Familial Hypercholesterolemia

KEY POINTS FH is an autosomal dominant genetic condition that leads to severe

elevations in cholesterol levels.◦ Average LDL is 220mg/dl in HeFH and > 500mg/dl in HoFH

Lifetime burden of high cholesterol leads to huge increased risk of cardiovascular disease.◦ 20 fold increased risk of premature cardiovascular disease (CVD)

FH is among the most common inherited conditions: ◦ Prevalence of heterozygous FH (HeFH) is 1:300-1:500. ◦ Homozygous FH is rare at 1:1,000,000 but has terrible consequences◦ FH affects all race/ethnic groups

FH can be diagnosed based on a combination of lipid levels, family history, physical exam findings and genetic testing.

FH is massively underdiagnosed and undertreated.◦ There are > 600,000 people in the US with FH but only 10% have

been diagnosed. FH is treatable

◦ With statin-based therapy, risk of CVD can be greatly reduced Because of the genetic nature of the disease, once one person in a

family is diagnosed with FH, it is mandatory to screen the rest of the family members (so called “cascade screening”)

OVERVIEWFamilial Hypercholesterolemia

Overview of FH FH is almost always inherited as an autosomal dominant disorder with a

very rare autosomal recessive form1,2

Low-density lipoprotein cholesterol (LDL-C) generally exceed the 95th percentile during childhood in patients with FH2,3

LDL-C concentrations are generally 2- to 3 fold higher in people with HeFH and 3- to 6-fold higher than normal in HoFH.4

Patients with FH have heightened risk of CVD due to life-long exposure to elevated cholesterol 5,6

If left untreated, individuals with HoFH often develop symptomatic CVD before age 25. Those with untreated HeFH often experience the same by age 55.1

A small fraction of treated FH patients have cardiovascular disease (CVD) and persistently elevated LDL-C levels >200 mg/dL (5.17 mmol/L) or have no CVD but persistently elevated LDL-C levels >300 mg/dL (7.75 mmol/L) despite maximally tolerated lipid-lowering therapy. These FH patients are referred to as severe FH and are currently eligible for LDL apheresis in the United States.

1. Marais AD. Clin Biochem Rev. 2004;25(1):49-68.2. Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology;

2008. 3. Graaf et al . Circulation. 2011;123:1167-1173.).4. Vella A, et al. Mayo Clin Proc. 2001;76(10):1039-1046.

5. Goldberg AC, et al. J Clin Lipidol. 2011:5:S1-S8.6. Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.7. Thompsen J, Thompson PD. Atherosclerosis. 2006;189:31-38.

Characteristics of HoFH, HeFH, and Severe FH1

Clinical characteristic HoFH HeFH Severe FH1

Untreated LDL-C (mg/dL) Generally >465 mg/dL2 Average >220 mg/dL N/A

Treated LDL-C >300 mg/dL after max tolerated drug therapy3

Mean 135 +/- 38 mg/dL after treatment with high

dose statins

>200 mg/dL with CVD after max drug therapy

or >300 mg/dL after max

drug therapy1

Cutaneous features

Tendon xanthomasXanthelasma

Tuberous xanthomasPlanar xanthomas

Tendon xanthomasXanthelasma

Tendon xanthomasXanthelasma

Corneal arcus Possible before age 20 Common after age 40 Common after age 40

Symptomatic Atherosclerosis Within 2nd decade Within 4th-5th decade Within 4th-5th

decade or earlier

Table adapted from Vella A, et al. Mayo Clin Proc. 2001;76:1039-1046.

1. Thompsen J, Thompson PD. Atherosclerosis. 2006;189:31-38.2. Raal FJ, et al. Atherosclerosis. 2000;150(2):421-428.3. Ito MK, et al. J Clin Lipidol. 5(3):S38-S45.

FH is due to impaired LDL clearance and increased secretion of ApoB particles

Increased LDL uptake bynon-LDLR-mediated pathways

Increased plasma LDL

Atherosclerosis and tissue damage

Impaired LDLR-mediated clearance

1. Barrett PH, Watts GF. Atheroscler Suppl. 2002;2(3):1-4.2. Sniderman AD, et al. Clin Sci (Lond). 2009;118(5):333-339.3. Fisher WR, et al. Arterioscler Thromb. 1994;14(4):501-510.4. Cummings MH, et al. Atherosclerosis. 1995;113(1):79-89.5. Tremblay AJ, et al. J Lipid Res. 2004;45(5):866-872.6. Twisk J, et al. J Clin. Invest. 2000;105(4):521-532.

