Prevalence and relevance of Lp(a) in familial hypercholesterolemia - PowerPoint PPT Presentation

University of Copenhagen & Copenhagen University Hospital Prevalence and relevance of Lp(a) in familial hypercholesterolemia Børge G Nordestgaard Professor, Chief Physician, MD, DMSc Conflict of Interest Disclosure: the Danish tax payer Consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Denka Seiken, Novartis, Novo Nordisk

Early studies FH-Lp(a) association

Other early studies on elevated Lp(a) in FH • Guo HC et al. Atherosclerosis 1991; 86: 69-83 • Leitersdorf E et al. L Lipid Res 1991; 32: 1513-1519 • Mbewe AD et al. Arterioscler Thromb 1991; 11: 940-946 • Soutar AK et al. J Clin Invest 1991; 88: 483-492 • Bowden JF et al. Arterioscler Thromb 1994; 14: 1561-1568

Role of ascertainment bias FH High LDL-C Lipid  Lp(a) + FH + clinic prema- ture MI

FH pathophysiology & genetics

Elevated LDL cholesterol Atherosclerosis LDLR >95% APOB 2-5% PCSK9 <1% Coronary heart disease Liver with only 50% functional LDL receptors Myocardial infarction Angina pectoris Mutations in LDL receptor, apolipoproteinB or PCSK9 Heterozygous familial hypercholesterolaemia Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)

Coronary disease & Untreated coronary death before age 20 disease before age 55/60 Homozygous FH Heterozygous FH 200 Cumulative LDL-C (mmol) 53yrs Female sex Threshold 12.5yrs for CHD 35yrs 48yrs 150 Smoking 55yr Start high Hypertension dose statin Diabetes  Triglycerides 100  HDL-C Start low  Lipoprotein(a) dose statin 50 Without FH 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Age in years Years Age Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)

FH diagnosis

DUTCH FH CRITERIA

Family pedigree Man Woman Index case: FH start of Death 76 yrs Age 78 yrs cascade No CHD CHD 58 yrs screening LDL 3.8 mmol/L LDL 7.4 mmol/L FH Age 50 yrs Age 48 yrs Age 47 yrs No CHD CHD 48 yrs No CHD LDL 3.3 mmol/L LDL 8.3 mmol/L LDL 2.4 mmol/L FH FH Age 18 yrs Age 15 yrs Age 8 yrs LDL 2.2 mmol/L LDL 6.1 mmol/L LDL 5.6 mmol/L Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)

Frequency of FH in general population Study Definition Country HeFH HoFH Benn JCEM 2012 Clinical Denmark 1:223 1:200,000 Sjouke EHJ 2015 Genetic Netherlands 1:244 1:300,000 Pajak AMC 2016 Clinical Poland 1:250 1:250,000 Benn EHJ 2016 Genetic Denmark 1:217 1:190,000 deFerranti Circ 2016 Clinical USA 1:250 1:250,000 Safarova JCL 2016 Clinical USA 1:310 1:385,000 Wald NEJM 2016 Gen+Clin UK 1:250 1:250,000 Nordestgaard 2016

Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access) High Lp(a)? Patient: treat LDL Clinical diagnosis Family: monitor LDL & consider treatment without mutation Clinical diagnosis Mutation diagnosis Patient: treat LDL Family: mutation test, monitor LDL, & consider treatment Mutation without Patient: monitor LDL & consider treatment clinical diagnosis Family: monitor LDL & consider treatment Adapted from Luis Masana

Does FH cause high Lp(a)?

Relative number of LDL receptors Nobel Prize 100 1985 ”Normal” adults 50 Adult animals & newborn FH FH humans homozygote heterozygote 0 0 6 9 12 15 18 3 LDL cholesterol, mmol/L Adapted from Brown & Goldstein Scientific American 1984; 251: 52-60

131 I-LDL Homozygous FH Heterozygous FH 2 Controls 125 I-Lp(a)

Role of LDL receptor in Lp(a) removal is unclear Cells JBC 2015; 290: 11649-62 Turnover Cohorts

Does high Lp(a) cause FH?

