LDL-Cholesterol : Old Story but New Insights & Emerging Evidence

The 10th. Central Vietnam Open Congress of Cardiology

Choo Gim Hooi MD Cardiac Vascular Sentral KL (CVSKL)

12th. July, 2019 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 Factors contributing to Atherosclerosis

• High LDL-C • Low HDL-C • Obesity (Central, Visceral) • Diet • Physical inactivity • Hypertension • Smoking • Diabetes mellitus • Genetics • Environment 1856 Rudolf Ludwig Carl Virchow

1821-1902

Atherosclerosis, Inflammation [endarteritis deformans] & Cholesterol deposit Cholesterol & Atherosclerosis model, 1913

Healthy Volunteers

Carrots & Salads Egg Yolk Fortified Food

Nikolaj Nikolajewitsch Anitschkow (1885-1964) 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 1974

Circulating LDL-C controlled by LDL-C Receptor activity

Goldstein JL, Brown MS. Cell 2015;161-161 1976 : Dr.Akira Endo Discoverer 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 Vagelos Alfred W. Alberts Constant Battle with the Myths & Fallacies about LDL-C and Statins ! http://www.tbyil.com/Lowering_Chole sterol.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’?

Physicians Pharma Industry

DONATION ? Let’s debunk the Myths : Show me the evidences - LDL-C is important in atherosclerosis Framingham Heart Study

1948-1951 1980 men / 2421 women First publication in 1961 Epidemiological link – Risk factor concept INTERHEART Study LDL accounted for ~50% of the Population Attributable Risk

Slide courtesy of MJ Chapman S. Yusuf et al. Lancet 2004; 364:937-52 Genetic studies ARIC: LDL-Cholesterol & CHD among Black Subjects with PCSK9 LOF Mutations (PCSK9142X or PCSK9679X Allele)

No Nonsense 30 50th Mutation Percentile 88 % reduction in the risk 20 (N=3278) 12 of CHD p=0.008 10

0 8

0 50 100 150 200 250 300 PCSK9142x or 679X

Frequency (%) Frequency PCSK9 30 (N=85) 4

20 28 % reduction in

mean LDL-C (%) Disease Heart Coronary 10 0 0 No Yes

0 50 100 150 200 250 300 PCSK9142x or LDL Cholesterol in Black Subjects (mg/dL) PCSK9679X

Adapted from Cohen JC. N Engl J Med 2006;354:1264-72; ARIC=Atherosclerosis Risk in the Community Therapeutic developments to lower LDL-C Early Primary-Prevention Trials: Overview

TC * CHD events * 0 -5 Oslo: Diet/smoking cessation N=1,232, P=0.02 -10 -9 -9 -8.5 WHO: Clofibrate -11 -15 -14 N=15,745, P<0.05 Upjohn: Colestipol -20 -19 -20 N=2,278, P0.02 %+ -25 -23 LRC-CPPT: -30 Cholestyramine -35 N=3,806, P<0.05 -34 HHS: Gemfibrozil -40 N=4,081, P<0.02 -45 -50 -47 N=number enrolled.

* Net difference between treatment and control groups (P values are for events).

Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521. Early Secondary-Prevention Trials: Overview

TC * CHD events * %+ CDP: Clofibrate (n=1,103) N=8,341, P=ns

CDP: Niacin (n=1,119) N=8,341, P=ns

Stockholm: Clofibrate + niacin N=555, P=ns

POSCH: Partial ileal bypass N=838, P<0.001

N=number enrolled; ns=not significant.

* Net difference between treatment and control groups (P values are for events).

Adapted from Levine GN et al. N Engl J Med. 1995;332:512-521. Partial Ileal Bypass to lower LDL-C Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Statin Trials 10 8 Nonfatal 5 5 MI/CHD CHD All-cause 5 TC LDL-C death death mortality 0 HDL-C -5 -10 -9 %+ -15 -20 -20 -20 -20 -22 -25 -24 -25 -26 -30 -28 -31 -30 -35 -33 -35 -34 -40 -45 -42 WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159) 1o prevention 2o prevention 2o prevention

N=number enrolled. Achieved LDL-C (mmol/l) : 2.3 3.2 2.9 2.5 (3.9mmol/l)

(3.4mmol/l)

(3.1mmol/l) (2.8mmol/l) (2.9mmol/l)

(2.0mmol/l) (2.1mmol/l) (1.9mmol/l) (1.6mmol/l) (1.6mmol/l) 49% 33% 42% 40% 39%

On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials – Lower is Better 30 4S - Placebo

25 Rx - Statin therapy Secondary Prevention PRA – pravastatin ATV - atorvastatin 4S - Rx 20

LIPID - Placebo 15 LIPID - Rx CARE - Placebo CARE - Rx Primary Prevention HPS - Rx TNT – ATV10 HPS - Placebo 10 TNT – ATV80 PROVE-IT - PRA WOSCOPS – Placebo PROVE-IT – ATV AFCAPS - Placebo 6 5 AFCAPS - Rx WOSCOPS - Rx ASCOT - Placebo ASCOT - Rx 0 40 60 (1.8) 80 100 120 140 160 180 200 (1.0) (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2) LDL-C achieved mg/dL (mmol/L)

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 <64 mg/dl 65-77 mg/dl (<1.7mmol/l) (1.7-2.0mmol/l)

78-90mg/dl 91-106mg/dl >106mg/dl (2.0-2.3mmol/l) (2.3-2.7mmol/l) (>2.7mmol/l) (2.1-2.6mmol/l)

(1.6-2.1mmol/l)

(1.0-1.6mmol/l)

