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LDL-Cholesterol : Old Story but
New Insights & Emerging Evidence
Choo Gim Hooi MD
Cardiac Vascular Sentral KL (CVSKL)
12th. July, 2019
The 10th. Central Vietnam Open Congress of Cardiology
Disclosure
• No conflicts with regards to this presentation / meeting
Sypnosis :
• Myth & Fallacies about LDL-C & Statins
• Brief historical facts
• Genetic, Epidemiological & Interventional Evidence
• New Frontiers in LDL-C management : Low & Ultra-low LDL-C targets, Plaque regression
• ?Cure for atherosclerosis
Atherosclerosis : Ancient Disease
Atherosclerosis in Ancient Egyptian Mummies: The Horus Study. JACC Apr 3, 2011; Adel H. Allam, Randall C. Thompson, L. Samuel Wann, Michael I. Miyamoto, Abd el-Halim Nur el-Din, Gomaa Abd el-Maksoud, Muhammad Al-Tohamy Soliman, Ibrahem Badr, Hany Abd el-Rahman Amer, M. Linda Sutherland, James D. Sutherland, and Gregory S. Thomas
Vietnam Health Statistics 2016
World Health Organization - Noncommunicable Diseases (NCD) Country Profiles, 2018.
Atherosclerosis timeline
Modified from Stary HC et al, Circulation 92:1355, 1995
Fatty Streak in Epicardial Coronary
Artery of a 3 year old boy
Slide courtesy of Dr.Peter Lansberg, Amsterdam Medical Centre
Prevalence of Atherosclerosis by Donor Age
Tuzcu. Circ 2001. 103:2075-10
Factors Contributing to Atherosclerosis
• High LDL-C
• Low HDL-C
• Obesity (Central, Visceral)
• Diet
• Physical inactivity
• Hypertension
• Smoking
• Diabetes mellitus
• Genetics
• Environment
Factors contributing to Atherosclerosis
1856 Rudolf Ludwig Carl Virchow
Atherosclerosis, Inflammation [endarteritis deformans] & Cholesterol deposit
1821-1902
Cholesterol & Atherosclerosis model, 1913
Nikolaj NikolajewitschAnitschkow (1885-1964)
Carrots & Salads Egg Yolk Fortified Food
Healthy Volunteers
Adolf Otto Reinhold Windaus
• Organic Chemistry Professor – one of the 1st. to Study Cholesterol structure 1910s
• Nobel Laureate in Chemistry 1928 for Research on Sterols & its connection to Vitamins
1964: Nobel Laureate for Physiology or Medicine : Elucidation of Cholesterol & Fatty
Acid Metabolism Pathway
Konrad Emil Bloch Feodor Lynen
Joseph Goldstein & Michael Brown :Nobel Laureate 1985
Circulating LDL-C controlled by LDL-C Receptor activity
1974
Goldstein JL, Brown MS. Cell 2015;161-161
1976 : Dr.Akira EndoDiscoverer of 1st.
HMG Co-A Reductase inhibitor • 1970s: Focus of Drug Companies –
Antibiotics• 1971 : Fungi Research Project started- >6000 experiments over 2 years- Initial experiments in rats unsuccessful- Later Dog experiments were successful
• Initially no Pharma interest, until Sankyo Co took notice
• Mevastin (Compactin) – 1st statin derived from Penicillium citinium
Developers [Merck] of Clinically useful Statins :Lovastatin & Simvastatin
Roy VagelosAlfred W. Alberts
Constant Battle with the Myths & Fallacies about
LDL-C and Statins !
http://www.tbyil.com/Lowering_Cholesterol.htm
Various myths about LDL-C and Statins ?
• No cause & effect relationship between cholesterol and Atherosclerosis
• Cholesterol is necessary for bodily function and should not be lowered
• Statins damage my kidney, liver
• Statins cause heart failure, cancer
• I can lower cholesterol without statins
• Once LDL-C is lowered, I can stop the statin or reduce the dose
• I need to take Coenzyme Q10 if I’m on a statin
Your physician is prescribing you unnecessary Statins because of ‘Corruption/Greed’?
PharmaIndustry
Physicians
DONATION ?
