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Fat, Cholesterol and Genetics 2019
Jacques Genest MD
Cardiovascular Health Across the Lifespan
McGill University Health Center
ACC-Rockies 12 March 2019
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▪ Pfizer
▪ Novartis
▪ AMGEN *
▪ Cerenis*
Disclosure J. Genest MD 2019
Scientific Advisory Board, Consultant
▪ Sanofi/Regeneron *
▪ Lilly*
▪ RengenXBio
• Stock ownership: none;
• Off label use: none
• CADTH, CDR
• INESSS
• EAS, IAS
• DSMB: RE-Energize
trial
Grants, Clinical Trials
Expertise
Laboratory
• We share all our reagents, cells, animal
models freely, without expectation of
Authorship or remuneration
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Fat, Cholesterol and Genetics 2019…
1. Triglycerides
▪ Chylomicronemia
▪ Severe hyper Tg
2. Lipoprotein Lp(a)
3. LDL-C, Genetics and Guidelines4. HDL-C
HDL-C
for the uninterested
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Primary and Secondary Lipoprotein Determinants
Recommendations
• Non HDL-C or apoB represent atherogenic lipoproteinsStrong Recommendation, High Quality Evidence
Canadian Guidelines 2016
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Triglycerides
2-10 mmol/L: moderate
>10 mmol/L: severe
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Definition of Hypertriglyceridemia
Lancet DM 2014
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Chylomicronemia Triglycerides > 10 mmol/L (885 mg/dL)
Type V Hyperlipidemia▪ Prevalence 1/600
▪ Polygenic
▪ Obesity, Met syn; BMI
▪ Diabetes
▪ HTA
▪ Alcohol excess
▪ Risk of ASCVD
▪ Labs:
▪ ApoB
▪ Elevated transaminases
Familial Chylomicronemia
Syndrome (FCS)
(Type I Hyperlipidemia)
Orphan disease
▪ Prevalence: 1/106
▪ LPL deficiency
▪ Rare (GPIHBP1
▪ APOC2, APOA5, LMF1)
▪ Young age
▪ Women>Men
▪ BMI normal
▪ Risk of pancreatitis
▪ Labs:
▪ ApoB
Chylomicrons/
remnants
VLDL
IDL
Lp(a)
LDL
HDL
Alothman L. Atheroscler 2019
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Hypertriglyceridemia Triglycerides 2-10 mmol/L (170- 885 mg/dL)
Type IV Hyperlipidemia▪ Prevalence v. common
▪ Polygenic +
▪ Obesity, Met syn; BMI
▪ Diabetes
▪ HTA
▪ Alcohol excess
▪ Risk of ASCVD
Labs:
▪ Non-HDL-C
▪ ApoB
Chylomicrons/
remnants
VLDL
IDL
Lp(a)
LDL
HDL
Treatment▪ Diet
▪ Lifestyle
▪ Weight reduction
▪ Exercise
▪ Diabetes control
▪ Statins
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Harmonization of US Cholesterol Guidelines 2018
Grundy SM. JACC in press
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2. Lp(a)
LDL
Apo (a)
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Lp(a) Lp(a) > 50 mg/dL
Lp(a) Excess
▪ Prevalence: 1:5 ?
▪ Genetically determined
(APOA gene polymorphisms)
▪ Risk of ASCVD
▪ Treatment:
▪ None accepted
▪ Statins ineffective
▪ PCSK9 25-30%
▪ asRNA
Chylomicrons/
remnants
VLDL
IDL
Lp(a)
LDL
HDL
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Lipoprotein (a)
LIPOPROTEIN (A)
❖Lipoprotein (a) [Lp (a)] is a heterogeneous macromolecule associated with early myocardial infarction, coronary artery disease, and stroke.
❖The structure of Lp (a) consists of an apolipoprotein (a) molecule linked to apolipoprotein B- 100 on a lipid-rich LDL core.
❖The level of Lp(a) is genetically controlled
❖Apo (a) has a strong structural homology to plasminogen, and their genes are adjacent on chromosome 6
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Lp(a) and ASCVD Risk
Nordesgaard B Eur Heart J. 2010 Dec; 31(23): 2844–2853.
