“PCSK9 inhibition and CV outcomes” PACE-CME Satellite Symposium, ESC Congress, Barcelona 2017 Understanding new PCSK9 outcome data : From the LDL-C hypothesis to LDL-C causality M. John Chapman BSc (Hons), Ph.D., D.Sc., FESC Director Emeritus, INSERM, Research Professor, University of Pierre and Marie Curie Past- President, European Atherosclerosis Society Pitié-Salpetriere University Hospital, Paris, France
PCSK9 inhibitor CV outcomes trials Alirocumab : Evolocumab : FOURIER 1 ODYSSEY OUTCOMES 2 N = 27,564 N ~ 18,000 History of MI Recent MI n = 22,356 < 1 year PAD n = 3640 History of stroke* n = 5330 *Non-haemorrhagic stroke. 1. Sabatine MS, et al. Am Heart J 2016;173:94 – 101. 2. Schwartz GG, et al. Am Heart J 2014;168:682 – 9.
PCSK9 CV outcome trials : FOURIER Active arm : Patient populations : Intensive statin therapy - MI + - Non-hemorrhagic stroke - Peripheral arterial disease PCSK9 inhibitor : Evolocumab Composite endpoints : Non-fatal MI Non-fatal stroke CV benefit across all patient populations
PCSK9 CV outcome trials : FOURIER Active arm : Patient populations : Intensive statin therapy - MI + - History of non- hemorrhagic stroke PCSK9 inhibitor : - Peripheral arterial Evolocumab disease On-treatment LDL-C = 30 mg/dL Composite endpoints : Non-fatal MI ; Non-fatal stroke CV benefit across all patient populations
TheMissing Link ASCVD Disease LDL-C CV event process reduction ? RF control
NY-160626.038/020131YlsjoLS1 Diabetes Hypertension Smoking (Glucose/AGE) Arterial Endothelium Permeability LDL Endothelial dysfunction Influx • Oxidative stress INTIMAL LDL-C • Proteolysis Retention + accumulation • Lipolysis • Aggregation Modified / Oxidised Proinflammatory LDL Monocytes: -endothelial Arterial M1 macrophages adhesion - diapedesis Proinflammatory Macrophage Foam cell Fatty Streak Lesions
NY-160626.038/020131YlsjoLS1 Fatty Streak Lesion : Macrophage Foam Cells
NY-160626.038/020131YlsjoLS1 Diabetes Hypertension Smoking (Glucose/AGE) Arterial Endothelium Permeability LDL Endothelial dysfunction Influx • Oxidative stress INTIMAL LDL-C • Proteolysis Retention + accumulation • Lipolysis • Aggregation Modified / Oxidised Proinflammatory LDL Monocytes: -endothelial Arterial M1 macrophages adhesion - diapedesis Proinflammatory Macrophage Foam cell Fatty Streak Lesions
Cellular interactions amplify intra-plaque inflammation M1 T regs Monocyte- T helper 1 Macrophage foam cells cells Smooth muscle cells
NY-160626.038/020131YlsjoLS1 Macrophage foam cells drive Plaque Progression Cholesterol TIMPs efflux Cholesterol MMPs Influx Matrix degradation Cholesterol accumulation Antioxidants Anti-inflammatory Oxidative cytokines Proinflammatory stress cytokines Lipid, protein oxidation Inflammation TFPI Cell viability Apoptosis TF Necrosis Prothrombotic activity Cell death
Thin cap, lipid-rich, rupture-prone atherosclerotic plaque
Ruptured plaques % Cell Type are rich in cholesterol in ruptured plaques 100 Stable 80 Rupture 60 40 20 0 Mac. SMC T-cells Kolodgie et al. Am J Pathol . 2000, 157:1259-1268. C.V. Felton, D. Crook, M.J. Davies, M.F. Oliver. ATVB 1997;17:1337-1345
Plaque contents are drivers of thrombosis Waxman et al, Circulation, 2006, 114: 2390
TheMissing Link ASCVD Disease LDL-C CV event process reduction ? RF control
Marked Statin-mediated LDL reduction stops coronary plaque progression and induces regression 2% IVUS 1% PAV 0% Mean % atheroma -1% volume (PAV) 95% CI -2% On-treatment LDL-C (mg/dL) Nicholls et al. JAMA 2007;297:499 – 508.
