familial hypercholesterolemia diagnosis and treatment · familial hypercholesterolemia diagnosis...

Familial Hypercholesterolemiadiagnosis and treatment:

Can we perform better?

G.K. Hovingh MD PhD MBAdept of vascular medicine Academic Medical Center

the Netherlandsg.k.hovingh@amc.uva.nl

9th International Congress of Internal MedicineAthens, Greece

Disclosure

- Consultant and/or speaker for pharmaceutical companies that developmolecules that influence lipoprotein metabolism,

including Regeneron, Pfizer, MSD, Sanofi, Amgen

- PI for clinical trials in dyslipidemia conducted with i.e.Amgen, Sanofi, Eli Lilly, Novartis, Kowa, Genzyme, Cerenis, Pfizer,

Dezima, Astra Zeneca

- Research grants: ZonMW, EU, Amgen, Sanofi, AstraZeneca Aegerion, Synageva

The department and/or Vascular Research Foundation receives the honoraria and investigator fees.

Screeningorganisation, efficacy, ROI

Treatmentold and new

Phenotypelipids, CVD and others

Geneticswhy, how, and what next

Guidelinesinternational collaboration

F H

Familial Hypercholesterolemiamultiple aspects

Screeningorganisation, efficacy, ROI

Treatmentold and new

Phenotypelipids, CVD and others

Geneticswhy, how, and what next

Guidelinesinternational collaboration

F H

Familial Hypercholesterolemiadiagnosis and treatment

“portrait of an elderly lady” by Frans Hals (1582 -1666)

Steinberg DJ, Lipid Res 2005;46:179-190

Professor Carl Müller, 1886-1983

Angina Pectoris In Hereditary Xanthomatosis

Archives of Internal Medicine1939.

76 cases from 17 Norwegian families

Enormous thickening of the Achilles tendons due to cholesterol deposition

“…the syndrome of cutaneous xanthomatosis, hypercholesterol-emia and angina pectoris presents itself as a well defined clinical entity… There can be hardly any doubt but that xanthomatous deposits in the coronary artery and consecutive myocardial ischemia are the cause of angina pectoris.”

Müller C: Arch Intern Med, 1939

Cholesterol accumulation

Diagnostic Criteria heFH (Dutch Lipid Network Criteria (DLCN))

Nordestgaard B et al European Heart Journal (2013) 34, 3478–3490

Group 1: Family historya) First degree relative with known premature (<55 years men; <60 years women) coronary heart disease (CHD) ORb) First degree relative with known LDL cholesterol >95th percentile by age and gender for countryc) First degree relative with tendon xanthoma and/or corneal arcus ORd) Child(ren) <18 years with LDL cholesterol >95th percentile by age and gender for country

Points1

1

22

Group 2: Clinical historya) Subject has premature (<55 years men; <60 years women) CHDb) Subject has premature (<55 years men; <60 years women) CVA or PAD

21

Group 3: Physical examinationa) Tendon xanthomab) Corneal arcus in a person <45 years

64

Group 4: Biochemical results (LDL cholesterol)

>8.5 mmol/L (>325 mg/dL)6.5-8.4 mmol/L (251-325 mg/dL)5.0-6.4 mmol/L (191-250 mg/dL)4.0-4.9 mmol/L (155-190 mg/dL)

8531

Group 5: Genetic testing (DNA analysis)a) Causative mutation shown in the LDLR, APOB or PCSK9 genes 8

Frequency of FH in the population

a) 1 in 100b) 1 in 250c) 1 in 500d) 1 in 2000

Familial Hypercholesterolemia: more prevalent than previously described

The Initial ReportheFH 1:500

Goldstein et al J Clin Invest. 1973;52:1544-1568

Copenhagen Heart Study

Benn et al JCEM 2013

FH, highly prevalent amongst patients with ACS

Nanchen et al. European Heart Journal (2015) 36, 2438–2445 doi:10.1093/eurheartj/ehv289

The American way...

Do et al Nature 2015

LDLR sequence data from >9000 IDs:controls : 1 in 217

CVD: 1 in 51RR 4-13

Who to Screen?

Nordestgaard B et al European Heart Journal (2013)

1) TC ≥8 mmol/L (≥310 mg/dL) in adult / adult family member(s) (or >95th percentile by age and gender for country) (children: TC ≥6 mmol/L (≥230 mg/dL)

2) premature CHD in the subject or family member(s),

3) tendon xanthomas in subject or family member(s),

4) sudden premature cardiac death in a family member.

