From the LDL-C hypothesis to LDL-C causality M. John Chapman BSc - - PowerPoint PPT Presentation

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From the LDL-C hypothesis to LDL-C causality M. John Chapman BSc - - PowerPoint PPT Presentation

Nov 12, 2022 216 likes •462 views

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

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SLIDE 1
  • 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 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

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SLIDE 2

PCSK9 inhibitor CV outcomes trials

  • 1. Sabatine MS, et al. Am Heart J 2016;173:94–101.
  • 2. Schwartz GG, et al. Am Heart J 2014;168:682–9.

History of MI n = 22,356

PAD n = 3640 History of stroke* n = 5330

Alirocumab : ODYSSEY OUTCOMES2 N ~ 18,000 Evolocumab : FOURIER1 N = 27,564 Recent MI < 1 year

*Non-haemorrhagic stroke.

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SLIDE 3

PCSK9 CV outcome trials : FOURIER

Patient populations :

  • MI
  • Non-hemorrhagic stroke
  • Peripheral arterial disease

Active arm :

Intensive statin therapy

+

PCSK9 inhibitor :

Evolocumab

Composite endpoints : Non-fatal MI Non-fatal stroke CV benefit across all patient populations

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SLIDE 4

PCSK9 CV outcome trials : FOURIER

Patient populations :

  • MI
  • History of non-

hemorrhagic stroke

  • Peripheral arterial

disease

Active arm :

Intensive statin therapy

+

PCSK9 inhibitor :

Evolocumab

Composite endpoints : Non-fatal MI ; Non-fatal stroke CV benefit across all patient populations

On-treatment LDL-C = 30 mg/dL

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SLIDE 5

TheMissing Link

LDL-C

RF control

ASCVD Disease process

?

CV event reduction

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SLIDE 6

NY-160626.038/020131YlsjoLS1

  • Oxidative stress
  • Proteolysis
  • Lipolysis
  • Aggregation

LDL

INTIMAL LDL-C Retention + accumulation

Influx Modified / Oxidised Proinflammatory LDL Arterial M1 macrophages

Monocytes:

  • endothelial

adhesion

  • diapedesis

Proinflammatory Macrophage Foam cell

Endothelial dysfunction

Fatty Streak Lesions

Hypertension Smoking Diabetes (Glucose/AGE) Arterial Endothelium

Permeability

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SLIDE 7

NY-160626.038/020131YlsjoLS1

Fatty Streak Lesion : Macrophage Foam Cells

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SLIDE 8

NY-160626.038/020131YlsjoLS1

  • Oxidative stress
  • Proteolysis
  • Lipolysis
  • Aggregation

LDL

INTIMAL LDL-C Retention + accumulation

Influx Modified / Oxidised Proinflammatory LDL Arterial M1 macrophages

Monocytes:

  • endothelial

adhesion

  • diapedesis

Proinflammatory Macrophage Foam cell

Endothelial dysfunction

Fatty Streak Lesions

Hypertension Smoking Diabetes (Glucose/AGE) Arterial Endothelium

Permeability

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SLIDE 9

M1 Monocyte- Macrophage foam cells

T regs T helper 1 cells

Smooth muscle cells Cellular interactions amplify intra-plaque inflammation

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SLIDE 10

NY-160626.038/020131YlsjoLS1

Macrophage foam cells drive Plaque Progression

Cholesterol Influx Cholesterol efflux MMPs Oxidative stress Antioxidants TF TFPI Cholesterol accumulation Proinflammatory cytokines Anti-inflammatory cytokines Inflammation Lipid, protein oxidation Matrix degradation Prothrombotic activity TIMPs

Apoptosis Necrosis

Cell viability

Cell death

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SLIDE 11

Thin cap, lipid-rich, rupture-prone atherosclerotic plaque

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SLIDE 12

C.V. Felton, D. Crook, M.J. Davies, M.F. Oliver. ATVB 1997;17:1337-1345

20 40 60 80 100 Mac. SMC T-cells Stable Rupture

Kolodgie et al. Am J Pathol. 2000, 157:1259-1268.

