,438 patients in the combined trials to receive bococizumab ( at a dose of 150 mg ) subcutaneously every 2 weeks or placebo . The primary end point was nonfatal myocardial infa rct ion , nonfatal stroke , hospitalization for unstable angina requiring urgent revascularization , or cardiovascular death ; 93 % of the patients were receiving statin therapy at baseline . The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies , as seen in data from other studies in the program . The median follow‐up was 10 months . RESULTS At 14 weeks , patients in the combined trials had a mean change from baseline in LDL cholesterol levels of ‐56.0 % in the bococizumab group and + 2.9 % in the placebo group , for a between‐group difference of –59.0 percentage points ( P<0.001 ) and a median reduction from baseline of 64.2 % ( P<0.001 ) . In the lower‐risk , shorter‐ duration trial ( in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [ 1.8 mmol per liter ] and the median follow‐up was 7 months ) , major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group ( hazard ratio , 0.99 ; 95 % confidence interval [ CI ] , 0.80 to 1.22 ; P=0.94 ) . In the higher‐risk , longer‐ duration trial ( in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [ 2.6 mmol per liter ] and the median follow‐up was 12 months ) , major cardiovascular events occurred in 179 and 224 patients , respectively ( hazard ratio , 0.79 ; 95 % CI , 0.65 to 0.97 ; P=0.02 ) . The hazard ratio for the primary end point in the combined trials was 0.88 ( 95 % CI , 0.76 to 1.02 ; P=0.08 ) . Injection‐site reactions were more common in the bococizumab group than in the placebo group ( 10.4 % vs. 1.3 % , P<0.001 ) . CONCLUSIONS In two r and omized trials comparing the PCSK9 inhibitor bococizumab with placebo , bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower‐risk patients but did have a significant benefit in the trial involving higher‐risk patients . ( Funded by Pfizer ; SPIRE‐1 and SPIRE‐2 Clinical Trials.gov numbers , NCT01975376 and NCT01975389 . BACKGROUND AND AIMS Despite hypercholesterolemia has been recognized to increase cardiovascular risk in human immunodeficiency virus (HIV)-infected patients , cholesterol-lowering therapy is underused in this population , due to fear of drug-drug interactions with antiretroviral therapy ( ART ) . We investigated the effects of a nutraceutical combination ( NC ) on lipid profile , proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) , sub clinical inflammation and arterial stiffness in ART-treated HIV-infected patients . METHODS This was a prospect i ve r and omized open-label trial with a cross-over design including 30 stable HIV-infected patients on ART with low-density lipoprotein cholesterol ( LDL-C ) > 115 mg/dL , not taking lipid-lowering treatment . After a 3-week lipid stabilization period , the effects associated with 3 months of an oral NC containing red yeast rice and berberine vs. no active treatment ( noNC ) were assessed for plasma total cholesterol ( TC ) , LDL-C , high-density lipoprotein cholesterol ( HDL-C ) , triglyceride ( TG ) , lipoprotein(a ) , PCSK9 , high-sensitivity C-reactive protein ( hs-CRP ) levels and aortic pulse wave velocity ( aPWV ) . RESULTS At baseline , significant correlations between PCSK9 levels , age ( rho = -0.51 , p=0.004 ) , waist circumference ( rho = 0.36 , p=0.005 ) and CD4 + cell count ( rho = -0.40 , p=0.027 ) were observed . NC treatment effects corrected for noNC were significant for TC ( -14 % , p<0.001 ) , LDL-C ( -19 % , p<0.001 ) , PCSK9 ( -12 % , p=0.02 ) , hs-CRP ( -14 % , p=0.03 ) and aPWV ( -6 % , p=0.005 ) . No significant effects were observed for HDL-C , TG and lipoprotein(a ) . NC treatment was safe and no significant alterations in muscle , liver and immunovirological parameters were observed . No carry over effect was recorded . CONCLUSIONS The tested NC significantly reduced plasma cholesterol and PCSK9 levels , attenuated sub clinical inflammation and improved arterial stiffness in stable HIV-infected patients on ART BACKGROUND Replacing SFAs with vegetable PUFAs has cardiometabolic benefits , but the effects on liver fat are unknown . Increased dietary n-6 PUFAs have , however , also been proposed to promote inflammation-a yet unproven theory . OBJECTIVE We investigated the effects of PUFAs on liver fat , systemic inflammation , and metabolic disorders . DESIGN We r and omly assigned 67 abdominally obese subjects ( 15 % had type 2 diabetes ) to a 10-wk isocaloric diet high in vegetable n-6 PUFA ( PUFA diet ) or SFA mainly from butter ( SFA diet ) , without altering the macronutrient intake . Liver fat was assessed by MRI and magnetic resonance proton ( 1H ) spectroscopy ( MRS ) . Proprotein convertase subtilisin/kexin type-9 ( PCSK9 , a hepatic LDL-receptor regulator ) , inflammation , and adipose tissue expression of inflammatory and lipogenic genes were determined . RESULTS A total of 61 subjects completed the study .  