Ipercolesterolemia familiare: come riconoscerla, come ... · patologia genetica clinicamente...

U n i t à O p e r a t i v a d i C a r d i o l o g i a

Ospedale di Arzignano - Ovest Vicentino

Ipercolesterolemia familiare: come riconoscerla, come trattarla?

Claudio Bilato

UOC di Cardiologia, ULSS 5 Ovest Vicentino



Il caso:

• Paola, ♀ 54 anni, non precedenti di rilievo;

• Giunge in PS per comparsa di dolore toracico oppressivo, intensità 7/10, retrosternale, irradiato alla base del collo, associato a sudorazione ed astenia, no cardiopalmo, no dispnea, insorto nel pomeriggio verso le 16.30 rincasando in bicicletta dal lavoro, temporaneamente regredito con il riposo per ripresentarsi acuto alle 21 circa dopo cena, per cui allertava il 118; la sintomatologia migliorava in ambulanza dopo nitrati s.l.

• obiettività cardiovascolare, polmonare e neurologica negative

• Esami urgenti: emocromo, PT, INR, ionemia, funzionalità renale, D-dimero nella norma, hs-PCR 2,8 mg/L, Troponina I: 4,3 ng/ml (v.n. <0.015)



ECG



Prima Dopo

Coro/PCI primaria



Decorso e dimissione

• Picco troponinaalla 12 ora dall’ingresso pari a 10,3 ng/mL, Emocromo, formula leucocitaria, VES, PT, INR, ionemia, funzionalità renale ed epatica, glicemia, profilo proteico plasmatico, esame urine nella norma. TSH nella norma, CT 348 mg/dl, LDL-C 290 mg/dl, HDL-C=45 mg/dl, TG 64 mg/dl.

• Ecocardio post PCI: Ventricolo Sn di forma, volume e spessori parietali nella norma, lieve ipocinesia segmenti infero-posteriore, FE 61%, sezioni destre nella norma. Aorta bulbo ed ascendente nella norma, noduli calcifici su cuspidi aortiche. Esame Doppler nella norma

• EcoDoppler TSA: lesione in parte calcifica a margini regolari, al bulbo-origine della carotide sinistra con stenosi del 55%. IMT max 1,8 mm a Dx

• Dimessa in V giornata con diagnosi di: STEMI inferiore in paziente dislipidemicae con terapia con: ASA 100 mg/die, clopidogrel 75 mg/die, atorvastatina 80 mg/die, metoprololo 50 mg due volte al dì, ramipril 2,5 mg due volte al dì.

Va tutto bene?



Anamnesi e obiettività clinica

• Padredeceduto per IMA a 61 anni, PTCA a 54 anni, iperteso, ipercolesterolemico; zio paterno by-pass AC a 58 anni, IMA a 64, fumatore; un fratellodi 51 sottoposto a TEA carotide dx a 50 anni, ipercolesterolemico in terapia, un fratello di 47 anni riferito sano;

• In menopausada due anni, no HRT

• Nessuna patologia di rilievo da segnalare, talora fastidio tipo «tendinite» all'Achilleo sn dopo tennis; riferisce riscontro di ipercolesterolemia(≈360 mg/dl) dall’età di circa 30 anni trattata con dieta (mai data eccessiva importanza)

• xantomaal tendine d’Achille sinistro, ed ispessimento dell’achilleo destro

•• classica paziente in prevenzione secondaria?

• il colesterolo è solo fattore di rischio o è «la malattia» che ha portato alla coronaropatia precoce?



Consensus Statement of the EAS, European Heart Journal , 2013

Se la paziente fosse affetta da ipercolesterolemia familare?



Ipercolesterolemia familare(FH): patologia genetica clinicamente riconoscibile

• Patologia genetica, autosomica dominante1

• Comunemente dovuta a mutazioni del gene per ilrecettoredelle LDL2,3 che conduce a ridotta clearance delle LDL nelplasma1

• Altre mutazioni note includono il gene per Apo B e PCSK9

• Manifestazioni cliniche1,2

• Grave ipercolesterolemiada accumulo di LDL

• Accumulo di colesterolo nei tendini (xantomi), pelle edocchi (xantelasmi, gerontoxon)

• Evidenza di patologia cardiovascolare precoce

1. Marais AD. Clin Biochem Rev. 2004; 2. Mahley RW, Williams Textbook of Endocrinology. 2008; 3. Rader DJ, J Clin Invest. 2003



Nel ns. caso vi sonoelementi di sospetto?

