Robert A. Vogel, MD Clinical Professor of Medicine ...The LDL (lipid) hypothesis is the concept that...

Robert A. Vogel, MD

Clinical Professor of Medicine

University of Colorado Denver

Disclosures:Disclosures:

National Coordinator: ODYSSEY Outcomes Study(Phase III – Sanofi)

Speakers Bureau: Sanofi, Regeneron

Case Report

A 67y/odiabeticm anhasCHD andanEFof30%(AICD). Hehasbeenangina-freeafteranL AD(AICD). Hehasbeenangina-freeafteranL ADstenosisw astreatedw ithaDES oneyearago. T hreem onthsago,hepresentedw ithanginaago. T hreem onthsago,hepresentedw ithanginaandadenovolesionofhisR CA notpresentoneyearago. N ow hisL AD stentlesionhasalsore-stenosed. Hehasbeenon20m gofCrestor,10m gstenosed. Hehasbeenon20m gofCrestor,10m gofZetia,w ithT C 170,L DL -C 80,T G 150 andHgbA1C,6.5. Arew edoingasm uchasw ecandoforA1C,6.5. Arew edoingasm uchasw ecandoforhislipids?

The LDL (lipid) hypothesis is the concept thatexcess LDL and other atherogenic lipoproteinsexcess LDL and other atherogenic lipoproteinsare the predominant causal factors in thedevelopment of atherosclerosis. This hypothesisalso assumes that reducing LDL, regardless ofalso assumes that reducing LDL, regardless ofthe means, should produce a correspondingreduction in cardiovascular events.reduction in cardiovascular events.

Adapted from Jarcho JA, Keaney,J Jr, NEJM 2015; 372:2448

Cell Division

Lipid

R udolfVirchow 1856

Lipid

Michael Brown

Joseph Goldstein Regulation of Cholesterol Metabolism via LDL Receptor – Nobel 1985

Details of the LDL Hypothesis

↑ Atherogenic particlesparticles

DepositionOxidationMɸ uptake → foam

VLDLRemnants Mɸ uptake → foam

cellsCellular proliferationMatrix production

Remnants

LDL

Matrix productionInflammationPlaque rupture &

Chylo (Apo-B48)Remnants

Plaque rupture &erosion

Thrombosis

Primary factorFacilitating factors

Boekholdt SM et al, JACC 2014;64:485

Cardiovascular Risk vs. Statin Treatment-achievedLDL-C in 8 RCTs (N = 38,153)LDL-C in 8 RCTs (N = 38,153)

Achieved LDL-C (mg/dl)

Nikpay M et al, Nature Genetics 2015;47:1121-32

1000 Genomes-based Genome-wide Association Analysis ofCHD (185K cases and controls, 6.7 M common and 2.7M rare variants)CHD (185K cases and controls, 6.7 M common and 2.7M rare variants)

Confirmed

LDLR PCSK9

Confirmedtraditionalrisk factors:

LDL• LDL• Lp(a)• RLPs• RLPs• TG• SBP

Ference BA et al, JACC 2012;60:2631

Mendelian Randomization Analysis:Genetically Lower LDL-C (9 variants) vs. CHD Risk in 312,321 Subjects

30%

Genetically Lower LDL-C (9 variants) vs. CHD Risk in 312,321 Subjects

30%

CH

DR

isk

Re

du

ctio

n

rs11591147

20%

CH

DR

isk

Re

du

ctio

n

rs4420638

10%

CH

DR

isk

Re

du

ctio

n

rs599839

rs6511720rs646776

rs2228671

CH

DR

isk

Re

du

ctio

n

rs4299376

rs1206510rs12916

0 5 10 15LDL-C (mg/dl) Reduction

0%

Ference BA et al, JACC 2012;60:2631

Early vs. Late Cholesterol Lowering for Reducing CHD Risk: Statin Trialsvs. Mendelian Analysis (9 SNPs, 6 genes) in 312,321 Subjectsvs. Mendelian Analysis (9 SNPs, 6 genes) in 312,321 Subjects

1.0 mmol/L

0.5 mmol/L

0.25 mmol/L0.25 mmol/L

0.125 mmol/L

CHD RiskGenetically lower

Statin trials

Case Study: 86 yoF,asym ptom aticw ithonnom eds,w antsherm am m ography resultsm eds,w antsherm am m ography results

P M H:negative,nevertookm eds

FH:Fatherhadearly CHD,Vineberg,diedat66FH:Fatherhadearly CHD,Vineberg,diedat66

P .E.:BP 152/78,P 78,BM I24N orm alN orm al

L abs:T C 316,L DL -C 210,HDL -C 54,T G 258ECG:W N LECG:W N L

ClinicalCourse:livedto96,diedof“ oldage”

9Rodrigues F et al, JAMA Cardiol 2016, Nov 9.

“Statin Hypothesis”: Annual Mortality in 509,766Older VA Patients with ASCVD by Statin TreatmentOlder VA Patients with ASCVD by Statin Treatment

6%

7%

5%

6%

An

nu

alM

ort

alit

y

3%

4%

An

nu

alM

ort

alit

y

2%

3%

An

nu

alM

ort

alit

y

0%

1%

0%

No Statin Low-intensityStatin

M0d-intensityStatin

High-IntensityStatin

• LDL-C, IDL-C• LDL-C, IDL-C

• Triglycerides, RLPs

• NO Availability

LDL Receptors

Endothelial F’n• NO Availability

• NF-

• CRP

Endothelial F’n

• CRP

• M, MMP-1,

MMP-3, MMP-9

Inflammation

MMP-3, MMP-9

• Platelet Activation

TF Clotting• TF Clotting

Ridker et al, N Engl J Med Aug 27, 2017

CANTOS: Canakinumab (IL-1β inhibitor) 50, 150, and 300mg SC q3mo vs. Placebo in 10,061 Subjects with prior MI andSC q3mo vs. Placebo in 10,061 Subjects with prior MI and