Body weight modestly increased but was not different between groups . Liver fat was lower during the PUFA diet than during the SFA diet [ between-group difference in relative change from baseline ; 16 % ( MRI ; P < 0.001 ) , 34 % ( MRS ; P = 0.02 ) ] . PCSK9 ( P = 0.001 ) , TNF receptor-2 ( P < 0.01 ) , and IL-1 receptor antagonist ( P = 0.02 ) concentrations were lower during the PUFA diet , whereas insulin ( P = 0.06 ) tended to be higher during the SFA diet . In compliant subjects ( defined as change in serum linoleic acid ) , insulin , total/HDL-cholesterol ratio , LDL cholesterol , and triglycerides were lower during the PUFA diet than during the SFA diet ( P < 0.05 ) . Adipose tissue gene expression was unchanged . CONCLUSIONS Compared with SFA intake , n-6 PUFAs reduce liver fat and modestly improve metabolic status , without weight loss . A high n-6 PUFA intake does not cause any signs of inflammation or oxidative stress . Downregulation of PCSK9 could be a novel mechanism behind the cholesterol-lowering effects of PUFAs . This trial was registered at clinical trials.gov as NCT01038102 BACKGROUND Familial hypercholesterolemia ( FH ) is a dominant genetic disorder associated with elevated low-density lipoprotein cholesterol ( LDL-C ) and premature atherosclerotic events . Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 ( PCSK9 ) are indicated for LDL-C reduction among adult patients with FH , placebo-controlled outcome data among FH patients are scant . OBJECTIVE Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction of vascular Events ( SPIRE ) program . METHODS We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular event rates among 1578 FH patients and 15,959 patients without FH who were selected for comparable lipid levels ( on-statin levels of LDL-C > 100 mg/dL or non-high-density lipoprotein cholesterol > 130 mg/dL ) . All patients were r and omized by computer generated codes to bococizumab 150 mg subcutaneously every 2 weeks or to matching placebo in the SPIRE clinical trials program and were followed over a median period of 11.2 months for major adverse cardiovascular events ( nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death ) . Analysis is by intention to treat . The SPIRE trials are closed and registered at Clinical Trials.gov : NCT01968954 , NCT01968967 , NCT02100514 , NCT01968980 , NCT01975376 , and NCT01975389 . RESULTS Compared to non-FH patients , FH patients enrolled in the SPIRE trials were on average younger ( 58 vs 63 years ) , more likely to be women ( 42 vs 35 % ) , more likely to be primary prevention patients ( 42 vs 23 % ) , had higher mean baseline LDL-C levels ( 151 vs 127 mg/dL ) , and lower rates of diabetes ( 25 vs 52 % ) and hypertension ( 59 vs 82 % ) . FH and non-FH patients both had 55 % reductions in LDL-C with bococizumab . Among FH patients , major adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and 22 of 797 allocated to placebo ( hazard ratio 0.83 ; 95 % confidence interval 0.44 - 1.54 , P = .55 ) . This best estimate of effect was similar in magnitude to that observed in the much larger group of patients without FH ( hazard ratio 0.79 , 95 % confidence interval 0.64 - 0.97 , P = .023 ) with no statistically significant evidence of heterogeneity between groups ( P = .87 ) . Incidence rate ratios comparing bococizumab to placebo for adverse events were similar among those with and without FH . The proportion of patients developing antidrug antibodies was higher among those with FH compared to those without FH ( 43 % vs 36 % , P < .001 ) . CONCLUSIONS In these r and omized placebo-controlled data , the subgroup of statin-treated FH patients had a similar magnitude of risk reduction for hard cardiovascular events with the PCSK9 inhibitor bococizumab as did patients without FH , with no evidence of statistical heterogeneity between groups
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 We sought to examine the efficacy and safety of 2 PCSK9 ( proprotein convertase subtilisin/kexin type 9 ) inhibitors : alirocumab and evolocumab .