Figure adapted from data and concepts in adjacent references.

Decreased degradation of ApoB and increased production and secretion of ApoB-containing lipoproteins into the circulation

GENETIC BASISFamilial Hypercholesterolemia

D

FH is almost always autosomal dominant

Most common FH-causing mutations are in the LDL receptor gene (LDLR). Less common defects include mutations in APOB or PCSK9 genes1

Heterozygotes inherit a single abnormal gene from one parent, Given the dominant mode of inheritance, these individuals manifest the disorder.2

Heterozygotes have approximately 2- to 3-fold higher serum LDL-cholesterol levels than normal2

Homozygotes inherit an abnormal gene from both parents. They typically have an LDL- cholesterol level 3- to 6-fold higher than normal2

1. Marais AD. Clin Biochem Rev. 2004;25(1):49-68.2. Vella A, et al. Mayo Clin Proc. 2001;76(10):1039-1046.3. Pisciotta L, et al. Atherosclerosis. 2006;186(2):433-440.4. Tai ES, et al. Clin Chem. 2001;47(3):438-443. Image adapted from www.genetics.edu.au/pdf/factsheets/fs09.pdf.

Autosomal DominantLDLR, ApoB, and PCSK9 mutations

Affected orpredisposedmother with autosomaldominant faulty gene

Eggs

Affected orpredisposedfather with autosomaldominant faulty genes

Spermd

Unaffected Affected Severely affected

1 out of 4 chances 25%

2 out of 4 chances 50%

1 out of 4 chances 25%

dd Dd Dd DD

DdDd

d D

A small spectrum of affected heterozygotes may have unusually severe phenotypes; unusually severe phenotypes may also be seen in compound heterozygotes that have mutations in 2 different genes (1 from each parent

or both from the same parent)3,4

Affected orpredisposedfather with autosomaldominant faulty genes

FH is very rarely autosomal recessive

Mutations in the LDLRAP1 gene result in a very rare autosomal recessive form of homozygous FH called autosomal recessive hypercholesterolemia (ARH)1

The clinical phenotype of homozygous ARH is similar to that of classic homozygous familial hypercholesterolemia but it is somewhat milder in terms of serum total cholesterol and LDL-C levels1,2

Because it is a recessive disorder, most ARH patients are homozygous for the same allele inherited from consanguineous or related parents1

Because ARH is an autosomal recessive disorder, the heterozygotes are unaffected1

Autosomal RecessiveARH/LDLRAP1 mutations

Unaffected geneticcarriermother

Eggs

Unaffectedgeneticcarrierfather

Sperm

Non-carrier(unaffected)

Geneticcarriers

(unaffected)

1 out of 4 chances 25%

2 out of 4 chances 50%

1 out of 4chances 25%

RR Rr Rr rr

RrRr

Image adapted from www.genetics.edu.au/pdf/factsheets/fs09.pdf.

1. Soutar AK, et al. Arterioscler Thromb Vasc Biol. 2003;23(11):1963-1970.2. Pisciotta L, et al. Atherosclerosis. 2006;188(2):398-405.

rR R r

Severely affected

Liver cell

Circulation

LDL Particle

Apo Bacts as ligand, binding LDL particle to receptor

on hepatocyte, binds to Apo B on LDL particle, inducing endocytosis of LDL

LDL Receptor

LDLRAP1 (ARH)mediates internalization via clathrin coated pitsPCSK9 Enzyme

degrades LDL receptors

FH can be caused by mutations in 4 known genes

FH is typically caused by mutations in LDLR, ApoB, PCSK9, LDLRAP1 or other as yet other unidentified genes1

