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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