Jacques Genest, Jr', MD FRCPC FACC

1
Jacques Genest, Jr., MD FRCPC FACC

• Professor and Novartis Chair in Medicine, McGill
  University
• Director of the Division of Cardiology, McGill
  University Health Centre/Royal Victoria Hospital
• Montréal, Québec, Canada

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Ronnie W.F. Campbell 1946 1998Memorial Lecture
3
ACC Lake Louise Ronnie W. F. Campbell Memorial
Lecture
Fuster V. Circulation 1998982361
4
Disclosure J. Genest MD

• Advisory Board, Speakers Bureau, Consultant,
  Grants
• sanofi-aventis
• AstraZeneca
• Merck Frosst
• Schering Plough
• Pfizer (CV Research Award)
• Novartis
• Biotech Resverlogix (Research Grant)
• I used Lovastatin before any of you in October
  1986

5
Statins _at_ 21

• Cholesterol
• Evolution of a molecule
• How it is made
• How does one get rid of it
• What happens when you have too much?

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Cholestérine
M. Eugène Chevreul 1786-1889 Cholestérine (1815)
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Cholesterol

• Nobel Prizes n13
• H. O Weiland 1928, (structure of cholesterol)
• AOR Windhaus 1928 (structure of cholesterol)
• L. Ruzicka 1939, (structure of cholesterol)
• R. Robinson 1947 (structure of cholesterol)
• OPH Diels 1950 (structure of cholesterol)
• K. Bloch, F Leyden 1964 (Biosynthesis)
• RB Wodward 1965 (stereochemical synthesis)
• DHR Barton, O. Hassel 1965 (all chair
  conformation)
• JW Comforth, 1975 (H atoms orientation)
• Joseph Goldstein, Michael Brown 1985
  (LDL-receptor mediated endocytosis)

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Konrad Bloch 1912-2000
Nobel 1964
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US and Canada Convicted felon
UK Lord
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Evolutionary Perfection of a Molecule

• A hypothesis, based on the work of Konrad Bloch
  
• Cholesterol has been selected over the almost
  unimaginably long time scale of natural evolution
  for its ability to optimize certain physical
  properties of cell membranes with regard to
  biological functions.

Konrad Bloch (1912-2000). Blondes in Venitian
Paintings, the Nine-Banded Armadillo and Other
Assays in Biochemistry. Nobel 1985
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Cholesterol Synthesis Pathway
Squalene Synthase
Istvan E and Deisenhofer J. Science
20012921160-1164.
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Cholesterol
Cholesterol
Lanosterol
13
Cholesterol in Evolution
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Cholesterol in EvolutionArchean-Proterozoic
period?
The enzymes for the synthesis of cholesterol date
back 0.5 - 2 billions of years ago
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Evolution of the Lipid transport System
Complex organisms (gut muscles a good
description of men) require hydrophobic fat
transport system

• Apo C (apo AI) Ancestral apolipoprotein
• Apolipophorin (insects), vitellogenin (birds),
  apo B
• ABC transporters (ABCA, ABCC and ABCG)

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Lipoprotein Metabolism
FFA
Liver
HL
LPL
Exogenous Pathway
Chylo Remnant
Chylomicron
Peripheral Cells
Free Cholesterol
ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Fre
e cholesterol
Intestine
Steroidogenic Cells
HL
LCAT
HDL3
Nascent HDL
HDL2
LDL
Liver
ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Fre
e cholesterol
CETP PLTP
Tg
Endogenous Pathway
CE
3
Liver
HL
LPL
VLDL
IDL
FFA
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LDL-Receptor PathwaySREBP Pathway
LDL-receptor
Joseph GOLDSTEIN
Michael BROWN
Nobel Prize 1985
SREBP
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Causes of Familial Hypercholesterolemia
LDL-R Primary familial hypercholesterolemia
ARH Autosomal recessive familial
Hypercholesterolemia
PCSK9 Proprotein convertase subtilisin/kexin
type 9
ApoB Familial defective Apo B
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PCSK9 Gene Mutation(African-Americans)

• Lifelong low LDL-C protects against CAD

Cohen J. et al. NEJM 20063541264
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Drugs Affecting Lipoprotein Metabolism
21
Mononuclear Phagocytes
Libby P. Inflammation and atherosclerosis. Nature
2002420868
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Reverse Cholesterol Transport
Nascent HDL
Lipid-free apo AI
ABCA1
LCAT
Cholesterol
HDL3
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Speculation Role of HDL

• Complex animals cannot degrade the sterol nucleus
  
• Sterol accumulation in the ER triggers the UPR
  (unfolded Protein Response) via Jnk2 and CHOP
  pathways leading to apoptosis
• Amphipatic helical proteins (apo AI, E) prevent
  cellular sterol accumulation

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Sterol Accumulation in Macrophages
25
Statins _at_ 21

• The evidence
• Cholesterol lowering
• Clinical trials
• Death, MI
• Surrogate end-points
• Pleiotropic effects (?)