Image reproduced from http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

1. De Castro-Oros I, et al. Appl Clin Genet. 2010;3:53-64.

FH-related mutations

GeneDefect Genotype Plasma

LDL-C level Prevalence Frequency1 Metabolic defect

LDLRHeterozygote +++ 1:500

60%-80%1

↓ LDL clearance (1°)4

↑ LDL production (2o)4

↑ ApoB production (2o)2Homozygote +++++ 1:1,000,000

ApoBHeterozygote ++ 1:1000

1%-5%1

↓ LDL clearance (1°)4

↑ LDL production (2o)5

↑ ApoB production (2o)5Homozygote +++ 1:4,000,0001:4,000,000

PCSK9Heterozygote +++ <1:2,500

0%-3%1

↓ LDL clearance (1°)6

↑ LDL production (2o)6

↑ ApoB production (2o)6Homozygote ++++2 N/A

LDLRAP1 Homozygote ++++3 Very rare Very rare ↓ LDL clearance (1°)3

Unknown N/A +++ N/A 20%–40% Unknown

Phen

otyp

e of

FH

1. De Castro-Oros I, et al. Appl Clin Genet. 2010;3:53-64. 2. Noguchi T, et al. Atherosclerosis. 2010;210(1):166-172.3. Soutar AK, et al. Arterioscler Thromb Vasc Biol. 2003;23(11):1963-1970.

Table adapted from Rader DJ, et al. J Clin Invest. 2003;111:1795-1803 and De Castro-Oros I, et al. Appl Clin Genet. 2010;3:53-64.

4. Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.5. Zulewski H, et al. J Lipid Res. 1998;39(2):380-387. 6. Ouguerram K, et al. Arterioscler Thromb Vasc Biol. 2004;24(8):1448-1453.

PATHOPHYSIOLOGYFamilial Hypercholesterolemia

The atherosclerotic burden of FH reflects the lifelong accumulation of LDL and all ApoB-containing lipoproteins

VLDL Lp(a)

Apo(a)

IDL LDL

Cholesterol concentration

measures:

LDL-C

Non-HDL-C

ApoB- containing

lipoproteins:

Non-HDL-C: plasma cholesterol concentration of ApoB-containing particles

Adapted from Robinson JG* J Am Coll Cardiol. 2010;55(1):42-44.

ApoB 100

LDL accumulates to cause CHD early in life in FH

Normal

Female

Male HypertensionDiabetesSmoking

HeFHHoFH

Threshold for CHD

0

5

10

1 20 40 60 80

Cum

ulat

ive

LD

L-C

(g

/dL-

year

s)

Threshold for CHD reached by:– Age 15 y in HoFH patients– Age 40 y in HeFH patients

– Age >60 y in healthy individuals

Age Patients Meet CHD Threshold

Age (years)

Adapted from Horton JD, et al. J Lipid Res. 2009;50(Suppl):S172-S177.

0.08

0.06

0.04

0.02

0

–0.02

–0.04

Arterial Intima-media Thickness in children with FH

Significant differences in intima-media thickness (IMT) were noted by age 12 in children with FH versus unaffected siblings (P = 0.002)

Adapted from Wiegman A, et al. Lancet. 2004;363(9406):369-370.

8 10 12 14 16 18

Age (y)

FH –

con

trol I

MT

(mm

)

Child with FH

Unaffected sibling

Significant difference in IMT

Carotid IMT in FH versus non-FH patients

FH patients: ~45 yHealthy non-FH: ~80 y

FH individuals

Linear (pooled FH individuals)

1.6

1.4

1.2

1.0

0.8

0.6

0.4

10 20 30 40 50 60 70 80Age (y)

cIM

T (m

m)

Non-FH individualsLinear (pooled non-FHindividuals)

Adapted from De Groot E, et al. Circulation. 2004;109[ suppl III]:III33–III38.

LDL-C (mmol/L) in untreated patients

Rel

ativ

e fre

quen

cy

3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.510.010

.511

.011

.512

.012

.513

.013

.514

.014

.515

.015

.5

Median = 6.95 mmol/L(268.76 mg/dL) Mean = 7.22 mmol

(279.2 mg/dL)

LDL-C concentrations and physical signs in untreated FH patients

LDL-C Distribution in Untreated Patients With Definite FH3

Cumulative Prevalence of Physical Signs in Adult FH Patients3

Cum

ulat

ive

prev

alen

ce, %

15 25 35 45 55 65 75 85

Age (y)

0

25

50

75

100

Tendon xanthomas Arcus cornealis Xanthelasma

1. Marais AD. Clin Biochem Rev. 2004;25(1):49-68.2. Raal FJ, et al. Atherosclerosis. 2000;150(2):421-428. 3. Blom DJ, et al. S Afr Fam Pract. 2011;53(1):11-18.

