iPCSK9 Una nueva era en riesgo cardiovascular
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iPCSK9 Nuevo paradigma. Dislipemia en Cardiología: ¿Cuál es el futuro?
Dr. José Luis López-Sendón Hentschel
Jefe de Servicio de Cardiología. Hospital Universitario La Paz (Madrid)
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iPCSK9 Nuevo paradigma. Dislipemia en Cardiología: ¿Cuál es el futuro?
1. Inhibidores de PCSK9: el ultradescenso de LDL
iPCSK9 Nuevo paradigma
Dislipemia en Cardiología
¿Cuál es el futuro?
José López-Sendón
Hospital Universitario La
Paz Madrid. Spain
2. Inhibidores de PCSK9: el ultradescenso de LDL
Objetivo en Hipercolesterolemia
• Prevención primaria: LDL < 115 mg / dl
• Prevención secundaria: LDL < 70 mg / dl
• Controvertido; guías con recomendaciones diferentes
Guias ESC & EAS 2011;32:1769
3. Inhibidores de PCSK9: el ultradescenso de LDL
Reasons for NOT achieving LDL-C goals
•Low dosing (physician not compliant with guidelines)
•Poor patient compliance
•Secondary effects (allergic reactions, …)
•Poor biological response: (The severe hypercholest. phenotype)
4. Inhibidores de PCSK9: el ultradescenso de LDL
The severe hypercholesterolemia phenotype
All patients with marked elevation of LDL-C > 190 mg/dl
regardless of the cause
Multiple reasons, same phenotype
5. Inhibidores de PCSK9: el ultradescenso de LDL
The severe hypercholesterolemia phenotype
All patients with marked elevation of LDL-C > 190
• Extreme diet
• Autosomal dominant hypercholesterolemia
Mutations in LDL related genes:
• LDLR,
• Apolipoprotein B (apoB),
• Poprotein Convertase Subtilisin Kexin type 9 (PCSK9)
• Other genes not yet identified
• Polygenic, epigenetic, or acquired defects
6. Inhibidores de PCSK9: el ultradescenso de LDL
Drug Function Benefit
HMG CoA
reductase inh.
Decreases LDL Benefit, limited LDL lowering
CETP inh. Increases HDL Failure
LP-PLA2 inh. Reduces plaque inflammation Failure
VIA-2291 Reduces plaque imflammation Failure
PPAR (fibrates) Reduces triglycerides Failure Limitted benefit
Nicotinic acid Recudes LDL Failure
Cholesterol
absortion inh.
Impairs cholesterol absortion Improve-It Nov 2013
MAPK Inh. Reduces plaque inflammation Ongoing
Apo A-1 Milano Arginine -> cysteine mutation in Apo A-1 Ongoing
iPCSK9 Ultra-lowering of LDL Ongoing
Medical treatment of Dyslipemia
7. Inhibidores de PCSK9: el ultradescenso de LDL
Normal PCSK9 function
Loss of PCSK9 function mutations
8. Inhibidores de PCSK9: el ultradescenso de LDL
Dynamic Relationship Between Alirocumab Level, PCSK9 and LDL-C
-70
-60
-50
-40
-30
-20
-10
0
0
20
40
60
80
100
120
140
160
180
200
0 500 1000 1500 2000 2500
LDL-Cmean%change
2 W 4 W
Total alirocumab
Free PCSK9
LDL-C
Free/totalPCSK9Conc.(ng/mL)
Totalalirocumab(ng/mL)X0.01
Time (hours)
Stein EA et al. New Engl J Med 2012; 366: 1108–18.
9. Inhibidores de PCSK9: el ultradescenso de LDL
High risk pts on high dose statin +/- ezetimibe
% reaching LDL-C targed < 70 mg/dl
LAPLACE-TIMI 57 JACC 2014;63:457
11. Inhibidores de PCSK9: el ultradescenso de LDL
Alirocumab Evolocumab RN316
Soponsor Sanofi / Regeneron Amgen Pfizer
Trial ODYSSEY outcomes Fourier Spire I Spire II
Sample size 18.000 22.500 12.000 6.300
Patients 4-16w post ACS MI, stroke, PAD High CV risk
Statin Evidence based med Atorva > 20 Lipid Lowering
LDL-C mg/dl >70 > 79 70-99 > 100
PCSK9
dosing
2w 2w – 4w 2w
Endpoint CHD death, MI, isch
stroke, Hospt for UA
CV death, MI, stroke,
H for UA, coro revasc
CV death, MI,
stroke urg revasc
Completion 3 / 2018 12 / 2017 8 / 2017
CV Outcome Trials of PCSK9 inhibitors
12. Inhibidores de PCSK9: el ultradescenso de LDL
Conclusions
• High LDL-C is responsible for atheroesclerosis and CV events,
independently form its cause
• PCSK9 increase degradation of hepatic LDL-R, resulting in
hypercholesterolemia and major CV events
• Inhibition of PCSK9 in addition to statins potently reduced LDL-C
• Ongoing studies evaluate impact of inhibiting PCSK9 on CV events
• Other PCSK9 functions may also play an important role for
atherosclerosis beyond degradation of hepatic LDLR
• PCSK9 inhibition probably the most promising new theraphy ahead