Copenhagen General Population Study Unadjusted: P<0·0001 Lipoprotein(a), mg/dL Unlikely Possible Probable/definite Dutch Lipid Clinic Network N= 42,934 3082 184 Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

Copenhagen General Population Study Unadjusted LDL-C: P<0·0001 Lipoprotein(a), mg/dL Adjusted LDL-C: P=0.46 Adjusted LDL-C= LDL-C minus (Lp(a)*0.30) Unlikely Possible Probable/definite Dutch Lipid Clinic Network N= 42,934 43,699 3082 2360 184 141 Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

High lipoprotein(a) as a cause of clinical familial hypercholesterolemia (FH) Ranked genetic causes of Copenhagen clinical FH General FH Population 1:220 1. LDLR Study 2. Lp(a) (25%) N=46,200 3. APOB 4. PCSK9 Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

Does high Lp(a) misclassify FH?

Copenhagen General Population Study Unadjusted LDL-C: P<0·0001 Lipoprotein(a), mg/dL Adjusted LDL-C: P=0.46 Adjusted LDL-C= LDL-C minus (Lp(a)*0.30) Unlikely Possible Probable/definite Dutch Lipid Clinic Network N= 42,934 43,699 3082 2360 184 141 Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

High Lp(a) in FH causes CHD!

Lp(a) mg/dL < 50 Women ≥ 50 < 50 Men ≥ 50

Copenhagen General Population Study Cumulative incidence of myocardial infarction Clinical Lipo- 0.8 FH protein(a) 0.6 Yes >50mg/dL Yes ≤50mg/dL 0.4 Log-rank trend <0·0001 No >50mg/dL 0.2 No ≤50mg/dL 0 20 40 60 80 1 Age, years Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

Copenhagen General Population Study Lipo- Clinical Number/events FH protein(a) ≤50mg/dL No 35,153/502 No >50mg/dL 6921/137 ≤50mg/dL Yes 2300/89 Yes >50mg/dL 715/42 Clinical KIV-2 FH No >20% 28,144/478 ≤20% No 6917/133 Yes >20% 1985/84 ≤20% Yes 575/43 1 2 3 4 5 6 7 8 Hazard ratio for myocardial infarction (95%CI) Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

Consensus – Guidelines

Whom to screen for Lp(a)  • Premature CVD • Familial hypercholesterolemia • Family history premature CVD or Lp(a)  • Recurrent CVD despite statins • ≥3% 10 -year risk of fatal CVD • ≥10% 10 -year risk of fatal/nonfatal CHD • Aortic valve calcification or stenosis? Nordestgard et al. EAS Consensus Panel. Eur Heart J 2010;31:2844-2853 - updated

Screen for Lp(a)  in FH • EAS EU 2010 Yes • ESC/EAS EU 2016 Yes • CCS Can 2016 Unclear • AACE/ACE US 2017 Unclear • NICE UK 2017 Unclear • AHA/ACC US 2018 Unclear • NLA US 2019 Yes

LDL Cholesterol Clinical mmol/L mg/dL Mutation diagnosis diagnosis Homozygous LDL-receptor negative 20 770 Homozygous LDL-receptor Homozygous FH Compound defective or heterozygous homozygous 15 580 LDL-receptor/ LDLRAP1/ARH APOB/ PCSK9 13 500 Homozygous APOB defect/ 10 390 PCSK9 gain of function Heterozygous FH 5 190 Common hypercholesterolemia 0 0 Cuchel et al. EAS consensus. Eur Heart J 2014; 35: 2146-2157 (open access)

Danish clinical quality database on FH

Funded 100% by the Danish Government: Nationwide Danish clinical quality databases All hospitals must report patients to registries: • Breast cancer • Acute surgery • Schizophrenia • Heart failure • ..and 80 other nationwide disease registries Starting 2019/20 also a nationwide Danish clinical quality database on: • Familial hypercholesterolemia

Nationwide Danish clinical quality database on Familial Hypercholesterolemia: 14 standards Monitor and benchmark hospital regions 1. FH diagnoses 2. Family cascade screening 3. Non-pharmacological treatment 4. Pharmacological treatment 5. LDL cholesterol target attainment 6. Prognosis 1.5 Fraction of FH patients with Lp(a) measurement. Standard >80%

Conclusion

Evolution of FH understanding Multiallele LPA Recessive PCSK9 LDLRAP1 Codominant APOB LDL-R Clinical FH 2000 2020 1980 Nordestgaard 2019