NOVEDADES EN TRATAMIENTO HIPOLIPEMIANTEfármacos hipolipemiantes (ezetimibe) para disminuir los...

NOVEDADES EN TRATAMIENTO

HIPOLIPEMIANTE

Miguel Ángel Cobos Gil. H Clínico San Carlos. Madrid

The Statin Decade:For LDL: “Lower is Better”

0

5

10

15

20

25

30R² = 0.9029p < 0.0001

LDL Cholesterol (mg/dl)

CH

D E

ven

ts (

%)

Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

30 50 70 90 110 130 150 170 190 210

4S

CARE

LIPID

HPS

PROVE IT –TIMI 22

TNT

Recent Coronary IVUS Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

MedianChange

In PercentAtheroma

Volume(%)

Mean Low-Density Lipoprotein Cholesterol (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

A-Plusplacebo

ACTIVATEplacebo

Relationship between LDL-C and Progression Rate

ASTEROIDrosuvastatin

r2= 0.95p<0.001

Nissen S. JAMA 2006

Regresión

Progresión

Control de la concentración de c-LDL

0

20

40

60

80

100

TotalCoronario

DiabéticoMixto

86,07 88,4 8781,06

cLDL > 70 …

Po

rce

nta

je(%

)

Grupos de pacientes

Pérez de Isla L, et al. Rev Clin Esp. 2012;212(10):475-81.

The Statin Decade:

EUROASPIRE IV: A ESC survey on the lifestyle, risk factor and

therapeutic management of coronary patients from 24

European countries

European Journal of Preventive Cardiology 2015

DOI: 10.1177/2047487315569401

Proportions (%) at low-density lipoprotein cholesterol target

80%

• Potencia limitado de las estatinas.

• Ningún fármaco añadido a las estatinas ha demostrado

impacto sobre eventos cv.

• Dudas sobre la seguridad. Problemas de tolerancia

• Los pacientes siguen en riesgo.

The Statin Decade:

80%

Now this is not the end, it

is not even the beginning

of the end. But it

is, perhaps, the end of the

beginning.

2014…..

Ezetimibe: Background

➢ Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1)

protein

– located primarily on the epithelial brush border of

the GI tract

– resulting in reduced cholesterol absorption

➢ When added to statin, produces ~20% further

reduction in LDL-C

C-LDL y modificaciones lipídicas

1 Yr Mean LDL-C TC TG HDL hsCRP

Simva 69.9 145.1 137.1 48.1 3.8

EZ/Simva 53.2 125.8 120.4 48.7 3.3

Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5

Median Time avg

69.5 vs. 53.7 mg/dL

Endpoint primario — ITT

Simva — 34.7%

2742 events

EZ/Simva — 32.7%

2572 events

HR 0.936 CI (0.887, 0.988)

p=0.016

Muerte cardiovascular, IMA, Angina inestable que requiere

hospitalización, revascularización coronaria (≥30 días), o ictus

7-year event rates

NNT= 50

The Statin Decade:For LDL: “Lower is Better”

0

5

10

15

20

25

30R² = 0.9029p < 0.0001

LDL Cholesterol (mg/dl)

CH

D E

ven

ts (

%)

Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

30 50 70 90 110 130 150 170 190 210

4S

CARE

LIPID

HPS

PROVE IT –TIMI 22

IMPROVE IT6652

TNT

Reduction of LDL-C to <50mg/dL reduces CV risk by 10% vs ≥50mg/dL

Giugliano et al. Presented at the European Society of Cardiology, London, 2015 (preliminary data).

