prevalence and relevance of lp(a) in familial ... · atherosclerosis myocardial infarction angina...

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 payerConsultancies 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

clinicLp(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%

0

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

Cu

mu

lati

ve L

DL-

C (

mm

ol)

Years Age

HOZ Untreated Treat at 10yrs Non FH Treat at 18yrs

35yrs

53yrs

48yrs

55yr

12.5yrs

Start high dose statin

Start lowdose 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

Clin

ical dia

gnosis

Muta

tion d

iagnosis

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/L0 3 6 9 12 15 18

Adapted from Brown & Goldstein Scientific American 1984; 251: 52-60

0

50

100Relative 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

Lip

opro

tein

(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

Lip

opro

tein

(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

Lip

opro

tein

(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

0.2

0.4

0.6

0.8

20 40 60 80 100Age, years

Log-rank trend <0·0001

Clinical Lipo-

FH protein(a)

Yes >50mg/dL

Yes ≤50mg/dL

No >50mg/dLNo ≤50mg/dL

Cum

ula

tive

inci

den

ce o

f m

yoca

rdia

l in

farc

tion 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)NoNoYes

Yes

≤50mg/dL

≤50mg/dL>50mg/dL

>50mg/dL

Clinical

FH

NoNoYes

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

0

5

20

15

10

LDL Cholesterol

mmol/L mg/dL

0

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/ PCSK913 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