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

Prevalence and relevance of Lp(a) in familial hypercholesterolemia

Børge G Nordestgaard Professor, Chief Physician, MD, DMSc

University of Copenhagen & Copenhagen University Hospital

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

• 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

Other early studies on elevated Lp(a) in FH

Role of ascertainment bias

FH Lipid clinic Lp(a) + FH

High LDL-C + prema- ture MI

FH pathophysiology & genetics

Atherosclerosis Myocardial infarction Angina pectoris Elevated LDL cholesterol Mutations in LDL receptor, apolipoproteinB or PCSK9 Liver with only 50% functional LDL receptors Coronary heart disease

Heterozygous familial hypercholesterolaemia Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)

LDLR >95% APOB 2-5% PCSK9 <1%

50 100 150 200

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

Cumulative LDL-C (mmol) Years Age

35yrs 53yrs 48yrs 55yr 12.5yrs

Start high dose statin Start low dose statin

Threshold for CHD

Female sex Smoking Hypertension Diabetes Triglycerides HDL-C Lipoprotein(a)

Without FH Homozygous FH Heterozygous FH

Age in years

Coronary disease & death before age 20 Untreated coronary disease before age 55/60

Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)

FH diagnosis

DUTCH FH CRITERIA

Death 76 yrs No CHD LDL 3.8 mmol/L Age 78 yrs CHD 58 yrs LDL 7.4 mmol/L Age 48 yrs CHD 48 yrs LDL 8.3 mmol/L Age 47 yrs No CHD LDL 2.4 mmol/L Age 50 yrs No CHD LDL 3.3 mmol/L Index case: start of cascade screening Age 18 yrs LDL 2.2 mmol/L Age 8 yrs LDL 5.6 mmol/L Age 15 yrs LDL 6.1 mmol/L FH FH FH FH Man Woman

Family pedigree

Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)

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

Frequency of FH in general population

Nordestgaard 2016

Clinical diagnosis Mutation diagnosis Mutation without clinical diagnosis Clinical diagnosis without mutation Patient: treat LDL Family: monitor LDL & consider treatment Patient: treat LDL Family: mutation test, monitor LDL, & consider treatment Patient: monitor LDL & consider treatment Family: monitor LDL & consider treatment

Adapted from Luis Masana Nordestgaard et al. EAS Consensus. Eur Heart J 2013; 34: 3478-90 (open access)

High Lp(a)?

Does FH cause high Lp(a)?

LDL cholesterol, mmol/L

3 6 9 12 15 18 Adapted from Brown & Goldstein Scientific American 1984; 251: 52-60 50 100

Relative number of LDL receptors

FH heterozygote FH homozygote ”Normal” adults Adult animals & newborn humans

Nobel Prize 1985

131I-LDL 125I-Lp(a)

Homozygous FH Heterozygous FH 2 Controls

Role of LDL receptor in Lp(a) removal is unclear

JBC 2015; 290: 11649-62

Cells Cohorts Turnover

Does high Lp(a) cause FH?

N= 42,934 3082 184

Copenhagen General Population Study Dutch Lipid Clinic Network

Unlikely Possible Probable/definite

Lipoprotein(a), mg/dL

Unadjusted: P<0·0001

Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

Adjusted LDL-C: P=0.46

N= 42,934 43,699 3082 2360 184 141

Dutch Lipid Clinic Network

Unlikely Possible Probable/definite

Lipoprotein(a), mg/dL

Unadjusted LDL-C: P<0·0001

Adjusted LDL-C= LDL-C minus (Lp(a)*0.30)

Copenhagen General Population Study

Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

High lipoprotein(a) as a cause of clinical familial hypercholesterolemia (FH)

Copenhagen General Population Study N=46,200 FH 1:220 Ranked genetic causes of clinical FH

• 1. LDLR
• 2. Lp(a) (25%)
• 3. APOB
• 4. PCSK9

Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

Does high Lp(a) misclassify FH?

Adjusted LDL-C: P=0.46

N= 42,934 43,699 3082 2360 184 141

Dutch Lipid Clinic Network

Unlikely Possible Probable/definite

Lipoprotein(a), mg/dL

Unadjusted LDL-C: P<0·0001

Adjusted LDL-C= LDL-C minus (Lp(a)*0.30)

Copenhagen General Population Study

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 < 50 ≥ 50 ≥ 50 Women Men

0.2 0.4 0.6 0.8 20 40 60 80 1

Age, years

Log-rank trend <0·0001 Clinical Lipo- FH protein(a)

Yes >50mg/dL Yes ≤50mg/dL No >50mg/dL No ≤50mg/dL

Cumulative incidence of myocardial infarction

Copenhagen General Population Study

Langsted, Kamstrup, Benn, Tybjærg-Hansen, Nordestgaard 2016; Lancet DE; 2016; 4: 577-587.

1 2 3 4 5 6 7 8

Number/events 35,153/502 6921/137 2300/89 715/42 28,144/478 6917/133 1985/84 575/43

Hazard ratio for myocardial infarction (95%CI) Clinical FH KIV-2 Lipo- protein(a) No No Yes Yes ≤50mg/dL ≤50mg/dL >50mg/dL >50mg/dL Clinical FH No No Yes Yes >20% >20% ≤20% ≤20%

Copenhagen General Population Study

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

5 20 15 10 LDL Cholesterol mmol/L mg/dL 190 770 580 390

Homozygous FH Heterozygous FH Common hypercholesterolemia

Clinical diagnosis Mutation diagnosis

Homozygous LDL-receptor negative Homozygous LDL-receptor defective or homozygous LDLRAP1/ARH Homozygous APOB defect/ PCSK9 gain of function Compound heterozygous LDL-receptor/ APOB/ PCSK9

13 500

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

1980 2000 2020

Evolution of FH understanding

Clinical FH

Nordestgaard 2019

LDL-R APOB LDLRAP1 PCSK9 LPA Multiallele Recessive Codominant