% Cell Type in ruptured plaques Ruptured plaques are rich in cholesterol

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SLIDE 13

Waxman et al, Circulation, 2006, 114: 2390

Plaque contents are drivers of thrombosis

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SLIDE 14

TheMissing Link

LDL-C

RF control

ASCVD Disease process

?

CV event reduction

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SLIDE 15

 PAV On-treatment LDL-C (mg/dL)

2% 1% 0%

  • 1%
  • 2%

Marked Statin-mediated LDL reduction stops coronary plaque progression and induces regression

Nicholls et al. JAMA 2007;297:499–508. Mean % atheroma volume (PAV) 95% CI

IVUS

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SLIDE 16

Hattori K, Ozaki Y et al. J Am Coll Cardiol Img 2012;5:169–77 Fujita Health University

LDL-C reduction remodels Coronary artery plaque

  • 60
  • 50
  • 40
  • 30
  • 20
  • 10

10 20 30

  • 60
  • 40
  • 20

20 40 60 80 % Change in LDL-C y= 0.30x-4.19 r= 0.39 p= 0.011

  • 60
  • 30

30 60 90 120 150 180 210

  • 60
  • 40
  • 20

20 40 60 80 y= 0.63x+8.68 r= 0.40 p= 0.008

  • 40
  • 30
  • 20
  • 10

10 20 30 40 50

  • 60
  • 40
  • 20

20 40 60 80 y= -0.24x+1.20 r= -0.38 P= 0.013

  • 60
  • 40
  • 20

20 40 60 80 100 120 140

  • 60
  • 40
  • 20

20 40 60 80 y= -0.46x+17.67 r= -0.40 p= 0.010 (%)

Plaque volume index Fibrous volume index Lipid volume index Fibrous cap thickness

% Change in LDL-C % Change in LDL-C % Change in LDL-C % Change in Lipid Volume Index % Change in Fibrous Volume Index % Change in Fibrous Cap Thickness % Change in Plaque Volume Index

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SLIDE 17

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

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

Placebo SC monthly

  • Max. 6 weeks

Day 1 Week 36 Week 64 Week 24 Week 12 Week 4 Week 52 Week 76 Week 78

2–4 weeks

Randomisation 1:1

Evolocumab 420mg SC QM

End of study, 2016

Screening and placebo run-in period, n=970 Clinically indicated coronary angiogram IVUS based on coronary angiogram results SC injection of 3 mL placebo Up to 4 week lipid stabilisation period Assigned to atorvastatin background therapy

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SLIDE 18

Secondary Endpoint: Total Atheroma Volume

  • 0,9
  • 5,8
  • 7
  • 6
  • 5
  • 4
  • 3
  • 2
  • 1

Change in Total Atheroma Volume (mm3)

Statin monotherapy Statin-evolocumab P < 0.0001

P = NS P <0.0001

Nicholls et al, JAMA, 2016, 316: 2373

Mean On-treatment LDL-C : 36.6 mg/dL ( -60%)

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SLIDE 19
  • 0,35
  • 1,97
  • 2,4
  • 2,1
  • 1,8
  • 1,5
  • 1,2
  • 0,9
  • 0,6
  • 0,3

Change in PAV (%)

Statin monotherapy Statin- evolocumab

P < 0.0001

% Atheroma Volume

P = NS P <0.0001

Patients Showing Regression

Exploratory Subgroup: Baseline LDL-C <70 mg/dL

48,0% 81,2%

0% 20% 40% 60% 80% 100%

Percentage Regressing (%)

Statin monotherapy Statin- evolocumab Nicholls et al, JAMA, 2016, 316: 2373

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SLIDE 20

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
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SLIDE 21

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

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SLIDE 22

European Heart Journal. doi:10.1093/eurheartj/ehx144. Online at: https://academic.oup.com/eurheartj/article- lookup/doi/10.1093/eurheartj/ehx144

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SLIDE 23

Slowing and Reversing Atherosclerosis

Libby (2001) Circulation 104:365

VLDL remnants

LDL

Inflammation