Dov Gavish MD הטיפול בחולים בסיכון גבוה לאור המלצות ESC2011-2012 מאי 2013 ההסתדרות הרפואית בישראל – החברה לחקר, מניעה

Dov Gavish MDDov Gavish MD

המלצות לאור גבוה בסיכון בחולים הטיפולESC2011-2012

2013 מאי

ההסתדרות הרפואית בישראל – החברה לחקר, מניעה וטיפול בטרשת עורקיםIsrael Medical Association-Society for Research, Prevention and Treatment of Atherosclerosis

עורקים חולים עם משקעי כולסטרול

עורק לפני טיפול ואחריו

5

2006 AHA/ACC guidelinesfor patients with CHD2,b

<100 mg/dL:Goal for allpatients with CHD2,a

<70 mg/dL:A reasonable goal for all patientswith CHD2,a

ESC/EAS2011 -2012

<100 mg/dL:Patients with High CHD riskequivalents (10-year risk >20%)1

<70 mg/dL:Therapeutic goal for veryhigh-risk patients1,a

LDL-C Goals for High-Risk Patients

<100 mg/dL

<70 mg/dL

aFactors that place a patient at very high risk are established CVD plus: multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic syndrome (TG ≥200 mg/dL + non–HDL-C ≥130 mg/dL with HDL-C <40 mg/dL); and ACS. 1

bAnd other forms of atherosclerotic disease.2

ATP = Adult Treatment Panel; AHA = American Heart Association; ACC = American College of Cardiology; CVD = coronary vascular disease; TG = triglycerides; ACS = acute coronary syndrome.1. Grundy SM et al. Circulation. 2004;110:227–239; 2. Smith SC Jr et al. Circulation. 2006;113:2363–2372.

• If it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it generally is possible to achieve LDL-C reductions of >50% with more intensive LDL-C–lowering therapy, including drug combinations2

Good News Regarding Very Low LDLs

The Reduction in CHD Risk is The Reduction in CHD Risk is Proportional to the % LDL-C LoweringProportional to the % LDL-C Lowering

0.4

0.2

0

-0.2

-0.4

-0.6

-0.8

-1.0 0 5 10 15 20 25 30 35 40 45

% Change in LDL-Cholesterol

ALLHAT-LLT

LIPID

WOSCOPS

HPS

CARE

% C

han

ge in

CH

D

Even

t R

ate

LIPS

4S

Adapted from JAMA. 2002;288:2998-3007 and Circulation 2005; 111: 2280-2281.

Prove-It

ASCOT

TNT

A to Z

LRC-CPPT

RelativeRisk

for CHD

(Log Scale)

3.7

2.9

2.2

1.7

1.3

1.0

LDL-C (mg/dL)

40 70 100 130 160 190

0

1

Grundy SM et al. Grundy SM et al. CirculationCirculation 2004;110:227 2004;110:227––239.239.

1988

1993

2001

2004

Lower is Better, But How Low?Lower is Better, But How Low?

Hazard Ratio of the Primary Endpoint Compared Hazard Ratio of the Primary Endpoint Compared with with

Achieved LDL-C < 100 PROVE-IT (TIMI 22) Achieved LDL-C < 100 PROVE-IT (TIMI 22) Substudy* Substudy*

*Adjusted for age, gender, baseline LDL-C, diabetes mellitus, and prior MI.

Lower better Higher worse0 1 2

> 80-100

> 60-80

> 40-60

40

Referent

0.80 (0.59, 1.07)

0.67 (0.50, 0.92)

0.61 (0.40, 0.91)

Hazard Ratio

Ach

ieve

d L

DL

-C (

mg

/dL

)

n = 256

n = 631

n = 576

n = 193

Wiviott SD et al. JACC. 2005;46:1411-1416.

Atorvastatin 80 mg vs pravastatin 40 mg in 2099 ACS patients for 24 months

Endpoint: CHD death, nonfatal MI, CVA, recurrent ischemia, revascularization

JUPITER: Event* Reduction Among JUPITER: Event* Reduction Among Subjects Subjects

Attaining LDL-C <50 mg/dLAttaining LDL-C <50 mg/dL

*Events: MI, stroke, revascularization, UA, and CV death.** P = 0.0001.

0 0.1 1 10

Placebo

LDL-C not <50 vs Placebo

LDL-C <50† vs Placebo

LDL-C <50 vs not <50

0.76 (0.57, 1.00)

0.35 (0.25, 0.49)**

0.39 (0.26, 0.59)**

Hazard Ratio

Hsia J et al. JACC. 2011;57:1666-1675.

Rosuvastatin 40 mg vs placebo in 17,802 patients with LDL-C < 130 mg/dL and hsCRP > 2.0

n = 8150

n = 4000

n = 4154

† Median 44 mg/dLRange 38-50 mg/dL

Target : New Rx To reduce LDL

לא על ידי LDLמחקרים חדשים על הורדת סטטינים .