-0.6

-0.7

-1.1

-0.8

-0.9

-1.0

0 25 50 75 100 125 150

Odds o

f th

e p

rim

ary

endpoin

t

(log s

cale

)

Achieved LDL-C on study drug (mg/dL) at Month 1

Adjusted HR 0.90 (0.85–0.96)

P=0.002

50mg/dL

(2.3mmol/L)

Primer estudio que demuestra un beneficio adicional cuando se añade un fármaco no estatínico (ezetimiba) al tratamiento con estatina:

SI: Reducción de C-LDL con tratamiento no-estatina EZETIMIBA reduce los eventos CV

SI: Incluso el C-LDL cuanto más bajo mejorC- LDL 53 vs. 70 mg/dL a 1 año

SI: Confirma el perfil de seguridad de Ezetimiba

- Reafirma la hipótesis del C-LDL, reduciendolo se previenen eventoscardiovasculares

Conclusiones

Updated slide kit, February 2006

16

The Heart Outcomes Prevention Evaluation

(HOPE) – 3 Trial

Eva Lonn, Jackie Bosch, Salim Yusuf

For the HOPE-3 Investigators

Population Health Research Institute, (PHRI)

McMaster University and Hamilton Health Sciences,

Hamilton, Canada

Unique Aspects of Cholesterol Lowering Arm

• No entry criteria based on lipid level. No CVD

• No routine monitoring

• No dose titration

• Low dose of rosuvastatin

CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure

Years

Cu

mu

lati

ve H

azard

Rate

s

0.0

0.0

20

.04

0.0

60

.08

0.1

0

0 1 2 3 4 5 6 7

Placebo

Rosuvastatin

HR (95% CI) = 0.75 (0.64-0.88)

P-value = 0.0004

6361 6241 6039 2122

6344 6192 5970 2073

Rosuva

Placebo23

Cholesterol Lowering: Conclusions

• Rosuvastatin 10mg/day reduced:

– LDL-C by 34.6 mg/dl (0.9 mmol/l; i.e. 27% in LDL-C)

– CVD by 25%

• Consistent benefits regardless of:

– LDL-C

– SBP

– Risk

– CRP

– Ethnicity

• Excess in muscle pain/weakness (reversible) and

perhaps cataract surgery

• No excess in rhabdomyolysis, myopathy or new diabetes27

Interpretation of the evidence for the efficacy

and safety of statin therapy

Rory Collins, Christina Reith, Jonathan Emberson, Jane Armitage, Colin Baigent, Lisa

Blackwell, Roger Blumenthal, John Danesh, George Davey Smith, David DeMets, Stephen

Evans, Malcolm Law, Stephen MacMahon, Seth Martin, Bruce Neal, Neil Poulter, David

Preiss, Paul Ridker, Ian Roberts, Anthony Rodgers, Peter Sandercock, Kenneth Schulz, Peter

Sever, John Simes, Liam Smeeth, Nicholas Wald, Salim Yusuf, Richard Peto

Published Online: 08 September 2016

Probable excepción de Pitavastatina

10,9

14,9

18,2

5,1

0

10

20

Pravastatin Atorvastatin Simvastatin Fluvastatin

PA

TIE

NT

S W

ITH

MU

SC

UL

AR

S

YM

PT

OM

S (

%)

Trial details1 Myalgia1

Trial Total No. Agent Dose, mg Duration, yr Statin Placebo

4S 4,444 Simvastatin 20–40 5.4 3.7% 3.2%

WOSCOPS 6,595Pravastatin 40

4.9 3.5% 3.7%

PROSPER 5,804 3.2 1.2% 1.1%

CARDS 2,838

Atorvastatin10

3.9 4.0% 4.8%

ASPEN 2,410 4.0 3.0% 1.6%

SPARCL 4,731 80 4.9 5.5% 6.0%

JUPITER 17,802 Rosuvastatin 20 1.9 7.9% 6.9%

Statin intolerance may be less common than the

5–18% suggested by observational data


27

LDLR

PCSK9

3. C-terminus2. Prodomain1. Catalytic

domain

PCSK9

• A serine proprotein convertase1

• Expressed in

hepatocytes, kidney

mesenchymal cells, intestinal

ileum and colon epithelia, CNS2

• Regulates hepatic LDLRs, which

bind and internalise LDL

particles3

1. Abifadel et al. Hum Mutat 2009;30:520–529.

2. Seidah et al. Proc Natl Acad Sci USA 2003;100:928–933.

3. Horton et al. J Lipid Res 2009;50:S172–S177.

1

2

3

LDL Receptor Function

and Life Cycle

LDL=low-density lipoprotein; LDLR=LDL receptor; SREBP2=sterol regulatory element-binding protein-2.Source: Semenkovich CF et al. In: Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: Elsevier Saunders; 2011:1633-1674.