CRP >2 on Lipid Lowering over 4 YearsMI, CVA, CVD with Canakinumab 150mg vs. Pbo

(Initial LDL-C 82 mg/dl)

N EnglJM ed 2006;354:1264-72

Sequence variations in PCSK9, low

N atureGenetics2003;534:154

Sequence variations in PCSK9, lowLDL, and protection againstcoronary heart disease

CohenJC,Boerw inkleE,M osley T H Jr,HobbsHH

RESULTS:O fthe3363 blacksubjectsexam ined,2.6 percenthadO fthe3363 blacksubjectsexam ined,2.6 percenthadnonsensem utationsinP CS K9;thesem utationsw ereassociated w itha28 percentreductioninm eanL DLcholesterolandan88percentreductionintheriskofCHD(P =0.008 forthereduction;hazard ratio,0.11;95 percentconfidenceinterval,0.02 to0.81;P =0.03).O fthe9524confidenceinterval,0.02 to0.81;P =0.03).O fthe9524w hitesubjectsexam ined,3.2 percenthad asequencevariationinP CS K9 thatw asassociated w itha15 percentreductioninL DL cholesteroland a47 percentreductionintheriskofCHD (hazardratio,0.50;95 percentconfidenceinterval,0.32 to0.79;P =0.003).interval,0.32 to0.79;P =0.003).CONCLUSIONS:T hesedataindicatethatm oderatelifelongreductionintheplasm alevelofL DL cholesterolisassociated w ithasubstantialreductionintheincidenceofcoronary events,substantialreductionintheincidenceofcoronary events,eveninpopulationsw ithahighprevalenceofnon-lipid-related cardiovascularriskfactors.

B/E Receptor)

LDL, IDL,RLPs

CholesterolCholesterol

17

HMGHMG--CoACoA--RR

(Sterol regulating element(Sterol regulating element--binding protein)binding protein)

PCSK9 Regulation of LDL Receptor Expression

Forillustrationpurposesonly

18

Cohen JC, et al. NEJM 2006; 354: 1264–72

Loss-of-Function PCSK9 Genetic Variants areAssociated with ↓ LDL-C and ↓↓ CHD

CHD ↓88% CHD ↓47%

Associated with ↓ LDL-C and ↓↓ CHD

LDL-C LDL-C↓15%

LDL-C↓28% ↓15%

Black Subjects White Subjects

Hooper AJ et al, Atherosclerosis 2007;193:445

Sabatine MS et al, N Engl J Med 3/17/17

N EnglJM ed3/17/17

FOURIER Trial: Adverse Events

Ridker PM et al, N Engl J Med 3/17/17

Bococizumab in 27K Subjects with ASCVD, DM, or CKD with >1RF

SPIRE 1SPIRE 1LDL-C >707 Months

SPIRE 2SPIRE 2LDL-C >10012 Months

Statin vs. Pbo, Statin vs. Statin, IMPROVE-IT, and FOURIERTrials: Relationship of LDL-C Lowering to CVE Reduction

CTT Collaboration. Lancet 2005; 366:1267; Lancet 2010;376:1670. Wiviott SD et al. JACC 2005;46:1411 Pedersen T et al, JAMA 2005;294:2437

Trials: Relationship of LDL-C Lowering to CVE Reduction

IMPROVE-IT PROVE-IT TNT St FOURIER Statin vs. PboIMPROVE-IT PROVE-IT TNT St FOURIER Statin vs. Pbo(simva 40/80 + eze) (prava 40 vs. atorva 80) (atorva 10 vs. 80) (simva + evolocumab)

Hepatic CellHepatic Cell

LDL-RLDL-R

PCSK9

EGF-A Domain Catalytic Site

Monoclonal antibodies:Fully andpartly hum anm Ab(FDA-approved)

PCSK9

Monoclonal antibodies:Fully andpartly hum anm Ab(FDA-approved)

Peptide mimics:P eptidesthatm im ictheEGF-A dom ainoftheL DL receptor

Gene silencing:m R N A antisenseoligonucleotides

Anti-cleavage (furin) compounds

Anti-PCSK9 vaccine

Case Report

A 67y/odiabeticm anhasCHD andanEFof30%(AICD). Hehasbeenangina-freeafteranL AD(AICD). Hehasbeenangina-freeafteranL ADstenosisw astreatedw ithaDES oneyearago. T hreem onthsago,hepresentedw ithanginaago. T hreem onthsago,hepresentedw ithanginaandadenovolesionofhisR CA notpresentoneyearago. N ow hisL AD stentlesionhasalsore-stenosed. Hehasbeenon20m gofCrestor,10m gstenosed. Hehasbeenon20m gofCrestor,10m gofZetia,w ithT C 170,L DL -C 80,T G 150 andHgbA1C,6.5. Arew edoingasm uchasw ecandoforA1C,6.5. Arew edoingasm uchasw ecandoforhislipids?

ACC and NLA Guidelines on PCSK9-I Use

• PCSK9 induces LDL receptor degradation• PCSK9 induces LDL receptor degradation

• mAb PCSK9 inhibitors reduce LDL-C 50-70%in patients on/off statins and in HeFH

Initial two-year data demonstrates a 20%• Initial two-year data demonstrates a 20%reduction in major CVEs in CHD subjects onstatinsstatins

• The early safety profile appears good

• Initial annual retail cost is ≈ $15K• Initial annual retail cost is ≈ $15K

• Other approaches to ↓PCSK9 are ac� vely being investigatedbeing investigated