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Antisense APO(a) mRNA for elevated Lp(a)
Viney NJ. Lancet 2016; 388: 2239
IONIS-APO(a) Rx
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3. LDL-C
Xanthelasma
Corneal Arcus
Xanthomas Xanthomas
Familial Hypercholesterolemia
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LDL LDL-C > 5.0 mmol/L
LDL-C > 5.0 mmol/L
▪ Prevalence: 0.05
▪ Familial Hypercholesterolemia
▪ 0.004
▪ Risk of ASCVD
▪ Treatment:
▪ Statins
▪ Ezetimibe
▪ PCSK9
▪ PCSK9 asRNA
Chylomicrons/
remnants
VLDL
IDL
Lp(a)
LDL
HDL
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Leo E Akioyamen; Genest J; Tu J. BMJ Open 2017
Prevalence:
0.004 or
1/250
Meta-analysis of Familial Hypercholesterolemia Prevalence
1/125 in Cath
Lab patients
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Genetic testing for FH – impact of ASCVD risk
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CCS Guidelines 2016
Strong Recommendation, Moderate-Quality Evidence
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US Guidelines 2018
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Grundy SM. JACC in press
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Vancouver
VictoriaCalgary
Edmonton
Regina
Saskatoon
Winnipeg
Toronto (2x)
Ottawa
Quebec
LondonHamilton
St-John
St. John’s
HalifaxMontreal (2x)
Chicoutimi
Familial Hypercholesterolemia Canada
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New Canadian
Definition for Familial
Hypercholesterolemia
Ruel I. Can J Cardiol. 2018;34(9):1210-1214
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LDL-C 95% Percentile
0.00
1.00
2.00
3.00
4.00
5.00
6.00
95
th p
erce
nti
le o
f LD
L (m
mo
l/L)
Age Group in 5-year segment
Comparison in 95th percentile of LDL between males and females cohort: GDML lab data
Female
Male
n=3,336,046 patients
Overall, the 95th
percentile for the population was 5.0 mmol/L in men and in women
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Results: baseline vs. imputed baseline LDL-C- There were no
statistically significant
differences (P >0.002)
observed except for
ezetimibe (P< 0.001)
- the mean±SEM baseline
LDL-C was 6.28±0.06
mmol/L
- the mean±SEM imputed
baseline LDL-C was
6.31±0.07 mmol/L
- (P=0.48)
- There was no difference
in response with regard
to the patient’s sex
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Other initiatives: CardioRisk Calculator
http://www.circl.ubc.ca
iTunes Store CardioRisk Calculator Free!
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DNA Diagnosis for FH MUHC CMDL
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LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a
function of the age of initiation of statin therapy.
Nordestgaard B G et al. Eur Heart J 2013;eurheartj.eht273
© The Author 2013. Published by Oxford University Press on behalf of the European Society of
Cardiology.
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Risk Level Initiate therapy if Primary TargetLDL-C
Alternate Target
High FRS ≥ 20%
Consider treatment in all(Strong, High)
≤ 2 mmol/L or ≥50% decrease in LDL-C(Strong, High)
▪ Apo B ≤ 0.8 g/L▪ Non HDL-C ≤ 2.6
mmol/L
Intermediate FRS 10-19%
LDL-C ≥ 3.5 mmol/L (Strong, Moderate)For LDL-C < 3.5 consider if:Apo B ≥ 1.2 g/L orNon-HDL-C ≥ 4.3 mmol/L
≤ 2 mmol/L or ≥50% decrease in LDL-C(Strong, Moderate)
▪ Apo B ≤ 0.8 g/L▪ Non HDL-C ≤ 2.6
mmol/L
Low FRS <10%
➢LDL-C ≥ 5.0 mmol/L➢Familial hypercholesterolemia(Strong, Moderate)
≥50% reduction in LDL-C(Strong, Moderate)
Targets
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LDL-C• Total cholesterol
• Non-HDL-C
• Apo B
• LDL particle size
• LDL particle number
• Apo A-I / Apo B
• Apo AI / Remnant Chol.
• Log10Tg/HDL-C
Note that the clinical trial data used LDL-C as a measurement
Targets
Lower is Better → Lowest is Best
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CHD-free survival in HeFH according to statin Rx(P < 0.001 for difference)
Nordestgaard B G et al. Eur Heart J 2013;34:3478-3490
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Scandinavian Simvastatin Survival Study (1994)
4S=Scandinavian Simvastatin Survival Study Group.
