Successfully reported this slideshow.
Inhibidores de PCSK9: el ultradescenso de LDL
iPCSK9 Nuevo paradigma
Dislipemia en Cardiología
¿Cuál es el futuro?
José Ló...
Inhibidores de PCSK9: el ultradescenso de LDL
Objetivo en Hipercolesterolemia
• Prevención primaria: LDL < 115 mg / dl
• P...
Inhibidores de PCSK9: el ultradescenso de LDL
Reasons for NOT achieving LDL-C goals
•Low dosing (physician not compliant w...
Inhibidores de PCSK9: el ultradescenso de LDL
The severe hypercholesterolemia phenotype
All patients with marked elevation...
Inhibidores de PCSK9: el ultradescenso de LDL
The severe hypercholesterolemia phenotype
All patients with marked elevation...
Inhibidores de PCSK9: el ultradescenso de LDL
Drug Function Benefit
HMG CoA
reductase inh.
Decreases LDL Benefit, limited ...
Inhibidores de PCSK9: el ultradescenso de LDL
Normal PCSK9 function
Loss of PCSK9 function mutations
Inhibidores de PCSK9: el ultradescenso de LDL
Dynamic Relationship Between Alirocumab Level, PCSK9 and LDL-C
-70
-60
-50
-...
Inhibidores de PCSK9: el ultradescenso de LDL
High risk pts on high dose statin +/- ezetimibe
% reaching LDL-C targed < 70...
Inhibidores de PCSK9: el ultradescenso de LDL
10
MENDEL-2: Safety and Tolerability
Adverse Events (AEs), n (%)
Placebo
(N ...
Inhibidores de PCSK9: el ultradescenso de LDL
Alirocumab Evolocumab RN316
Soponsor Sanofi / Regeneron Amgen Pfizer
Trial O...
Inhibidores de PCSK9: el ultradescenso de LDL
Conclusions
• High LDL-C is responsible for atheroesclerosis and CV events,
...
Upcoming SlideShare
Loading in …5
×

iPCSK9 Nuevo paradigma. Dislipemia en Cardiología: ¿Cuál es el futuro?

1,092 views

Published on

iPCSK9 Una nueva era en riesgo cardiovascular
17 de Mayo de 2014, 17:00h
http://iPCSK9.secardiologia.es

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)

Published in: Health & Medicine
  • Be the first to comment

iPCSK9 Nuevo paradigma. Dislipemia en Cardiología: ¿Cuál es el futuro?

  1. 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. 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. 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. 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. 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. 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. 7. Inhibidores de PCSK9: el ultradescenso de LDL Normal PCSK9 function Loss of PCSK9 function mutations
  8. 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. 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
  10. 10. Inhibidores de PCSK9: el ultradescenso de LDL 10 MENDEL-2: Safety and Tolerability Adverse Events (AEs), n (%) Placebo (N = 154) Ezetimibe (N = 154) Evolocumab (N = 306) Treatment-emergent AEs 68 (44) 70 (46) 134 (44) Common treatment-emergent AEs* Headache Diarrhea Nausea Urinary Tract Infection Constipation Nasopharyngitis Upper Respiratory Infection 4 (3) 6 (4) 1 (1) 2 (1) 4 (3) 3 (2) 4 (3) 5 (3) 3 (2) 3 (2) 3 (2) 1 (1) 6 (4) 5 (3) 10 (3) 9 (3) 8 (3) 7 (2) 6 (2) 6 (2) 5 (2) Serious AEs 1 (1) 1 (1) 4 (1) AEs leading to study drug discontinuation 6 (4) 5 (3) 7 (2) Deaths 0 (0) 0 (0) 0 (0) Potential injection site reactions† 8 (5) 7 (5) 16 (5) Muscle-related SMQ‡ Myalgia Musculoskeletal pain 6 (4) 3 (2) 2 (1) 5 (3) 3 (2) 1 (1) 8 (3) 3 (1) 3 (1) Neurocognitive AEs 0 (0) 0 (0) 0 (0) CK > 5 x ULN 2 (1) 0 (0) 2 (1) ALT or AST > 5 x ULN 2 (1) 0 (0) 1 (0.3) Anti-evolocumab antibodies§ NA NA 0 MENDEL II. ACC 2014
  11. 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. 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

×