8

The Role of PCSK9 in the Regulation of

LDL Receptor Expression

LDL=low-density lipoprotein; LDLR=LDL receptor; PCSK9=proprotein convertase subtilisin/kexin type 9; SREBP2=sterol regulatory element-binding protein-2. Source: Lambert G et al. J Lipid Res. 2012;53:2515–2524.

9

Impact of Alirocumab

on LDL Receptor Expression

LDL=low-density lipoprotein; LDLR=LDL receptor; PCSK9=proprotein convertase subtilisin/kexin type 9; SREBP2=sterol regulatory element-binding protein-2. Source: Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1):18-28.

1

LDL-CLDLR

proteinPCSK9

LDL-CLDLR

proteinPCSK9 X

PCSK9 Promotes Degradation of LDLRs

LDL-C=low-density lipoprotein cholesterol; LDLR=low-density lipoprotein receptor.

1


34

Loss-of-Function PCSK9 Mutations in AA Are Associated

with Low LDL-C and Low Prevalence of CHD Events

Adapted from Cohen JC. N Engl J Med 2006;354:1264-72 ARIC=Atherosclerosis Risk in the Community

30

20

10

09.7%

PCSK9142x or PCSK9679X

No Yes

12

8

4

0

0 50 100 150 200 250 300

30

20

10

00 50 100 150 200 250 300

No Nonsense Mutation

(N = 3278)50th Percentile

Plasma LDL Cholesterol in Black Subjects (mg/dL)

Fre

qu

en

cy (

%)

1.2%

PCSK9142x or PCSK9679X

(N=85)

Coro

na

ry H

ea

rt D

ise

ase

(%

)

Mean 138 mg/dL

Mean 100 mg/dL

(-28%)

Reduction in the risk of

CHD events during 15-

year follow-up

RRR 88%

LDL-C reductions were maintained over 1 year

Sabatine et al. N Engl J Med 2015;372:1500–1509.

LD

L–

C (

mg/d

L)

Standard therapy

Weeks

Evolocumab

Baseline

1,219

2,508 n =394

864

Standard therapy

Evolocumab

– LDL-C ↓ from baseline maintained with alirocumab:

• significantly greater ↓ vs PBO in COMBO I (48% vs 2% placebo; P<0.0001)

• significantly greater ↓ vs ezetimibe in COMBO II at week 24 (51% vs 21% with ezetimibe;

P<0.0001)

– Mean achieved LDL-C levels of 53.3 mg/dL in COMBO I and 53.3 mg/dL in COMBO II at

week 52 with alirocumab

– Consistent effects of alirocumab vs comparator through 52 weeks

Consistent LDL-C Reductions Over 52 Weeks

24

COMBO I COMBO II

Evolocumab is not associated with adverse CV events

60 adjudicated events of death, MI, unstable angina requiring

hospitalisation, heart failure requiring hospitalisation or coronary

revascularisation, stroke or transient ischaemic attack

0 30 60 90 120 150 180 210 240 270 300 330 365

Days since randomisation

0

1

2

HR 0.47

95% CI 0.28–0.78

P=0.003

Evolocumab plus standard of

care (n=2,976)

Standard of care alone

(n=1,489)

0.95%

2.18%

3

Cum

ula

tive C

V e

vent

incid

ence (

%)

Sabatine et al. N Engl J Med 2015;372:1500–1509.