EPIDEMIOLOGYFamilial Hypercholesterolemia

FH is a common inherited disorder

0.0

0.5

1.0

1.5

2.0

2.5

Freq

uenc

y pe

r 100

0 bi

rths

The prevalence of HeFH is ~1:5001-3

The prevalence of HoFH is ~1:1,000,0002,3

Figure adapted from Genetic Alliance UK. Available at http://www.geneticalliance.org.uk/education3.htm.

1. Citkowitz E. Familial Hypercholesterolemia. http://emedicine.medscape.com/article/121298-overview#a0199.2. Vella A, et al. Mayo Clin Proc. 2001;76(10):1039-1046.3. Austin MA, et al. Am J Epidemiol. 2004;160(5):407-420.

Dominant otosclerosis

Adult PCKD

Sickle cell disease

Multiple exostoses

Huntington's disease

Fragile X syndrome

Neuro-fibromatosis

Cystic fibrosis

Duchenne muscular dystrophy

FH

2.0 per 1000

1.00.8

0.5 0.5 0.5 0.5 0.4 0.40.3

PCKD, polycystic kidney disease.

In some populations FH is even more common

Adapted from Austin MA, et al. Am J Epidemiol. 2004;160(5):407-420.

1:72 to 1:100

1:67

1:1651:270

1:85

1:500

General population

Founder Populations

CLINICAL PRESENTATIONFamilial Hypercholesterolemia

Heterozygous FH

20-fold increased risk of CVDIf untreated:

◦Men have 50% risk of CVD by age 50◦Women have 30% risk of CVD by age 60

Many HeFH patients present with established CVD (angina, MI)

Physical exam findings in FH

A. XanthelasmaB. Corneal arcusa  C. Achilles tendon xanthomasD. Tendon xanthomasb,1-3

E. Tuberous xanthomasc

F. Planar xanthomasc

Figure adapted from Mahley RW, et al. In: Kronenberg HM. Williams Textbook of Endocrinology. 11th ed. Philadelphia: Saunders; 2008.

A B

C D

E F

A Common in older individuals (even non-FH); definitive of FH in younger individuals.

B 30%-50% of the HeFH population have tendon xanthomas.C Seen mostly in HoFH, and not as often in HeFH

1. Ferrières J, et al. Circulation. 1995;92(3):290-295.2. Bertolini S, et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-E52.3. Descamps OS, et al. Atherosclerosis. 2001;157(2):514-518.

1. Citkowitz E. Familial Hypercholesterolemia. http://emedicine.medscape.com/article/121298-overview#a0199.2. Allen JM, et al. Br Heart J. 1980;44(4):361-368.

• Image A reproduced from Brown/Goldstein Lab. Department of Molecular Genetics at UT Southwestern. http://www4.utsouthwestern.edu/moleculargenetics/pages/gold/past.html.

• Image B reproduced from Li SG, et al. N Engl J Med. 2009;360(18):1885.• Image C reproduced from Thappa DM, Karthikeyan K. Indian Pediatr. 2003;40(6):574-575.

Clinical presentation of HoFH

Cutaneous xanthomas at birth or by early childhood1

Planar xanthomas (on hands, elbows, buttocks, or knees), which are diagnostic for the homozygous state1

Tuberous xanthomas (on hands, elbows, or knees)1

Tendon xanthomas (especially on extensor tendons of hands or Achilles tendon)1

Valve affection murmur of aortic stenosis may be heard1,2

Six-year-old girl with HoFH. Bumps on skin are deposits of cholesterol derived from LDL.

A

B C

HoFH clinical courseSevere vascular disease at an early age.Numerous case reports of CABG or death

before age 10.◦Severe aortic stenosis common

Untreated, usually results in death before age 30.

