Bài giảng LDL-Cholesterol: Old story but new insights & emerging evidence

The lecture presents the content atherosclerosis ancient disease; Vietnam health statistics 2016; atherosclerosis timeline; fatty streak in epicardial coronary artery of a 3 year old boy; prevalence of atherosclerosis by donor age; constant battle with the myths and fallacies about LDL-C and statins; various myths about LDL-C and statins...

LDL-Cholesterol : Old Story but

New Insights & Emerging Evidence

Choo Gim Hooi MD Cardiac Vascular Sentral KL (CVSKL)

12th July, 2019

The 10 th Central Vietnam Open

Congress of Cardiology

Sypnosis :

• Myth & Fallacies about LDL-C & Statins

• Brief historical facts

• Genetic, Epidemiological & Interventional

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

1856 Rudolf Ludwig Carl Virchow

Atherosclerosis, Inflammation [endarteritis deformans]

& Cholesterol deposit

1821-1902

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Cholesterol & Atherosclerosis model, 1913

Nikolaj Nikolajewitsch

Anitschkow (1885-1964)

Healthy Volunteers

Adolf Otto Reinhold Windaus

1964: Nobel Laureate for Physiology or

Medicine : Elucidation of Cholesterol & Fatty

Acid Metabolism Pathway

Joseph Goldstein & Michael Brown :

1976 : Dr.Akira Endo

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) – 1 st statin derived

from Penicillium citinium

Developers [Merck] of Clinically useful Statins :

Lovastatin & Simvastatin

Roy Vagelos

Alfred W Alberts

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Constant Battle with the Myths & Fallacies about

LDL-C and Statins !

sterol.htm

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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’?

Pharma Industry

Physicians

DONATION ?

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Let’s debunk the Myths : Show me the evidences - LDL-C is important in atherosclerosis

Framingham Heart Study

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

Adapted from Cohen JC N Engl J Med 2006;354:1264-72; ARIC=Atherosclerosis Risk in the Community

28 % reduction in mean LDL-C

Therapeutic developments

to lower LDL-C

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).

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

N=number enrolled.

HDL-C

Summary of Effects of Lipid Lowering on Lipids

and Clinical Events in Statin Trials

Nonfatal MI/CHD death

CHD death

All-cause mortality

%+

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Achieved LDL-C (mmol/l) :

(2.0mmol/l) (2.1mmol/l)(1.6mmol/l) (1.6mmol/l)

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

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)

(1mmol/l) (1.0-1.6mmol/l) (1.6-2.1mmol/l) (2.1-2.6mmol/l)

IMProved Reduction of Outcomes: Vytorin E fficacy International T rial

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

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)

LDL-C and Lipid Changes

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

(-0.4mM)

-19.3(0.5mM)

-16.7(-0.2mM)

+0.6(0.1mM)

Primary Endpoint — ITT

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.

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

R esearch with PCSK9 I nhibition in

subjects with E levated R isk

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 – 66 th Annual Scientific

Session Late-Breaking Clinical Trial

March 17, 2017

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

RRR 15%

Key Secondary Endpoint :

CV death, MI, Stroke

Months from Randomization

Evolocumab

9.9%

20 % RRR

No Safety Concern at such Low LDL-C

Evolocumab (N=13,769)

Placebo (N=13,756)

New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC

Moving from LDL-target to LDL-eradication

LDL-C < 0.26 mmol/L

11.9

7.8 7.3

HR 0.59 (0.37-0.92) P=0.02

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

Can we alter the natural history of

atherosclerosis?

Modified from Stary HC et al, Circulation 92:1355, 1995

reduction

Abhishek Keraliya, M.D., and Ron Blankstein, M.D Regression of Coronary Atherosclerosis with Medical Therapy

N 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 statins

by 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

‘STABILISATION’

• 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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