*Based on primary endpoint for the ODYSSEY OUTCOMES trial, including CHD death, non-fatal MI, fatal and non-fatal

ischemic stroke, and unstable angina requiring hospitalization.

Unstable angina requiring hospitalization was considered based on strict criteria / clear progression of ischemia.

Post hoc Analysis of Adjudicated

Major Adverse Cardiovascular Events*

Placebo + maximally

tolerated statin ±

Alirocumab + maximally

tolerated statin ±

Cu

mu

lati

ve

pro

ba

bil

ity o

f e

ve

nt

Time (weeks)

Cox model analysis

HR = 0.52 (95% CI 0.31 to 0.90)

Nominal p-value = 0.02

No. at riskPlacebo

Alirocumab

788 776 731 700 670 653 644 597

1550 1533 1445 1392 1342 1306 12661170

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 36 52 64 78 86

0.06

0.04

0.02

0.00

0 12 24 36 52 64 7886

J. Robinson et al., N Engl J Med 2015;372(16):1489-1499

RECOMENDACIONES USO Inhibidores PCSK9SEC

DOCUMENTO SEC 2016. NECESIDADES NO CUBIERTAS CON EL TRATAMIENTO HIPOLIPEMIANTE:

IDENTIFICACIÓN DE PACIENTES PRIORITARIOS EN EL ÁMBITO DE LA ENFERMEDAD CORONARIA

….los dioses perciben el futuro,

los hombres el presente, y los sabios

lo que se avecina.

Filostrato

Pathobiological Determinants of

Atherosclerosis in Youth


45


47

Conclusiones

• Debemos optimizer el uso de las estatinas y otros

fármacos hipolipemiantes (ezetimibe) para disminuir los

eventos cardiovasculares de nuestros pacientes.

• La incorporación de los anticuerpos anti PCSK9 supone

un cambio cualitativo en el tto hipolipemiante. Podemos

curar la arteriosclerosis !!


50


51

Tasa de ocurrencia de síntomas musculares con estatinas

individuales. Estudio PRIMO

Bruckert E et al. Mild to Moderate Muscular Symptoms with High-Dosage Statin Therapy in Hyperlipidemic Patients

—The PRIMO Study. Cardiovasc Drugs Ther 2005; 19:403-14.

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Fluvastatin XL n=3121

Pravastatin n=1901

Simvastatin n=1027

Atorvastatin n=1844

5,10%

10,90%

18,20%14,90%

% p

acie

nte

s e

n t

rata

mie

nto

co

n e

sta

tin

as a

alt

as d

osis

co

n

sín

tom

as

mu

sc

ula

res

7924 pacientes dislipémicos tratados con estatinas a dosis altas


52


53


54


55

…AND PHYSIOLOGICALLY NORMAL.

Tomado de O’Keefe JH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dL. Lower is better and physiologically normal. Journal of the American College of Cardiology 2004;43(11):2142-6.

Las cifras de C-Total en cazadores-recolectores, primates salvajes y mamíferos salvajes, oscilan generalmente entre 70 y 140 mg/dL, que corresponde a concentraciones de c-LDL de aproximadamente 35 a 70 mg/dL

SERES HUMANOSCAZADORES RECOLECTORES

Hazda

Esquimales

Ikung

Pigmeos

San

Babuino

Mono aullador

Mono de noche

Caballo

Jabalí

Pécari

Rinoceronte negro

Elefante africano

PRIMATES SALVAJES

MAMÍFEROS SALVAJES

SERES HUMANOS MODERNOS

Colesterol total medio (mg/dL)

50 70 80 110 130 150 170 190 210

Norteamericano adulto


56

Patients stabilized post ACS ≤ 10 days:LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)

Standard Medical & Interventional Therapy

Ezetimibe / Simvastatin

10 / 40 mg

Simvastatin

40 mg

Duration: Minimum 2 ½-year follow-up (5314 events)