Almost all HoFH patients require LDL apheresis but even with maximal medical therapy there is disease progression.

DIAGNOSIS AND SCREENINGFamilial Hypercholesterolemia

LDL-C categories often used for FH diagnosis

LDL-C Categories Often Used for FH Diagnosis3

Minimum LDL-C, mg/dL

Category Description Age <20 y Age 20-29 y Age 30+ y

1 General population 95th percentile 130 160 190

2 80% have FH in first-degree relativesa 150 170 200

3 80% have FH in general population 190 220 260

4 99% have FH in general population 220 240 280

5 99.9% have FH in general population 240 260 300

The diagnosis of FH is largely based on ◦ Extreme hypercholesterolemia early in life (LDL-C ≥190 mg/dL [adults] or ≥160

mg/dL [children or adolescents])1

◦ Clinical evidence of premature CVD and/or family history of hyperlipidemia2

According to National Lipid Association (NLA) criteria, FH should be suspected inthe following cases1

◦ Children, adolescents, young adults (<20 y) with LDL-C ≥160 mg/dL or non-high-density lipoprotein cholesterol (HDL-C) ≥190 mg/dL

◦ Adults (≥20 y) with LDL-C ≥190 mg/dL or non-HDL-C ≥220 mg/dL Formal diagnosis through MEDPED, Simon-Broome or Dutch criteria

1. Goldberg AC, et al. J Clin Lipidol. 2011:5(3 Suppl):S1-S8.2. Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.3. Hopkins PN, et al. J Clin Lipidol. 2011;5(Suppl 3):S9-S17.

aThis category is relevant for diagnosis of FH patients who are first-degree relatives of a knownFH case. At the LDL-C level shown, ~ 80% of first-degree relatives can be expected to have FH.

High cholesterol screening recommendations from the NLA

Universal screening for serum cholesterol levels is recommended◦ Cholesterol screening should be considered starting at age 2 for

children with a family history of premature CVD or high cholesterol.

◦ All children should be screened between the ages of 9 – 11 regardless of family history.

For all children with an LDL-C ≥160 mg/dL after adequate lifestyle interventions lipid altering medications are recommended.

“Cascade screening” of all first-degree relatives of diagnosed FH patients should be performed; newly identified FH cases may reveal additional relatives who should be screened

Goldberg AC, et al. J Clin Lipidol. 2011:5(3 Suppl):S1-S8.

Genetic testing for FH

In the US, the diagnosis of FH is usually made on clinical grounds.

However, genetic testing is the gold-standard for the diagnosis of FH and is widely used in many countries.◦ Genetic testing can be used in cases where the diagnosis

is unclear. Testing generally involves sequencing 3 genes (LDLR, APOB

and PCSK9).◦ The yield on genetic testing is ~85% in “definite” FH cases

and ~50% in “possible” FH. As genetic testing becomes cheaper it is probable that this

method will be used more widely. ◦ May be particularly useful for cascade screening.

The CDC has classified genetic testing for FH as a “Tier 1” application (Best evidence to support use)

CURRENT TREATMENTFamilial Hypercholesterolemia

ManagementDiet/lifestyle changes important

◦ Reduce saturated fat◦ High soluble fiber: 10-20g/day◦ Dietician referral

Statins are the mainstay of therapy◦ Many will require 2 or more drugs◦ Goal to reduce LDL ≥ 50% (or LDL < 100 ideal)

Treat other risk factors (HTN, smoking)DO NOT USE STANDARD RISK ASSESSMENT TOOLS

TO ESTIMATE RISK◦ Framingham score is not valid in FH patients

Goals of therapy

FH patients are considered “high risk” based on NCEP, AHA/ACC guidelines◦Rule of thumb to try to cut LDL by 50%◦Ultimate goal LDL < 100

Many would try to get LDL < 70Unlike “garden variety” HLD, non-statin

agents are standard of care.With proper therapy can reduce risk of

CHD by 80%.