LDL-C reduction remodels Coronary artery plaque Plaque volume index Lipid volume index % Change in Plaque Volume Index % Change in Lipid Volume Index 30 210 20 180 10 150 y= 0.63x+8.68 0 120 r= 0.40 p= 0.008 -10 90 y= 0.30x-4.19 -20 60 r= 0.39 -30 p= 0.011 30 -40 0 -50 -30 -60 -60 -60 -40 -20 0 20 40 60 80 -60 -40 -20 0 20 40 60 80 % Change in LDL-C % Change in LDL-C Fibrous volume index Fibrous cap thickness (%) % Change in Fibrous Cap Thickness 50 140 % Change in Fibrous Volume Index 120 40 y= -0.46x+17.67 y= -0.24x+1.20 100 r= -0.40 30 r= -0.38 P= 0.013 p= 0.010 80 20 60 10 40 0 20 -10 0 -20 -20 -30 -40 -40 -60 -60 -40 -20 0 20 40 60 80 -60 -40 -20 0 20 40 60 80 % Change in LDL-C % Change in LDL-C Hattori K, Ozaki Y et al. J Am Coll Cardiol Img 2012;5:169 – 77 Fujita Health University
GLAGOV: GLobal Assessment of plaque reGression with a PCSK9 antibOdy as measured by intraVascular ultrasound • Lowering LDL-C with evolocumab is expected to reduce the atheroma burden • IVUS imaging enables measurement of the changes in the atheroma burden Randomisation Screening and End of study, 2016 Up to 4 week placebo run-in Evolocumab 420mg SC QM lipid period, n=970 stabilisation Clinically indicated 1:1 period coronary angiogram IVUS based on Assigned to coronary angiogram atorvastatin results background Placebo SC monthly SC injection of 3 mL therapy placebo 2 – 4 weeks Max. 6 weeks Day 1 Week 4 Week 12 Week 24 Week 36 Week 52 Week 64 Week 76 Week 78 Primary endpoint: Nominal change in PAV from baseline to 78 weeks post randomisation Puri et al. Am Heart J 2016; doi: 10.1016/j.ahj.2016.01.019
Secondary Endpoint: Total Atheroma Volume Mean On-treatment LDL-C : 36.6 mg/dL ( -60%) 0 -0,9 -1 P = NS -2 Change -3 in Total P < 0.0001 Atheroma -4 Volume (mm 3 ) -5 -5,8 -6 P <0.0001 -7 Statin Statin-evolocumab monotherapy Nicholls et al, JAMA, 2016, 316: 2373
Exploratory Subgroup: Baseline LDL-C <70 mg/dL Patients Showing Regression % Atheroma Volume 0 100% -0,35 Percentage Regressing (%) -0,3 81,2% P = NS 80% Change in PAV (%) -0,6 -0,9 60% P < 0.0001 48,0% -1,2 40% -1,5 -1,8 -1,97 20% -2,1 P <0.0001 -2,4 0% Statin Statin- Statin Statin- monotherapy evolocumab monotherapy evolocumab Nicholls et al, JAMA, 2016, 316: 2373
NY-160626.038/020131YlsjoLS1 Potential Mechanisms contributing to plaque regression, remodelling and stabilisation arterial accumulation of LDL-C and other apoB-LPs efflux of plaque cholesterol and toxic lipids intracellular and extracellular lipid content plaque inflammation ; increase in ECM - Influx of healthy phagocytes ; removal of necrotic debris - Efferocytosis of macrophage foam cells
LDL is causal in ASCVD • Dietary- and genetically-induced atherosclerosis in animal models • Epidemiology of risk factors for myocardial infarction • Familial hypercholesterolemia • Mendelian randomisation studies • PCSK9 genetics (LOF; GOF) • RCTs with statins, cholesterol absorption inhibition and PCSK9i’s lower LDL-C levels, induce plaque regression and reduce CV events • Statins remodel coronary plaque composition and favour plaque stabilisation
European Heart Journal. doi:10.1093/eurheartj/ehx144. Online at: https://academic.oup.com/eurheartj/article- lookup/doi/10.1093/eurheartj/ehx144
Slowing and Reversing Atherosclerosis Inflammation VLDL remnants LDL Libby (2001) Circulation 104:365
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