Primary Endpoint: CV death, MI, hospital admission for UA,

coronary revascularization (≥ 30 days after randomization), or stroke

N=18,144

Diseño del estudio

Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

HR Simva* EZ/Simva* p-value

All-cause death 0.99 15.3 15.4 0.782

CVD 1.00 6.8 6.9 0.997

CHD 0.96 5.8 5.7 0.499

MI 0.87 14.8 13.1 0.002

Stroke 0.86 4.8 4.2 0.052

Ischemic stroke 0.79 4.1 3.4 0.008

Cor revasc ≥ 30d 0.95 23.4 21.8 0.107

UA 1.06 1.9 2.1 0.618

CVD/MI/stroke 0.90 22.2 20.4 0.003

Ezetimibe/Simva

Better

Simva

Better

Eventos CV:Endpoints

0.6 1.0 1.4*7-year

event rates (%)

Safety — ITT

No statistically significant differences in cancer or muscle- or gallbladder-related events

Simva

n=9077

%

EZ/Simva

n=9067

% p

ALT and/or AST≥3x ULN 2.3 2.5 0.43

Cholecystectomy 1.5 1.5 0.96

Gallbladder-related AEs 3.5 3.1 0.10

Rhabdomyolysis* 0.2 0.1 0.37

Myopathy* 0.1 0.2 0.32

Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64

Cancer* (7-yr KM %) 10.2 10.2 0.57

* Adjudicated by Clinical Events Committee % = n/N for the trial duration

IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit

CTT Collaboration.

Lancet 2005; 366:1267-78;

Lancet 2010;376:1670-81.

IMPROVE-IT

Novedades ACC 2015

Risk Stratification for Cardiovascular Events in the IMPROVE-IT Trial

E.A. Bohula May, J.A. White, M.A. Blazing, R.P.

Giugliano, T.A. Musliner, A.M. Tershakovec, A.

McCagg, D.L. Bhatt, C.P. Cannon, R.M. Califf & E.

Braunwald

on behalf of the IMPROVE-IT Investigators

Risk Prediction by Quartiles -Pooled Treatment Groups

CV death/MI/Stroke/UA/Cor Revasc

Q4Q3

p-value7yr KM (%)

<0.00133.7<0.00141.5

Q2 0.01530.7

Hazard Ratio (95% CI) with REACH Q1 Score as Referent0.81.0 8.0

1.261.63

1.09

HR

Q1 -30.8Ref

CV death

Q4Q3 <0.0017.0

<0.00115.3

Q2 <0.0014.32.476.27

1.68Q1 -3.2Ref

MI

Q4Q3 <0.00114.3

<0.00116.2

Q2 0.2912.01.311.56

1.06Q1 -12.7Ref

Stroke

Q4Q3 <0.0014.9

<0.0018.3

Q2 0.0033.52.093.87

1.44Q1 -2.7Ref

Unstable Angina

Q4Q3 0.272.1

0.172.0

Q2 0.541.91.231.24

1.10Q1 -1.9Ref

Coronary Revasc ≥ 30d

Q4Q3 0.8021.6

0.8421.5

Q2 0.8522.21.010.99

0.99Q1 -24.0Ref

1.6 2.4 3.2 4.4

Subgroup Analysis by Randomized Treatment

0.7 1.0 1.2

Hazard Ratio (95% CI)

Favors EZ/simva Favors simva

CV death/MI/Stroke/UA/Cor Revasc

Q4

Q3

Simva

34.2

43.0

Q2 32.3

0.95

0.91

0.90

HR

Q1 30.90.99

Overall 34.70.94

33.2

39.9

29.1

30.7

32.7

EZ/S p-int

0.58

7yr KM (%)

EZETIMIBE ES IGUAL DE EFICAZ INDISTINTAMENTE DEL RIESGO BASAL

DEL PACIENTE

Reduction in Total (First and Recurrent) Cardiovascular Events with Ezetimibe/Simvastatin compared with Simvastatin Alone post ACS in the IMPROVE-IT Trial