NCEP ATP Guidelines, Circ 2002

Current therapeutic options for FH: statinsStatins competitively inhibit HMG CoA reductase,

reducing endogenous cholesterol synthesis

LDL

Fatty Acids Acetyl-CoA

HMG CoA

Cholesterol

ACAT2

MTP

Cholesterol Esters

Triglycerides

ApoB-100VLDLApoB-100

VLDLApoB-100

LDLApoB-100

Reduced cholesterolsynthesis

=Statin

ApoB

LDL receptor

Increased receptor expression

Lipid core-cholesteryl esters

LDL

Figure adapted from Stancu C, Sima A. J Cell Mol Med. 2001;5(4):378-387.

Increased ApoB-LDL uptake

Effect of statins and lipid-lowering therapy in FH

Statins have demonstrated significant MI-free survival benefits in HeFH patients

Delayed CV events and prolonged survival in HoFH patients have altered the disease spectrum of HoFH from a fatal disease in childhood to that seen in untreated HeFH

Figure 1 adapted from Versmissen J, et al. BMJ. 2008;337:a2423.Figure 2 adapted from Raal FJ, et al. Circulation. 2011;124(20):2202-2207.

Figure 1 Figure 2

Cum

ulat

ive

even

t-fre

e su

rviv

al (%

)

100

80

60

40

20

00 2.5 5.0 7.5 10.0 12.5

Follow-up (y)

Statin treatment HeFH No statin treatment

HeFHNo statin treatment –general population

1.0

Surv

ival

pro

babi

lity

Age (y)

0.8

0.6

0.4

0.2

0

0 10 20 30 40 50 60 70

Benefit From Lipid Therapy (Endpoint: Death)

YesNo

A.

1.0Su

rviv

al p

roba

bilit

y

0.8

0.6

0.4

0.2

0

0 10 20 30 40 50 60Age (y)

Benefit From Lipid Therapy (Endpoint: MACE)

YesNo

B.

Mechanism of action of current therapies

ClassPrimary and secondary

mechanism of action

LDL-lowering response

HeFH HoFH

Statins ↑ LDLR activity (1O) >35%1 Up to 28%2

Bile acid sequestrants ↓ Bile acid re-absorption (1O), ↑ LDLR activity (2O) 15% <10%

Cholesterol absorption inhibitors ↓ Cholesterol absorption (1O), ↑ LDLR activity (2O) 15% <10%

Stanol esters ↓ Cholesterol absorption (1O), ↑ LDLR activity (2O) 10% <10%

Nicotinic acid ↓ VLDL synthesis (1O) 20% <10%

LDL apheresis Removes LDL 20-40% (up to 76% acutely)6,7

In FH patients, statins are highly effective but the LDL-cholesterol responsiveness to statins is influenced by the nature of the LDL receptor gene mutation and some LDLR mutations tend to render statins less effective 4,5

Because most current therapies directly increase LDL-C clearance via the LDLR or decrease LDL-C via other clearance mechanisms that secondarily up-regulates the LDLR, their effectiveness in FH patients can be limited

Current therapies with the exception of niacin, do not significantly impact LDL/ApoB production

1. Kastelein JJ, et al. N Engl J Med. 2008;358(14);1431-1443.2. Raal FJ, et al. Atherosclerosis. 2000;150(2):421-428. 3. Konrad RJ, et al. Lipids Health Dis. 2011;10:38.4. Vohl et al, Atherosclerosis 160 (2002) 361–368

Table adapted from Radar DJ, et al. J Clin Invest. 2003;111(12):1796-1803.5. Chaves et al. lin Endocrinol Metab 86: 4926–4932,20016. Gordon BR, et al. Am J of Card. 1998;81(4):407-411.7. Ito MK, et al. J Clin Lipidol. 2011;5(3 Suppl):S38-S45.

For the worst affected FH patients LDL apheresis is added

LDL-C reductions withapheresis:• Acute: Up to 76%1

• Time averaged: 20-40%2

1 2 3 4 6 7 8 9 105

Treatments

LDL-

C (m

g/dL

)

Reproduced from Thompson GR. Curr Opin Lipidol. 2010. 1. Gordon BR, et al. Am J of Card. 1998;81(4):407-411. 2. Ito MK, et al. J Clin Lipidol. 2011;5(3 Suppl):S38-S45.