Who to screen and how to diagnose? a practical German approach

Laufs and Parhoffer EHJ 2016 (editorial with Odyssey)

LDL-C >4.9 mmol/l (190 mg/dl)(children >4 mmol/l (155 mg/dl)

positive family historyfirst degree family member with-LDL-C >4.9 mmol/lOR- premature CVD (M<55, F<60)OR - xantoma

presence of xantoma orarcus <45 yrs

OR

Clinical FH

+

LDL-C <100mg/dl or <70mg/dl

Screening models

- Case finding by large-scale “universal” screening- Cascade screening: genetics- Cascade screening: lipids- Cascade screening: combined lipids - genetics

Molecular FH: genetic cascade screening

•

Molecular FH present Molecular FH absent Molecular FH unknown

Molecular FH: genetic cascade screening

•

Molecular FH present Molecular FH absent Molecular FH unknown

Autosomal Dominant Hypercholesterolemia

• In vast majority of FH patients causal genetic mutation can be discovered1-2

• LDLR (>90%), •APOB (5%), •PCSK9(< 1%).

• Molecular diagnosis enables genetic cascade screening.

1Austin MA, et al Am J Epidem 2004;160:407-420.2van der Graaf, et al. Circulation. 2011;123:1167-73.

J Clin Lipidol. 2016 Jul-Aug;10(4):748-56.

41 LDLR mutationsNo APOB and PCSK9 mutationsFounder effect in northern part of Greece

• HoFH: 1:300.000

• heFH: 1:220

FH detection

Universal screening

Elevated LDL-C levels; always FH?

No,... phenocopies

FH; “one disease?”

clinical +, mutation -

clinical -, mutation +

EAS-consensus

patient: treat LDL-Cfamily: “monitor LDL-C”

patient: treat LDL-Cfamily: mutation test consider to treat LDLC

patient: monitor LDL-Cfamily: monitor LDL-C

The prevalence of mutations;

a population studyLDLR, APOB and PCSK9 were sequenced in 26,025 IDs; 5,549 CAD , 8,577 CAD free, and 11,908 IDs from prospective studies

Khera A et al JACC 2016;67:2578

Diagnostic Criteria heFH (Dutch Lipid Network Criteria (DLCN))

Nordestgaard B et al European Heart Journal (2013) 34, 3478–3490

Group 1: Family historya) First degree relative with known premature (<55 years men; <60 years women) coronary heart disease (CHD) ORb) First degree relative with known LDL cholesterol >95th percentile by age and gender for countryc) First degree relative with tendon xanthoma and/or corneal arcus ORd) Child(ren) <18 years with LDL cholesterol >95th percentile by age and gender for country

Points1

1

22

Group 2: Clinical historya) Subject has premature (<55 years men; <60 years women) CHDb) Subject has premature (<55 years men; <60 years women) CVA or PAD

21

Group 3: Physical examinationa) Tendon xanthomab) Corneal arcus in a person <45 years

64

Group 4: Biochemical results (LDL cholesterol)

>8.5 mmol/L (>325 mg/dL)6.5-8.4 mmol/L (251-325 mg/dL)5.0-6.4 mmol/L (191-250 mg/dL)4.0-4.9 mmol/L (155-190 mg/dL)

8531

Group 5: Genetic testing (DNA analysis)a) Causative mutation shown in the LDLR, APOB or PCSK9 genes 8

Screeningorganisation, efficacy, ROI

Treatmentold and new

Phenotypelipids, CVD and others

Geneticswhy, how, and what next

Guidelinesinternational collaboration

F H

Familial Hypercholesterolemiamultiple aspects, a personal view

FH: Importance of early treatmentIM

T

0.8

10 80Age (years)

40

DUTCH EXPERIENCE: FH undertreated

Pijlman et al Athersoclerosis 2009

Atherosclerosis. 2016 Jun;249:17-21. doi:

320 patients with STEMI < 35 years20.3 % definite/probable FH (DLCN)2 years after ACS: 84.3% statin2.3% LDL-C <1.8mmol/LMean 9.1 years after event: event 33.8%FH: HR: 1.6

Retrospective analysis:combining StOEH, Pharmo and

hospital ICD code databases

primary outcome: all cause mortality, CVD

Cox proportional analysis, Inverse Probability-of-Treatment Weighing

Absolute numbers: lifetime risk for first event- untreated FH: 103 in 100.000 person-years- treated: 58- unaffected family member: 29

•Affected family members with:

•Total cholesterol in 90th percentile,Tendon xanthomas, CHD Early MI Stroke

PCSK9- a major breakthrough

Screeningorganisation, efficacy, ROI

Treatmentold and new

Phenotypelipids, CVD and others

Geneticswhy, how, and what next

Guidelinesinternational collaboration

F H

Familial HypercholesterolemiaConclusions

Diverse, CVD risk increased

Crucial: classification of risk and novel biology. NGS

“Too late, too little.” Novel

therapies around the corner

Collaboration = key in order to expand

knowledge

Screening is cost effective

Familial Hypercholesterolemiadiagnosis and treatment:

Can we perform better?