חולים בסיכון בינוני עד גבוה על מקסימום טיפול נסבל.

דב גביש וולפסון

1313

3 Genes Affecting LDL Uptake Can Cause FH

Apo B: acts as ligand binding LDL particle to receptor (APOB gene, 1:1,000)LDL Particle

Liver cell

Circulation

LDLR: on hepatocyte, binds to Apo B on LDL particle, inducing endocytosis of LDL

(LDLR mutations, 1:500 )PCSK9 Enzyme: degrades LDL receptors (PCSK9 mutations, 1:2,500)

1,000+ mutations identified to date

1. Kumar V, Abbas AK, Fausto N, et al. Robbins and Cotran Pathologic Basis of Disease. 2009.2. Rader DJ, Cohen J, Hobbs HH. J Clin Invest. 2003;111:1795–1803.Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

1414

FH-related Genes Affect Uptake of LDL Particles

LDL Particle

Liver cell

Circulation

Apo B: acts as ligand binding LDL particle to receptor

LDLRinduces endocytosis of LDL

into hepatocyte PCSK9: enzyme that degrades LDL receptors

14


1515

Apo B

LDL Particle

LDLR

LDLR binding site prevents binding of ApoB

Normal FH: LDLR

LDLR Mutations Change the Shape of Receptors, Preventing Binding of LDL Particles


1616

APOB Mutations Affect the Shape of Apo B and Ability to “Grab” the LDL Receptor

Apo B

LDLR

Mutation impairs Apo B binding ability to LDL

receptor

LDL Particle

Normal FH: Apo B


1717

PCSK9 Mutations Increase Degradation of the LDLR, Preventing Binding and Endocytosis

Apo B

PCSK9

LDLR

LDLR are degraded at a faster rate by increased PCSK9 activity

LDL Particle

Normal FH: PCSK9+


Inherited Syndromes of Extremes Inherited Syndromes of Extremes of LDL-C: Story of PCSK9of LDL-C: Story of PCSK9

Fre

qu

en

cy (

%)

LDL-C

Gain of function mutations in PCSK9

Loss of function

mutations in PCSK9

Concept of Lifetime Cumulative LDL-C Concept of Lifetime Cumulative LDL-C Exposure and Vascular RiskExposure and Vascular Risk

Age (years)Age (years)

0 20 40 60 80

Horton, Cohen, Hobbs Journal of Lipid Research 2009

Cu

mu

lati

ve L

DL

Exp

osu

reC

um

ula

tive L

DL

Exp

osu

re HoFHHoFH HeFH HeFH Normal NormalHoFH HeFH Normal

Concept of Lifetime Cumulative LDL-C Concept of Lifetime Cumulative LDL-C Exposure and Vascular RiskExposure and Vascular Risk

Age (years)Age (years)0 20 40 60 80

Horton et al, J Lipid Res 2009: 50: S172-S177

Cu

mu

lati

ve L

DL

Exp

osu

reC

um

ula

tive L

DL

Exp

osu

re

HoFH HeFH High Risk Mod Risk

PCSK9 LOFPCSK9 GOF

% LDL-C Change at 2 Weekly Intervals % LDL-C Change at 2 Weekly Intervals from Baseline to Week 12 with SAR236553from Baseline to Week 12 with SAR236553

22

Mean % change in LDL-C from baseline to weeks 2, 4, 6, 8, 10, and 12, by Q2W treatment group.

LDL-

C M

ean

(S

E)

% C

hang

e f

rom

Bas

elin

e

∆ - 8.5%

∆ - 30.5%

∆ - 53.6%

∆ - 62.9%

∆ - 64.2%

∆ - 5.1%

∆ - 39.6%

∆ - 72.4%

McKenney et al. J Am Coll Cardiol 2012;59 2344-2353

-100

The Impact of Atorvastatin Dose on The Impact of Atorvastatin Dose on % LDL-C Change With SAR236553% LDL-C Change With SAR236553

LS mean (±95% CI) percentage change in calculated LDL-C from baseline to Week 12 for each dose/regimen

SAR23655SAR236553350 mg Q2W 200 mg Q4W 300 mg Q4W 100 mg Q2W 150 mg Q2W

LD

L-C

Mean

(+

/- 9

5%

CI)

%

LD

L-C

Mean

(+

/- 9

5%

CI)

%

Ch

an

ge f

rom

Baselin

e t

o W

eek 1

2

Ch

an

ge f

rom

Baselin

e t

o W

eek 1

2

vs.

Pla

ceb

ovs.