• Familiaritàper CHD prematura (padre, zio)

• Padre e fratello ipercolesterolemici(quali valori?)

• La nostra paziente con CHD prematura (54 anni)

• Presenza di xantomi tendineinella paziente

• Valori elevati di LDL-C (290 mg/dl), senza statina



Ipercolesterolemia Familiare EterozigoteCriteri per la Diagnosi del Dutch Lipid Clinic Network (DLCN)

Consensus Statement of the EAS, European Heart Journal, 2013



Nella nostra paziente

Consensus Statement of the EAS, European Heart Journal, 2013

Score DLCN= 14Diagnosi CERTA di Ipercolesterolemia

Familiare!



The most cost-effective approach for identification of new FH subjects is cascade screening of family

members of known index cases



Ipercolesterolemia Familiare:le dimensioni del problema

patologia sotto-diagnosticata e sotto-trattata

FH diagnosticati, % basata sulla prevalenza nazionale stimata

Numero di pazienti FH ( basato su prevalenza 1/500 ) FH diagnosticati (stima)

33,300 Netherlands

9,900 Norway

600 Iceland

15,600 Switzerland

123,000 United Kingdom

92,200 Spain

22,200 Belgium

10,900 Slovakia

11,100 Denmark

100,000 South Africa

45.000 Australia

14,100 Hong Kong

130,900 France

46,300 Taiwan

121,000 Italy

5,700 Oman

621,200 USA

68,600 Canada

254,800 Japan

34,300 Chile

381,500 Brazil

214,900 Mexico

71%

43%

19%

13%

12%

6%

4%

4%

4%

3%

1%

1%

1%

1%

<1%

<1%

<1%

<1%

<1%

<1%

<1%

<1%

Consensus Statement of the EAS, Eur Heart J, 2013



Prevalenceof Definite or ProbableFH Accordingto the DLCN* Criteria

Copenhagen General Population Study by 20-year age class and gender based on 69.016 individuals

Pre

vale

nce

(%

)

Pre

vale

nce

(ra

tio)

WomenMen

Age (years)

1/100

1/133

1/200

1/400

1.0

0.75

0.5

0.25

020-39 40-59 60-79 80+ all

Benn et al. JCEM 2012;97:3956-64

PREVALENZA REALE (1/200-300): SUPERIORE

RISPETTO A QUELLA STIMATA (1/500)!

In Italia circa 250.000 pazienti con FH



CHD risk as function of the DLCN Criteria for a Diagnosis of FH in Individuals Off Lipid-lowering Medication from the General Population

X 13

No. dipartecipanti

No. diCHD

Odds ratio (95% CI)

FH improbabile

FH possibile

FH certa o probabile

260

3,380

58,158 2,592

604

84

1 (reference)

4.8 (4.3−5.3)

13.2 (10.0−17.4)

0.5 1 2 4 8 16 32

Benn, J Clin Endocrinol Metab 2012

Se non trattati, gli uomini e le donne con Ipercolesterolemia Familiare eterozigote vanno incontro a eventi cardiovascolari prima di 50 e 55 anni rispettivamente



Cumulative Burden of LDL-C in Individuals With and Without FH as Function of Age

Starr, Clin Chem Lab Med 2008Huijgen, Circ Cardiovasc Genet 2012

Acc

um

ula

tion

of L

DL-

Cm

mo

l/L/y

ears

Age (Years)

Women

SmokingHypertensionDiabetes↑Triglycerides↓HDL-C↑ Lp(a)

Thresholdfor CHD

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 65

200

150

100

50

0

Homozygous FH

12.5 yrs

Heterozygous FH

35 yrs

No FH

55 yrs


Ospedale di Arzignano - Ovest Vicentino Watts, Heart, Lung and Circulation 2012

Definite or probable FH 54%

Possible or unlikely FH 46%

On statin therapy 38%

Not on statin therapy 62%

1334 patients with premature (<55 year in men, <60 year in women) CAD admitted to a Department of Cardiology



Cumulative Burden of LDL-C in Individuals With and Without FH as Function of Age

Starr, Clin Chem Lab Med 2008Huijgen, Circ Cardiovasc Genet 2012

Acc

um

ula

tion

of L

DL-

Cm

mo

l/L/y

ears

Age (Years)

Women

SmokingHypertensionDiabetes↑Triglycerides↓HDL-C↑ Lp(a)

