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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