Pla

ceb

o

0

-20

-40

-60

-80 Atorvastatin 10 mg (N=66)Atorvastatin 20 mg (N=69)Atorvastatin 40 mg (N=44)


Changes in Apo B, nonHDL-C, and Lp(a) from Changes in Apo B, nonHDL-C, and Lp(a) from Baseline to Week 12 with SAR236553 (“565” Baseline to Week 12 with SAR236553 (“565”

Study”)Study”)

% C

han

ge

fro

m B

asel

ine

to W

eek

12

1LS mean (SE)2median (Q1-Q3)* p < 00001† p = 0.0022


10

0

-10

-20

-30

-40

-50

-60

-70

Apo B nonHDL-C Lp(a)

-2% -2%

-34%*

-56%*

-63%*

-0%

-13%†

-26%*-29%*-27%*

-48%*

-56%*

ApoB & LDL-C ResponseApoB & LDL-C ResponseMean % Change from Baseline, Day 57Mean % Change from Baseline, Day 57

%

* P < 0.0001 vs. Placebo† P < 0.01 vs. Placebo

****

**

†**

**

**

Stein et al NEJM 2012; 366:1108-18

Dias et al Presented at ACC, Chicago. March 25, 2012

LD

L-C

Mea

n (

SE

) %

Ch

ang

e fr

om

Bas

elin

e

BSL 120.6 mg/dLWK8 40.4 mg/dL∆ - 66.2%

BSL 121.1 mg/dLWK8 100.0 mg/dL∆ - 17.3%

BSL 126.9 mg/dLWK8 36.8 mg/dL∆ - 73.2% *

**P<0.0001 vs PL + A80mg

% LDL-C Change at 2 Weekly Intervals % LDL-C Change at 2 Weekly Intervals

from Baseline to Week 12 with from Baseline to Week 12 with SAR236553SAR236553

Roth EM et al. N Engl J Med, Published online Oct 31, 2012

Antisense Technology as a New Approach Antisense Technology as a New Approach for Drug Discoveryfor Drug Discovery

Mechanism of Action Mechanism of Action Antisense OligonucleotideAntisense Oligonucleotide

DNA mRNA Disease-Associated Protein

Transcription Translation

Antisense Drug (Oligonucleotide)

Transcription

Traditional Drug

No Disease-Associated Proteins Produced

RNaseH Degrades RNA No

Translation

Goldberg AC. J Clin Lipidol. 2010;4:350-6.

Inhibition of Apo B-100 productionInhibition of Apo B-100 production

Cholesterol

Apo B Triglyceride

VLDL

VLDL IDL

LDL1LDL2 LDL3

Lp(a)

► Apo B-100 is an important Apo B-100 is an important structural and functional structural and functional component of lipoproteins component of lipoproteins

► Blocking Apo B-100 production Blocking Apo B-100 production blocks VLDL, LDL and Lp(a) blocks VLDL, LDL and Lp(a) productionproduction

Apo B antisense

(Mipomersen)

Inhibition of Apo B-100 productionInhibition of Apo B-100 production

Cholesterol

Apo B Triglyceride

VLDL

► Apo B-100 is an important Apo B-100 is an important structural and functional structural and functional component of lipoproteins component of lipoproteins

► Blocking Apo B-100 production Blocking Apo B-100 production blocks VLDL, LDL and Lp(a) blocks VLDL, LDL and Lp(a) productionproduction

Apo B antisense

(Mipomersen)

Mipomersen Monotherapy: Mipomersen Monotherapy: Dose Ranging Phase 2 Trials Dose Ranging Phase 2 Trials

Kastelein et al Circulation 2006; 114:1729-1735

Mipomersen in Homozygous FH: Early Mipomersen in Homozygous FH: Early StudiesStudies

ApoB and LDL-C Reductions*ApoB and LDL-C Reductions*

ApoB LDL-C

*300 mg per week

Inhibition of MTPInhibition of MTP

Cholesterol

Apo B Triglyceride

VLDL

► MTP is an important enzyme MTP is an important enzyme required for lipidation of Apo B and required for lipidation of Apo B and formation of VLDL in liver and formation of VLDL in liver and chylos in gutchylos in gut

► Blocking MTP reduces hepatic Blocking MTP reduces hepatic VLDL, LDL and Lp(a) production VLDL, LDL and Lp(a) production and intestinal chylomicron and intestinal chylomicron formationformation

MTPi(lomitapide)

VLDL IDL

LDL2

LDL1

LDL3Lp(a)

Inhibition of MTPInhibition of MTP

Cholesterol

Apo B Triglyceride

VLDL

► MTP is an important enzyme MTP is an important enzyme required for lipidation of Apo B and required for lipidation of Apo B and formation of VLDL in liver and formation of VLDL in liver and chylos in gutchylos in gut

► Blocking MTP reduces hepatic Blocking MTP reduces hepatic VLDL, LDL and Lp(a) production VLDL, LDL and Lp(a) production and intestinal chylomicron and intestinal chylomicron formationformation

MTPi(lomitapide)

Documents

Dov Gavish MD הטיפול בחולים בסיכון גבוה לאור המלצות ESC2011-2012 מאי 2013 ההסתדרות הרפואית בישראל – החברה לחקר, מניעה