Thresholdfor CHD

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 65

200

150

100

50

0

Homozygous FH

12.5 yrs

Heterozygous FH

35 yrs

No FH

55 yrs



Ipercolesterolemia familiare: come trattarla

•statine + ezetimibe• inibitori della PCSK9• lopitamide•aferesi delle LDL



Ipercolesterolemia familiare: goal di trattamento

LDL-CFH Target #1

in tutte leLinee Guida

FH senza CVD (rischio CV elevato)

LDL-C < 100 mg/dl

ESC/EAS Guidelines - Eur Heart J 2011

Pazienti FH: NON vanno utilizzate le carte del rischio (es. SCORE)

FH con CVD (rischio CV molto elevato)

LDL-C < 70 mg/dl



Cumulative coronary heart disease-free survival among patients with FH according to statin treatment

• absolute risk of first onset of coronary heart disease was 11/1000 person year in statin treated patients compared with 119/1000 person year in untreated patients.

• after adjustment for year of birth and sex, statin treated patients had a 76% reduction in risk of coronary heart disease compared with untreated patients

BMJ 2008;337:a2423

P<0.001



Baseline LDL-CReduction to reach an

LDL-C Target <100 mg/dLReduction to reach an

LDL-C Target <70 mg/dL

>200 >50% >50%

180-200 45-50% >50%

160-180 40-45% >50%

LDL-C>50%

LDL-C<50%

Medium HighStatin dose*

StatinsEzetimibe

HeFH

Riduzione del colesteroloLDL con lestatine disponibili a vari dosaggi

Solo 1 su5 pazientiFH raggiunge

i target di LDL-C raccomandati!



LDL-C Reductionwith StatinMonotherapyand StatinPlus Ezetimibe: GRAVITY

Ballantyne CM et al. Presented at EAS, 2013

Primary Endpoint — ITT

Simva — 34.7% 2742 events

EZ/Simva — 32.7% 2572 events

HR 0.936 CI (0.887, 0.988)p=0.016

Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

7-year event rates

NNT= 50



Gli inibitori della PCSK9 (Proprotein Convertase Subtilisin-like Kexin type 9)

Genetic Variants of PCSK9 Demonstrate Its Importance in Regulating LDL Levels

PCSK9 Gain of Function = LessLDLRs

PCSK9 Loss of Function= MoreLDLRs



Hepatic LDLRs Play a Central Role in Cholesterol Homeostasis

Elaborated from 1. Brown MS, et al. Proc Natl Acad Sci 1979;76:3330-3337.Elaborated from 2. Qian YW, et al. J Lipid Res. 2007;48:1488-1498.Elaborated from 3. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547.




Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles




PCSK9 Regulates the LDLRs Surface Expression by Targeting for

Lysosomal Degradation



LDLR and PCSK9 Expression Are Both UpregulatedWhen Intracellular

Cholesterol Levels Are Low

Elaborated from 1. Goldstein JL, et al. Arterioscler Thromb Vasc Biol. 2009;29:431-438.Elaborated from 2. Dubuc G, et al. Arterioscler Thromb Vasc Biol. 2004;24:1454-1459.

*[SREBP] = sterol regulatory element-binding protein.



Blockade of PCSK9/LDLR Interaction May Lower LDL Levels

Elaborated from Chan JC, et al. Proc Natl Acad Sci U S A. 2009;106:9820-9825.