≤40 (1mmol/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 Study Design

Patients stabilized post ACS ≤ 10 days: *3.2mM LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx) **2.6mM

N=18,144 Standard Medical & Interventional Therapy

Uptitrated to Simvastatin Simva 80 mg Ezetimibe / Simvastatin if LDL-C > 79 40 mg (adapted per 10 / 40 mg FDA label 2011) Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference 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

Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12 LDL-C and Lipid Changes Baseline LDL 2.5mM (IQR)

1 Yr Mean LDL-C TC TG HDL hsCRP

(2.6mM) Simva 69.9 145.1 137.1 48.1 3.8 (1.8mM) (3.8mM) (1.5mM) (1.2mM) EZ/Simva 53.2 125.8 120.4 48.7 3.3 (2.3mM) (1.4mM) (3.3mM) (1.4mM) (1.3mM) Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5 (2.1mM) (-0.4mM) (0.5mM) (-0.2mM) (0.1mM)

(1.8mM) Median Time avg 69.5 mg/dL (1.8mmol/L) vs. 53.7 mg/dL (1.4mmol/L) (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. Primary Endpoint — ITT

Cardiovascular death, MI, documented unstable angina requiring rehospitalization, coronary revascularization (≥30 days), or stroke

HR 0.936 CI (0.887, 0.988) Simva — 34.7% p=0.016 2742 events NNT= 50

EZ/Simva — 32.7% 2572 events

7-year event rates Cannon CP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. NEJM 2015. DOI: 10.1056/NEJMoa1410489. CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 Simva — 22.2% NNT= 56 1704 events

EZ/Simva — 20.4% 1544 events

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

LDL particles

PCSK9 routes LDL-R for lysosomal LDL-R degradation

LDL-R recycling blocked

PCSK9 secretion

Horton et al. J Lipid Res 2009;50:S172–S177. FOURIER Further cardiovascular OUtcomes Research 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

27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe)

LDL-C ≥70 mg/dL (1.8mmol/l) or non-HDL-C ≥100 mg/dL(2.6mmol/)

RANDOMIZED Evolocumab SC DOUBLE BLIND Placebo SC 140 mg Q2W or 420 mg QM Q2W or QM

Follow-up Q 12 weeks

Sabatine MS et al. Am Heart J 2016;173:94-101 LDL Cholesterol

100 Baseline 90mg/dl; (2.3mmol/l) Placebo 90

80 59% mean reduction (95%CI 58-60), 70 P<0.00001 60 Absolute reduction: 56 mg/dl (95%CI 55-57) 50

LDL Cholesterol (mg/dl) Cholesterol LDL Evolocumab 20 (median 30 mg/dl, IQR 19-46 mg/dl) 10 [0.8mmol/l]

0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks Primary Endpoint [CV death, MI, stroke, hosp. for UA, or coronary revascularisation 16% Hazard ratio 0.85 14.6% 14% (95% CI, 0.79-0.92) P<0.0001 12.6%

12% Placebo Revasc

10% Cor 8% RRR 15% Evolocumab 6%

CV Death, Death, CV MI, Stroke, 4% Hosp for UA, Hosp for UA, or

0% 0 6 12 18 24 30 36 Months from Randomization Key Secondary Endpoint : CV death, MI, Stroke

10% 9.9%

9% Hazard ratio 0.80 (95% CI, 0.73-0.88) 8% P<0.00001 7.9% Placebo 7%

6% 20 % RRR

4% Evolocumab

3% CV Death, Death, CV MI, Stroke or 2%

0% 0 6 12 18 24 30 36 Months from Randomization No Safety Concern at such Low LDL-C

Evolocumab Placebo (N=13,769) (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-eradication LDL-C < 0.26 mmol/L

N=504: Median [IQR] LDL-C 0.18 [0.13-0.23] mM = 7 [5-9] mg/dL

Cardiovascular Efficacy Safety

15 HR 0.69 (0.49-0.97) ≥2.6 mM 30 HR 0.94 (0.74-1.20) ≥2.6 mM P=0.03 <0.26 mM P=0.61 <0.26 mM 11.9 25 23.3 22.8 HR 0.59 (0.37-0.92) 10 P=0.02 20 7.8 7.3 15 HR 1.08 (0.63-1.85) 4.4 5 10 P=0.78

5 3.4 3.4 0 0 CVD, MI, Stroke, UA, Cor CVD, MI, Stroke Serious adverse event AE -> drug discontinued Revasc

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 A control-group coronary artery with shows dense fibrous plaque high-grade plaque shows a large lipid core, inflammation, and a thin fibrous (H&E, 10× objective with × overall magnification ×100). cap. (H&E, 4 objective with overall magnification ×40). (Tex Heart Inst J 2008;35 (2):99-103) Changes in angioscopic findings from baseline to follow-up

After 1 yr statin Rx After 1 yr of No Rx

Takano, M. et al. J Am Coll Cardiol 2003;42:680-686

Modified from Stary HC et al, Circulation 92:1355, 1995 Baseline Baseline Rosuvastatin 40 mg/day 1.6mmol/l of LDL-C reduction

Atheroma: 10.16 mm2 Percent

Follow-up atheroma volume Plaque regression & ischaemia reversal

42yr old man.

After 4 years of High Intensity Statin & Ezetimide

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 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

PCL started at week 30 ( ), 40 ( ), or 50 ( ).

Bjo rkegren̈ 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. Plaque Regression after lipid lowering gene modification at different stages of atherosclerosis

Early Statin Rx: Late Statin Rx : To regress disease Large atherosclerosis ‘CURE’ Burden; more calcific & Fibrous components Modified from Stary HC et al, Circulation 92:1355, 1995 ‘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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