Primary end point of trial was total mortality. Secondary end point was first major coronary event defined as coronary death, nonfatal definite or
probable myocardial infarction (MI), silent MI, or resuscitated cardiac arrest.
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.
Simvastatin
Placebo
Pro
po
rtio
n a
live
Years since randomization
−30%
Total mortalityP=.0003
0.80
0.85
0.90
0.95
1.00
Pro
po
rtio
n w
ith
ou
t m
ajo
r co
ron
ary
e
ve
nt
Years since randomization
0.50
0.60
0.70
0.80
0.90
1.00
0 1 2 3 4 5 60 1 2 3 4 5 6
Simvastatin
Placebo
−34%
Major coronaryevents
P=.00001
Primary End Point: Total Mortality
Secondary End Point: Major Coronary Events
Mean LDL – 4.9 mmol/l
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An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
10%
12%
14%
16%
Primary Endpoint
Evolocumab
Placebo
Months from Randomization
CV
Death
, M
I, S
tro
ke,
Ho
sp
fo
r U
A,
or
Co
rR
evasc
0 6 12 18 24 30 36
Hazard ratio 0.85
(95% CI, 0.79-0.92)
P<0.0001 12.6%
14.6%
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ACC.18
32
Primary Efficacy Endpoint: MACE
ARR* 1.6%
*Based on cumulativeincidence
MACE: CHD death,
non-fatal MI,
ischemic stroke, or
unstable angina requiring
hospitalization
HR 0.85(95% CI 0.78, 0.93)
P=0.0003
SACA.ALI.18.03.0184- 1.2 - 1.04 MB
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Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events in the ODYSSEY OUTCOMES Trial
Michael Szarek, Harvey D. White, Gregory G. Schwartz, Marco Alings, Deepak L. Bhatt, Vera A. Bittner,
Chern-En Chiang, Rafael Diaz, Jay M. Edelberg, Shaun G. Goodman, Corinne Hanotin,
Robert A. Harrington, J. Wouter Jukema, Takeshi Kimura, Robert Gabor Kiss, Guillaume Lecorps,
Kenneth W. Mahaffey, Angèle Moryusef, Robert Pordy, Matthew T. Roe, Pierluigi Tricoci, Denis Xavier,
Andreas M. Zeiher, Ph. Gabriel Steg
On behalf of the ODYSSEY OUTCOMES Investigators and Committees
American Heart Association – 2018 Scientific SessionsNovember 11, 2018
ClinicalTrials.gov: NCT01663402SACA.ALI.18.11.084511/15/2018
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Alirocumab Reduced Total Events
*Excludes blinded switch to placebo
5,425 total nonfatal CV events or deaths; 77% greater than first events
Among patients with a first nonfatal CV event:
• 82%* of alirocumab patients and 85% of placebo patients were on assigned treatment; all but 4 alirocumab patients and 3 placebo patients continued treatment after first event
• 1,261 (48%) had at least one additional event
SACA.ALI.18.11.084511/15/2018
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Conclusions
Genetic Lipoprotein disorders and ASCVD
1. Hyper Tg is rare and mostly driven by poor lifestyle, diabetes and polygenic presisposition.
2. Elevated Lp(a) is frequent and our best guess is to further lower LDL-C. New therapies are coming…
3. Familial Hypercholesterolemia is more frequent than previously thought. Opportunity for cascade screening
4. PCSK9 inhibition with evolocumab and alirocumab significantly & safely major cardiovascular events when added to statin therapy
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2016 CCS Lipid Guidelines Recommend: PCSK9 inhibitors for ASCVD and FH
ASCVD, atherosclerotic cardiovascular disease; CCS, Canadian Cardiovascular Society, FH, familial hypercholesterolemia, PCSK9, proprotein convertase subtilisin/kexin type 9Anderson TJ1, Grégoire J, et al. Can J Cardiol. 2016;32(11):1263-1282.
PCSK9 INHIBITORS
ASCVDwith
sub-optimal LDL-Cdespite taking
maximally tolerated statin ±ezetimibe
PCSK9 INHIBITORS
Heterozygous FHwith
sub-optimal LDL-Cdespite taking
maximally tolerated statin± ezetimibe
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Merci