Inibitori della PCSK9

nome azienda tipo

Evolocumab AmgenAnticorpo

umano

Alirocumab Sanofi/RegeronAnticorpo

umano

Bococizumab PfizerAnticorpo umanizzato



Evolocumab: studi di fase II

trials pazienti posologia% caloLDL

ref

LAPLACE-TIMI 57

Iper CT (LDL > 85 mg/dL) on top di statine + ezetimibe

70-480 mg s.c. ogni 2-4 wks per 12 wks

-41 -66

Lancet2012

MENDELIper CT (LDL 100-190

mg/dL) no terapia o ezetmibe70-480 mg s.c. ogni 2-4 wks per 12 wks

-41 -51

Lancet2012

RUTHER-FORD

FH eterezigoti (LDL > 100 mg/dL) in statine + ezetimibe

350-480 mg s.c. ogni 4 wks per 12 wks

-43 -55

Circul2012

GAUSSAlto rischio CVS intolleranti

alle statine; + ezetimibe280-480 mg s.c. ogni

4 wks per 12 wks-41 -63

JAMA2012



Studi di fase IIItrials farmaco pazienti % LDL reduction

DESCARTES evolocumabIper CT + on statine +

ezetimibe-57% in 52

weeks

LAPLACE-2 evolocumabIper CT on top di statine vs

ezetimibe o placebo-59 -71% in 12

weeks

MENDEL-2 evolocumab Iper CT no statine vs ezetmibe-40 -57% in 12

weeks

RUTHER-FORD-2

evolocumabFH eterezigoti in statine +

ezetimibe-59 -61% in 12

weeks

GAUSS-2 evolocumabintolleranti alle statine vs

ezetimibe-70% in 12

weeks

TESLA B evolocumabFH omozigoti in statine +

ezetimibe-31% in 12

weeks

ODYSSEY mono

alirocumab Iper CT no statine vs ezetmibe-32% in 24

weeks



84 weeks

placebo n=788

2,341 patients with hypercholesterolaemia at very high risk, including patients with heterozygous FH (18%), who wereon maximally tolerated statin therapy (44% on high-dose intensive statin therapy) with or without other lipidloweringtreatment. Baseline LDL cholesterol was 3.2 mmol/L (122 mg/dL).

alirocumab (150 mg every 2 wks) n=1553

+0.8%

-61%

LD

L-C

CH

D d

ea

th, n

on-f

ata

lMI,

is

cha

em

icst

roke

, uns

tabl

ea

ngin

a

HR =.46 (95% CI 0.26 to 0.82)

p<0.01

1

2

3

Long TermOdysseytrial(a post-hoc analysis)

ESC meeting 2014



DESCARTES: Treatment Emergent Adverse Events

n (%)PlaceboN = 302

EvolocumabN = 599

Any Treatment Emergent Adverse Event 224 (74.2) 448 (74.8)

Serious 13 (4.3) 33 (5.5)

Adjudicated atherosclerotic CV events 2 (0.7) 6 (1.0)

Death 0 (0.0) 2 (0.3)

Leading to discontinuation of study drug 3 (1.0) 13 (2.2)

Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study

New Engl J Med 2014

DESCARTES:Treatment Emergent Adverse Events II

n (%)PlaceboN = 302

EvolocumabN = 599

Most Common Treatment Emergent AEs

Nasopharyngitis 29 (9.6) 63 (10.5)

Upper respiratory tract infection 19 (6.3) 56 (9.3)

Influenza 19 (6.3) 45 (7.5)

Back pain 17 (5.6) 37 (6.2)

Neurocognitive AEs* 2 (0.7) 1 (0.2)

Amnesia - Short-term memory loss 0 (0.0) 1 (0.2)

Dementia With Lewy Bodies 1 (0.3) 0 (0.0)

Encephalopathy 1 (0.3) 0 (0.0)Treatment emergent adverse events are adverse events occurring between the first dose of Study Drug and End of Study* Searched HLGT terms: Deliria (incl confusion); cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and perception; mental impairment disorders

New Engl J Med 2014



DESCARTES:Hepatic and Muscle Safety

n (%)PlaceboN = 302

EvolocumabN = 599

Liver function tests

ALT or AST > 3 × ULN* 3 (1.0) 5 (0.8)

ALT or AST > 5 × ULN* 1 (0.3) 3 (0.5)

Muscle TEAEs and Laboratory Results

Myalgia 9 (3.0) 24 (4.0)

CK > 5 × ULN* 1 (0.3) 7 (1.2)

CK > 10 × ULN* 1 (0.3) 3 (0.5)

* At any visit post baseline, TEAE = Treatment emergent adverse event

New Engl J Med 2014



DESCARTES: Glycemic ParametersChange from baseline at week 52

Placebo

Evolocumab

Diet alone

A 10 mg/d

A 80 mg/d

A 80 mg/d + E10 mg/d

n 273 63 225 131 114

Glucose, (mg/dL);mean (SE)

0.4(0.9)

-0.5 (1.5)

1.7 (1.2)

0.3 (1.0)

2.6 (1.9)

n 273 64 227 129 115

HbA1C, (%); mean (SE)

0.00(0.03)

–0.09 (0.04)

0.04 (0.02)

–0.02 (0.03)

0.09 (0.04)

