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Familial Hypercholesterolemiadiagnosis and treatment:
Can we perform better?
G.K. Hovingh MD PhD MBAdept of vascular medicine Academic Medical Center
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?