Cholesterol Rebound After Receiving LDL Apheresis

Treatment algorithm for the worst affected FH patients

All HeFH patients require lipid-lowering drugs to reach target LDL-C levels1,2

Adult Treatment Panel (ATP) III guidelines indicate that most FH patients will require combination therapy1,2

LDL apheresis and/or liver transplant is only required in rare cases1,2

1 - NIH. NCEP, Final Report. Pub No. 02-5215. September 2002..2 – Ito et al. Management of Familial Hypercholesterolemias in adult patients: Recommendations from the National Lipid Association Expert Panel on Familial

Hypercholesterolemia Journal of Clinical Lipidology (2011) 5, S38–S45

Lifestyle changesProper diet, reduction in body weight if overweight,

smoking cessation, and exercise

Statin treatment

Combination therapy

LDL apheresis or liver transplant

HoFH and severe FH patients

Schematic adapted from adjacent references

ADDITIONAL RISK FACTORS TO CONSIDERFamilial Hypercholesterolemia

Additional CVD risk factors to consider in HeFH

Lipoprotein(a) [Lp(a)] ≥50 mg/dL1,3,4

Tendon xanthomas1-3

Men: ≥30 y1

Women: ≥45 y or postmenopausal1 Cigarette smoking: active smokers1

Family history of premature CVD1

◦ CVD in male first-degree relative <55 y or in female first-degree relative <65 y

HDL-C <40 mg/dL (1.0 mmol/L)1

Blood pressure >140/90 mmHg1

Diabetes mellitus1

1. Goldberg AC, et al. J Clin Lipidol. 2011:5(2 Suppl):S1-S8.2. Neil HA, et al. Atherosclerosis. 2003;170(1):73-78.3. Civeira F, et al. Arterioscler Thromb Vasc Biol. 2005;25(9):1960-1965.

− Independent CVD risk factors3,4

− In FH, independent CVD risk factors couldpotentially interact with lifelong high LDL-Clevels to compound risk5

4. Holmes DT, et al. Clin Chem. 2005;51(11):2067-2073.5. Mbewu AD, et al. Arterioscler Thromb. 1991;11(4):940-946.

Risk factors in FH independent of LDL-C Tendon xanthomas

◦ Tendon xanthomas in FH are associated with CV risk independently of the LDLR gene mutation1

◦ Approximately 30%-50% of heterozygous FH patients with genetic diagnosis have tendon xanthomas2-4

Lipoprotein(a)◦ Elevated serum Lp(a) concentrations may be regarded as a component of

the clinical syndrome of FH5

◦ In homozygous or heterozygous FH, mutations in the LDLR show clear gene-dose effect on Lp(a) plasma levels6

◦ Lp(a) is an independent risk factor for CVD in heterozygous FH7

◦ Potential interactions between high plasma concentration of Lp(a) as seen in FH and additional risk factors for CVD (such as elevated life long accumulations of LDL-c as seen in FH) may also potentiate the very high CVD risk of FH patients5

1. Civeira F, et al. Arterioscler Thromb Vasc Biol. 2005;25(9):1960-1965.2. Ferrières J, et al. Circulation. 1995;92(3):290-295.3. Bertolini S, et al. Arterioscler Thromb Vasc Biol. 2000;20(9):E41-E52. 4. Descamps OS, et al. Atherosclerosis. 2001;157(2):514-518.5. Mbewu AD, et al. Arterioscler Thromb. 1991;11(4):940-946.6. Kraft HG, et al. Arterioscler Thromb Vasc Biol. 2000;20(2):522-528.7. Holmes DT, et al. Clin Chem. 2005;51(11):2067-2073.