Sabina A. Murphy, Christopher Cannon, Robert Giugliano, Michael

Blazing, Thomas Musliner, Andrew Tershakovec, Jennifer White, Kelly

Im, Naveen Deenadayalu, Haral Darius, Witold Ruzyllo, Andrew

Tonkin, Uma Kher, Robert Califf, Eugene Braunwald

On behalf of the IMPROVE IT Investigators

Ezetimibe en el paciente ESTABLE

Total Primary Endpoint Events

# E

ve

nts

Ezetimibe

Simvastatin

Simvastatin

Alone

45624983

Total Events

RR 0.91

P=0.007

Additional

Events

RR 0.88

(0.79-0.98)

1st Event

HR 0.936

P=0.016

-421

-251

-170

Conclusiones

➢ These data provide further support of the benefit

of continuation of intensive combination lipid

lowering therapy after a recurrent CV event

➢ Analyses of recurrent events are important as total

events have implications:

– Patient morbidity

– Need for recurrent hospitalizations

– Costs

➢ These considerations not always accounted for

when analyzing first events only

RP Giugliano1, CP Cannon1, MA Blazing2, JA

White2, SA Murphy1,

AM Tershakovec3, TA Musliner3, RM Califf2, E

Braunwald1

Baseline LDL-C and Clinical Outcomes With Addition of Ezetimibe to Statins

in18,144 Patients Post ACS:

An Analysis From IMPROVE IT†

Preliminary Results – Presented at ACC 2015 by R Giugliano

LDL-C at Admission and after 4 Monthsof Therapy by Quartiles of Admission LDL-C

Admission LDL-C (mg/dL)

63

4549

69

50

72

53

69

Me

dia

n L

DL

-C a

t 4

Mo

nth

s

(mg

/dL

)

Q1 Q2 Q3 Q4

Simvastatin Ezetimibe + Simvastatin

69

88

102118

All

≤79 79-95 95-110 ≥110Range 10-253

Median 69 88 102 118 95

95

68

49


Hazard Ratios for the Primary Endpointby Quartiles of LDL-C at Admission

0.91

0.95

0.95

0.8 1.0 1.25

FavorsEzetimibe+Simvastatin

FavorsSimvastatin

EZ/S(%) HR

Simvastatin(%)

0.93

32.7 34.7 0.936

HR

PrimaryEndpoint

69

88

102

118

2

3

1

4

Overall

Quartile

MedianLDL-c

(mg/dL)P

Value

0.33

0.068

0.38

0.24

0.017

38.0 39.0

34.0 37.1

32.0 33.0

27.1 29.4

AdjPint

0.85

0.58

0.70

Ref

95

Adj Pint= 0.77 for

Rx* LDL in quartiles

Adj Ptrend = 0.76


Early or high-intensity lipid lowering in FH patients delays onset of CHD

Nordestgaard et al. Eur Heart J 2013;34:3478–3490.

00

Age in years

Cum

ula

tive L

DL

-C (

mm

ol)

200

150

100

50

Threshold

for CHD

603 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

Without FH

55 years

35 years

Heterozygous FH

12.5 years

Homozygous FH

48 years

Start high

dose statin

53 years

Start low

dose statin

Presentaciones

Atorvastatina + Ezetimibe

¿Qué vamos a conseguir?

Weng TC et al. J Clin Pharm Ther 2010; 35:139-151Mukhtar RY et al. Int J Clin Practice; 2005; 59 (2): 239-252

• Atorvastatina 20 mg/ Ezetimibe 10mg



N Engl J Med 2014; 371:2072-2082

Novedades COLESTEROL Y GENÉTICA

N Engl J Med 2015;372:1500-9.

NOVEDADES EN TRATAMIENTO HIPOLIPEMIANTEfármacos hipolipemiantes (ezetimibe) para disminuir los...

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