Let’s debunk the Myths :Show me the evidences -
LDL-C is important in atherosclerosis
Framingham Heart Study
1948-19511980 men / 2421 womenFirst publication in 1961Epidemiological link –Risk factor concept
Slide courtesy of MJ Chapman
S. Yusuf et al. Lancet 2004; 364:937-52
LDL accounted for ~50% of the Population Attributable Risk
INTERHEART Study
Genetic studies
ARIC: LDL-Cholesterol & CHD among Black Subjects with PCSK9
LOF Mutations (PCSK9142X or PCSK9679X Allele)
Adapted from Cohen JC. N Engl J Med 2006;354:1264-72; ARIC=Atherosclerosis Risk in the Community
30
20
10
0
PCSK9142x or
PCSK9679X
No Yes
12
8
4
0
0 50 100 150 200 250 300
30
20
10
0
0 50 100 150 200 250 300
No Nonsense
Mutation
(N=3278)
50th
Percentile
LDL Cholesterol in Black Subjects (mg/dL)
Fre
qu
en
cy (
%)
PCSK9142x or
PCSK9679X
(N=85)
Co
ron
ary
He
art
Dis
ea
se
(%
)
88 % reduction in the risk
of CHD
p=0.008
28 % reduction in
mean LDL-C
Therapeutic developments to lower LDL-C
-9
-47
-9
-20
-14
-23
-8.5
-19
-11
-34
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
%+
Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521.
* Net difference between treatment and control groups (P values are for events).
TC * CHD events *
N=number enrolled.
Early Primary-Prevention Trials: Overview
WHO: ClofibrateN=15,745, P<0.05
Oslo: Diet/smoking cessation N=1,232, P=0.02
Upjohn: ColestipolN=2,278, P0.02
LRC-CPPT: CholestyramineN=3,806, P<0.05HHS: Gemfibrozil N=4,081, P<0.02
CDP: Niacin (n=1,119)N=8,341, P=ns
CDP: Clofibrate (n=1,103)N=8,341, P=ns
Stockholm: Clofibrate + niacinN=555, P=ns
POSCH: Partial ileal bypassN=838, P<0.001
Early Secondary-Prevention Trials: Overview
Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521.
* Net difference between treatment and control groups (P values are for events).
N=number enrolled; ns=not significant.
TC * CHD events *%+
Partial Ileal Bypass to lower LDL-C
-20
-26
5
-31-33
-22-25
-35
8
-34
-42
-30
-20
-28
5
-24
-20
-9
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159)
N=number enrolled.
TC LDL-C
HDL-C
1o prevention 2o prevention 2o prevention
Summary of Effects of Lipid Lowering on Lipids
and Clinical Events in Statin TrialsNonfatal MI/CHD
deathCHD
deathAll-cause mortality
%+
Achieved LDL-C (mmol/l) :
2.3 3.2 2.9 2.5
(2.0mmol/l) (2.1mmol/l)
(1.6mmol/l) (1.6mmol/l)
(2.8mmol/l) (2.9mmol/l)
(3.9mmol/l)
(3.1mmol/l)
(3.4mmol/l)
(1.9mmol/l)
40% 39%
49% 33% 42%
TNT – ATV80
LDL-C achieved mg/dL (mmol/L)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - Placebo
AFCAPS - Rx WOSCOPS - Rx
ASCOT - Rx
4S - Rx
HPS - Placebo
LIPID - Rx
4S - Placebo
CARE - Rx
LIPID - Placebo
CARE - Placebo
HPS - Rx
0
5
10
15
20
25
30
40(1.0)
60(1.6)
80(2.1)
100(2.6)
120(3.1)
140(3.6)
160(4.1)
180(4.7)
6
Secondary Prevention
Primary Prevention
Rx - Statin therapyPRA – pravastatinATV - atorvastatin
200(5.2)
PROVE-IT - PRA
PROVE-IT – ATV
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:e-version
TNT – ATV10
On-Treatment LDL-C is Closely Related to CHD
Events in Statin Trials – Lower is Better
(1.8)
<64 mg/dl(<1.7mmol/l)
65-77 mg/dl(1.7-2.0mmol/l)
78-90mg/dl(2.0-2.3mmol/l)
91-106mg/dl(2.3-2.7mmol/l)
>106mg/dl(>2.7mmol/l)
≤40
(1mmol/l)
(1.0-1.6mmol/l)
(1.6-2.1mmol/l)
(2.1-2.6mmol/l)
IMProved Reduction of Outcomes: Vytorin Efficacy International Trial
A Multicenter, Double-Blind, Randomized Study to Establish the Clinical Benefit and Safety of Vytorin
(Ezetimibe/Simvastatin Tablet) vs Simvastatin Monotherapy in High-Risk Subjects Presenting
With Acute Coronary Syndrome
Patients stabilized post ACS ≤ 10 days:LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
Simvastatin
40 mg
Follow-up Visit Day 30, every 4 months
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Uptitrated to
Simva 80 mg
if LDL-C > 79
(adapted per
FDA label 2011)
Study Design
*3.2mM
**2.6mM
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
90% power to detect ~9% difference
LDL-C and Lipid Changes
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 69.9 (1.8mM)
145.1 (3.8mM)
137.1(1.5mM)
48.1(1.2mM)
3.8
EZ/Simva 53.2 (1.4mM)
125.8(3.3mM)
120.4(1.4mM)
48.7(1.3mM)
3.3
Δ in mg/dL -16.7 (-0.4mM)
-19.3(0.5mM)
-16.7(-0.2mM)
+0.6(0.1mM)
-0.5
Median Time avg69.5 mg/dL (1.8mmol/L) vs. 53.7 mg/dL (1.4mmol/L)
(2.6mM)
(2.3mM)
(2.1mM)
(1.8mM)
(1.6mM)
(1.3mM)
(1.0mM)
Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489.