Lipoprotein(a)

LDL particle

Apo(a)

ApoB-100

Lp(a): An independent and causal risk factor

Lp(a) consists of an LDL-like particle and the specific Apo(a), which is covalently bound to the ApoB of the LDL-like particle1,3

Because Apo(a) is structurally homologous to plasminogen, Lp(a)1,3

◦ Competitively inhibits plasmin generation – antifibrinolytic1,3

◦ Can bind to plasmin and fibrinogen, promoting atherosclerosis1,3

◦ Deposits oxidized phospholipids, increasing inflammation leading to atherosclerosis1,3

◦ Promotes plaque inflammation and instability1,3

Lp(a) has a causal relationship to increased CV risk2 and is recognized to predict atherosclerosis, MI1

2011 NLA Expert Panel cited Lp(a) as an independent driver of very high risk in FH4

1. Kiechl S, Willeit J, J Am Coll Cardiol. 2010;55(19):2168-2170.2. Clarke R, et al. N Engl J Med. 2009;361(26):2518-2528. 3. Kathiresan S. N Engl J Med. 2009;361(26):2573-2574. 4. Goldberg AC, et al. J Clin Lipidol. 2011;5(3 Suppl):S1-S8.

Figure adapted from Brown WV, et al. J Clin Lipidol. 2010;4(4):240-247.

Lp(a) elevations more frequent in FH

0

10

20

30

40

50

60

70

All S1 S2 S2/S3 S2/S4 S3 S4 S3/S4

Controls FH

In FH, Lp(a) levels increased 3-fold vs controls Across Lp(a) LMW range, levels are higher in FH versus

controls.

Low Molecular Weight.

High Molecular Weight

Apo(a) Isoforms

Lp(a

) (m

g/dL

)

Utermann G, et al. Proc Natl Acad Sci U S A. 1989;86(11):4171-4174.

UNMET MEDICAL NEEDFamilial Hypercholesterolemia

FH is an unmet medical need

Huge healthcare burden ◦Both in terms of morbidity and mortality

and health care expendituresHugely underdiagnosedHugely undertreatedResearch efforts for FH funded poorly

considering prevalence of diseaseNo national patient registry

The FH FoundationOur mission is to raise awareness of

Familial Hypercholesterolemia (FH) through education, advocacy, and

research.

Our goal is to save lives by increasing the rate of early diagnosis and

encouraging proactive treatment.

For more information, please contact us:info@thefhfoundation.org

www.TheFHFoundation.orgFacebook and Twitter: The FH Foundation

Summary: FH FH is an inherited disorder that is characterized by high levels of LDL

from early childhood1,2

The diagnosis of FH is based primarily on◦ Extreme hypercholesterolemia early in life (untreated LDL-C ≥190

mg/dL in early adulthood or ≥160 mg/dL in childhood or adolescence)3

◦ Clinical evidence of premature CVD and/or family history of hyperlipidemia4

Patients with FH have a high risk of CVD related to elevated LDL levels4,5

FH is primarily a problem of lipoprotein clearance and secondarily of increased ApoB particle production6,7

FH is an autosomal dominant condition so once a family member with FH is identified, ‘cascade’ screening in the rest of the family is mandatory.

1. Marais AD. Clin Biochem Rev. 2004;25(1):49-68.2. Mahley RW, et al. In: Kronenberg HM. Williams Textbook of Endocrinology.

11th ed. Philadelphia: Saunders; 2008.3. Goldberg AC, et al. J Clin Lipidol. 2011;5(3 Suppl):S1-S8.

4. Rader DJ, et al. J Clin Invest. 2003;111(12):1795-1803.5. Williams RR, et al. JAMA. 1986;255(2):219-224.6. Barrett PH, Watts GF. Atheroscler Suppl. 2002;2(3):1-4. 7. Sniderman AD, et al. Clin Sci (Lond). 2009;118(5):333-339.

Summary: FH (cont.) Statin based therapies have demonstrated significant MI free survival

benefits in HeFH patients1

Advances in lipid-lowering treatment, predominantly statin therapy, are associated with delayed CV events and prolonged survival in HoFH patients and have altered their disease spectrum of HoFH from a fatal disease in childhood to that seen in untreated heterozygous FH2

Despite these advances in lipid-lowering therapy, all HoFH patients and a significant proportion of heterozygous FH patients remain far from desired LDL-C goals1,2

There is a need for additional ApoB and LDL lowering therapies Emerging therapies include3

◦ ApoB inhibitors◦ MTP inhibitors◦ PCSK9 inhibitors

1. Versmissen J, et al. BMJ. 2008;337:a2423.2. Raal FJ, et al. Circulation. 2011;124(20):2202-2207.3. Costet P, et al. Pharmacol Ther. 2010;126(3):263-278.