A = Atorvastatin E = Ezetimibe

New Engl J Med 2014



-50%

84 weeks

Morte coronarica, IMA non

fatale, stroke, angina instabile

-50%

Dopo 24 settimane

on the top of statin

Rid

uzi

on

e d

i C

-LD

L

Iniezione

sottocute ogni 15

gg

Eventi avversi non differenti

tra trattamento e placebo

BloodVessel

Chylomicron

ChylomicronRemnant

ER

Lumen

Cytoplasm

Apo B100MTP

TG

VLDLLDL

ER

Lumen

Cytoplasm

Apo B48MTP

TG

NascentVLDL

NascentChylomicron

Hussain, J Lipid Res 2003

Liver Cell

IntestinalEpithelial Cell

Lopitamide: inibisce la Microsomal Triglyceride Transfer Protein (MTP) e quindi la sintesi di VLDL e chilomicroni


Ospedale di Arzignano - Ovest VicentinoData on File, Aegerion Pharmaceuticals

Riduzione del LDL-C dopo 26 settimane in 29 pazienti FH con Lopitamide

‡

Per

cent

Cha

nge

from

Bas

elin

e

‡ ‡‡ ‡ ‡

100

80

60

40

20

0

-20

-40

-60

-80

-100

#

Median

LomitapideDose (mg)

Patient ID

11-0

01

01-0

06

23-0

02

23-0

03

22-0

03

01-0

02

13-0

01

13-0

0202

-001

12-0

03

33-0

01

12-0

04

12-0

01

01-0

04

35-0

01

32-0

01

02-0

02

32-0

02

22-0

04

23-0

01

31-0

01

31-0

02

12-0

05

11-0

03

11-0

04

11-0

0212

-006

01-0

01

01-0

03

Mean

‡

Per

cent

Cha

nge

from

Bas

elin

e

‡ ‡‡ ‡ ‡

100

80

60

40

20

0

-20

-40

-60

-80

-100

5 (n=3)

10 (n=2)20 (n=6)40 (n=7)60 (n=11)

#

Median

11-0

01

01-0

06

23-0

02

23-0

03

22-0

03

01-0

02

13-0

01

13-0

0202

-001

12-0

03

33-0

01

12-0

04

12-0

01

01-0

04

35-0

01

32-0

01

02-0

02

32-0

02

22-0

04

23-0

01

31-0

01

31-0

02

12-0

05

11-0

03

11-0

04

11-0

0212

-006

01-0

01

01-0

03

240.

3

307.

0

152.

4

414.

5

260.

1

427.

0

305.

1

230.

5

157.

5

382.

6

476.

8

247.

322

8.4

500.

0

216.

4

357.

1

408.

5

165.

7

565.

0

477.

6

181.

2

396.

2

448.

8

328.

0

280.

0

414.

6

437.

7

388.

5

378.

5 Received apheresis

# Patient was a responder at later time points during the study.‡ Patients discontinued from the study. Numbers over the bars are baseline LDL-C in mg/dL

• 27/29 patients had a history of CVD at baseline

• 10 (35%) of 29 patients had undergone CABG surgery

• 5 of these patients were ≤21 years of age

• 3 patients under the age of 8 at the time of open-heart surgery

• 3 patients had undergone multiple CABG procedures

• Coronary angioplasty was performed in 3 patients (10%)

• Aortic valve replacement in 3 patients (10%) Mitral valve replacement or repair in 3 patients (10%)



Mea

n %

Cha

nge

from

B

asel

ine

(95%

CI)

Study Week

Efficacy Phase Safety Phase

%of

pat

ient

s w

ith

Gas

troi

ntes

tinal

eve

nts

Study Week

Cuchel, Lancet 2013



Aferesi delle LDL



Effetti della rimozione extracorporea delle LDL

Schuff-Werner, Clin Res Cardiol 2012



L’ aferesi delle LDL riduce gli eventi coronarici nei pazienti con ipercolesterolemia familiare

Lui, J Lipids 2014


Ospedale di Arzignano - Ovest Vicentino Leebmann, Circulation 2013

*p<0.0001



• E’ possibile fare diagnosi clinica!!

• Solo 1 su 5 FH a target per LDL-C

• La maggior parte dei pazienti FH necessita di ridurre il LDL-C di >60%

• Molti FH in statina + ezetimibe a dosiinsufficienti per raggiungere i target di LDL-C

• Nuovi farmaci molto promettenti

IpercolesterolemiaFamiliare:sottodiagnosticatae sottotrattata

Ipercolesterolemia familiare: come riconoscerla, come ... · patologia genetica clinicamente...

Documents

Transcript of Ipercolesterolemia familiare: come riconoscerla, come ... · patologia genetica clinicamente...