Baseline LDL 2.5mM (IQR)
Primary Endpoint — ITT
Simva — 34.7% 2742 events
EZ/Simva — 32.7% 2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (≥30 days), or stroke
7-year event rates
NNT= 50
Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489.
Simva — 22.2%
1704 events
EZ/Simva — 20.4% 1544 events
HR 0.90 CI (0.84, 0.97)
p=0.003
NNT= 56
CV Death, Non-fatal MI, or Non-fatal Stroke
7-year event rates
Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489.
Pushing the Boundaries: Targeting Ultra- Low LDL-C
Territory Unchartered ?
PCSK9 reduces LDLR recycling
Horton et al. J Lipid Res 2009;50:S172–S177.
LDL particles
LDL-R
PCSK9 secretion
PCSK9 routes LDL-R for lysosomal degradation
LDL-R recycling blocked
FOURIERFurther cardiovascular OUtcomesResearch with PCSK9 Inhibition in
subjects with Elevated Risk
MS Sabatine, RP Giugliano, AC Keech, N Honarpour,SM Wasserman, PS Sever, and TR Pedersen,
for the FOURIER Steering Committee & Investigators
American College of Cardiology – 66th Annual Scientific Session
Late-Breaking Clinical Trial
March 17, 2017
Trial Design
Evolocumab SC 140 mg Q2W or 420 mg QM
Placebo SCQ2W or QM
LDL-C ≥70 mg/dL (1.8mmol/l) ornon-HDL-C ≥100 mg/dL(2.6mmol/)
Follow-up Q 12 weeks
Screening, Lipid Stabilization, and Placebo Run-in
High or moderate intensity statin therapy (± ezetimibe)
27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)
RANDOMIZEDDOUBLE BLIND
Sabatine MS et al. Am Heart J 2016;173:94-101
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
LDL
Ch
ole
ste
rol (
mg
/dl)
Weeks
LDL Cholesterol
Evolocumab(median 30 mg/dl, IQR 19-46 mg/dl)
[0.8mmol/l]
Placebo
59% mean reduction (95%CI 58-60),P<0.00001
Absolute reduction: 56 mg/dl (95%CI 55-57)
Baseline 90mg/dl; (2.3mmol/l)
0%
2%
4%
6%
8%
10%
12%
14%
16%
Primary Endpoint
[CV death, MI, stroke, hosp. for UA, or coronary revascularisation
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%
RRR 15%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Key Secondary Endpoint :CV death, MI, Stroke
Months from Randomization
CV
Death
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
Hazard ratio 0.80(95% CI, 0.73-0.88)
P<0.00001
Evolocumab
Placebo7.9%
9.9%
20 % RRR
No Safety Concern at such Low LDL-C
Evolocumab
(N=13,769)
Placebo
(N=13,756)
Adverse events (%)
Any 77.4 77.4
Serious 24.8 24.7
Allergic reaction 3.1 2.9
Injection-site reaction 2.1 1.6
Treatment-related and led to d/c of study drug 1.6 1.5
Muscle-related 5.0 4.8
Cataract 1.7 1.8
Diabetes (new-onset) 8.1 7.7
Neurocognitive 1.6 1.5
Laboratory results (%)
Binding Ab 0.3 n/a
Neutralizing Ab none n/a
New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC
Moving from LDL-target to LDL-eradicationLDL-C < 0.26 mmol/L
11.9
7.87.3
4.4
0
5
10
15
CVD, MI, Stroke, UA, CorRevasc
CVD, MI, Stroke
≥2.6 mM
<0.26 mM
Cardiovascular Efficacy
HR 0.69 (0.49-0.97)P=0.03
HR 0.59 (0.37-0.92)P=0.02
N=504: Median [IQR] LDL-C 0.18 [0.13-0.23] mM = 7 [5-9] mg/dL
23.3
3.4
22.8
3.4
0
5
10
15
20
25
30
Serious adverse event AE -> drug discontinued
≥2.6 mM
<0.26 mM
HR 0.94 (0.74-1.20)P=0.61
HR 1.08 (0.63-1.85)P=0.78
Safety
Giugliano RP, Lancet 2017
Safety of UltraLow LDL-C :Healthy Individuals with Inactivating /Loss of
Function Mutations in Both PCSK9 Alleles
Zhao Z et al. Am J Hum Genet. 2006;79:514-23 Hooper AJ et al.. Atherosclerosis. 2007;193:445-8
New Insights : How does LDL-C lowering
reduce CV events?
Plaque rupture → Coronary Thrombosis
Men ~ 80%; Women ~ 60%
Statins Improve Human Coronary
Atherosclerotic Plaque Morphology
A study-group coronary artery shows dense fibrous plaque (H&E, 10× objective with overall magnification ×100).
A control-group coronary artery with high-grade plaque shows a large lipid core, inflammation, and a thin fibrous cap. (H&E, 4× objective with overall magnification ×40).
(Tex Heart Inst J 2008;35 (2):99-103)
Copyright ©2003 American College of Cardiology Foundation. Restrictions may apply.
Takano, M. et al. J Am Coll Cardiol 2003;42:680-686
Changes in angioscopic findings from baseline to follow-up
After 1 yr statin Rx After 1 yr of No Rx
Can we alter the natural history of
atherosclerosis?
Modified from Stary HC et al, Circulation 92:1355, 1995
Baseline
Atheroma: 10.16 mm2
Percen
t ath
ero
ma v
olu
me
Baseline
Follow-up
Rosuvastatin40 mg/day
1.6mmol/l of LDL-C reduction
Abhishek Keraliya, M.D., and Ron Blankstein, M.D. Regression of Coronary Atherosclerosis with Medical TherapyN Engl J Med 2017; 376:1370. April 6, 2017. DOI: 10.1056/NEJMicm1609054
Plaque regression & ischaemia reversal
42yr old man.
After 4 years of High Intensity Statin & Ezetimide
Myth: Once the LDL-C is lowered, we can stop or reduce the dosage of
statin/lipid lowering agent !
IT’S NOT ONLY HOW MUCH WE LOWER LDL-C BUT FOR HOW LONG WE
KEEP IT LOW!
When to Treat: Insights from Genetic Polymorphisms
Ference, BA et al. J Am Coll Cardiol 2015;65:1552–61.
Comparison of PCSK9 inhibitors and statinsby duration of treatment
Ference BA, et al. Eur Heart J. 2017
How about ‘CURING’ atherosclerosis?
Plaque Regression
Bjo ̈rkegren JLM, et al. (2014) Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis. PLoS Genet 10(2): e1004201.Feb 2014.
PCL started at week 30 ( ), 40 ( ), or 50 ( ).
Plaque Regression after lipid lowering gene modification at different stages
of atherosclerosis
Bjo ̈rkegren JLM, et al. (2014) Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis. PLoS Genet 10(2): e1004201.Feb 2014.
Atherosclerosis timeline
Modified from Stary HC et al, Circulation 92:1355, 1995
Early Statin Rx: To regress disease
‘CURE’
Late Statin Rx : Large atherosclerosis
Burden; more calcific &Fibrous components
‘STABILISATION’
Summary (1) :
• Causative link of LDL-C to atherosclerosis is unequivocal
• Lowering LDL-C improves clinical outcomes in all clinical scenarios
• The Lower the Better!
• No lower threshold has been reached whereby LDL-C lowering do not provide further benefit in CV event reduction or plaque regression
Summary (2) :
• Statin mainstay of Rx – effective & safe
• We have new armamentarium eg. PCSK9-inhibitors
• No signal of harm with very low achieved LDL-C levels
• LDL-C lowering should start early & be sustained for amplified benefits
Thank You Very Much!
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