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Managing Atherosclerosis the first 50 years
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Statins were discovered by Dr. Akira ENDO (Japan)
Dr. Arika Endo studied molds that produced an
inhibitor of cholesterol synthesis

• Statins were first given to a patient by Dr.
  Akira Yamamoto

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A Brief History of Statins
1970
1980
1990
2000
2010
Pravastatin
Cerivastatin
Rosuvastatin
Atorvastatin
Compactin
Simvastatin
Lovastatin
HPS
4S
PROVE-It
CARE LIPID
TNT SEARCH IDEAL
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Surrogate End-Points
IMT/IVUS
ACS
Biol. Pathways
Lipid Levels
CHD death, MI
Surrogate End-Points
Mortality/ Morbidity
Risk Factor
Biomarkers
ACS
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LDL-C Percentage Change from Baseline at Week 6
Dose (log scale)
10mg
20mg
40mg
80mg
0
-10
-20
-20
-24
Mean percentage change in
-28
LDL-C from baseline
-30
-30
-35
-37
-39
-40
-43
-46
-48
-46
-50

-52
-51
-55


-60
Rosuvastatin n473
Atorvastatin n634
Simvastatin n648
Pravastatin n485
Astra-Zeneca sponsored study
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A Brief History of Statins
1970
1980
1990
2000
2010
Pravastatin
Cerivastatin
Rosuvastatin
Atorvastatin
Compactin
Simvastatin
Lovastatin
HPS
4S
PROVE-It
CARE LIPID
TNT SEARCH IDEAL
32
Surrogate End-Points
IMT/IVUS
ACS
Biol. Pathways
Lipid Levels
CHD death, MI
Surrogate End-Points
Mortality/ Morbidity
Risk Factor
Biomarkers
ACS
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Pleiotropic Effects of Statins
34
0
10
20
LIPID
LRC
CARE
Reduction in events ()
POSCH
HPS
30
AFCAPS
4S
WOS
40
50
40
80
0
Reduction in plasma cholesterol (mg/dL)
35
Statins
Non Statins
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Biological Pathways

• While the evidence of pleiotropic effects on
  biological pathways is compelling, these
  observations have been made in-vitro, in
  well-defined cell based systems.
• Their clinical relevance is, for the most part,
  unknown

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Surrogate End-Points
IMT/IVUS
ACS
Biol. Pathways
Lipid Levels
CHD death, MI
Surrogate End-Points
Mortality/ Morbidity
Risk Factor
Biomarkers
ACS
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Results of RCTs of Cholesterol Lowering Using
Serial Coronary Arteriography
Brown GB, Circulation1993 871781-1789,
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ASTEROID
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Surrogate End-points

• The evaluation of atherosclerosis by imaging
  methods is not a substitute for clinical trials
• At best, they serve as a sentinel signal
  indicating potential trouble.

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Surrogate End-Points
IMT/IVUS
ACS
Biol. Pathways
Lipid Levels
CHD death, MI
Surrogate End-Points
Mortality/ Morbidity
Risk Factor
Biomarkers
ACS
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Outcomes in Primary Prevention, Stable and
Unstable Coronary Disease
Unstable angina/non-Q-wave MI (FRISC II)
Death/nonfatal MI ()
Stable angina (SAPAT)
Primary prevention (WOSCOPS)
0
2
4
6
8
10
12
Months of follow-up
Wallentin L et al. Lancet 2000356916. Juul-Moll
er S et al. Lancet 199234014211425. Shepherd J
et al. N Engl J Med 199533313011307.
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Prove-It (TIMI 22)
Pravastatin 40 mg
Atrovastatin 80 mg
Cannon CP et al. NEJM 2004350 (10.1056NEJMoa04058
3)
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the benefit of atorvastatin was evident very
early, even in the first 30 days of therapy.
P. Bogaty
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P. Bogaty
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ACS Studies

• ACS studies provide clinical events in a
  relatively short period of time
• They are being increasingly recognized to change
  clinical practice
• The wisdom of this (new) paradigm is uncertain

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Surrogate End-Points
IMT/IVUS
ACS
Biol. Pathways
Lipid Levels
CHD death, MI
Surrogate End-Points
Mortality/ Morbidity
Risk Factor
Biomarkers
ACS
52
Major Statin studies
Modified from Waters DD, et al. Am J Cardiol.
200493154-8
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CHD Reduction in Secondary Prevention Trials
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Relationship Between Proportional Reduction in
Events and Optimal LDL-C Reduction at 1 Year
A prospective meta-analysis of data from 90,056
individuals from 14 trials of statins1
A 1 mmol/L (39 mg/dL) reduction in LDL-C was
associated with a
Adapted from Baigent C, et al, Cholesterol
Treatment Trialists (CTT) Collaborators. Lancet
200536612671278.
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Cholesterol Treatment Trialists (CTT)
Lancet 20053661267
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Sudden Cardiac Death
Levantesi G et al. Meta-analysis of effect of
statin treatment on risk of sudden death. Am J
Cardiol. 2007 Dec 1100(11)1644-50
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Sudden Cardiac Death
Levantesi G et al. Meta-analysis of effect of
statin treatment on risk of sudden death. Am J
Cardiol. 2007 Dec 1100(11)1644-50
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Target Levels Dependent on Risk Category
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Statins _at_ 21

• Annoying sub groups
• Primary Prevention
• Women
• Elderly
• End-stage disease

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Primary Prevention
Major Coronary Events
Arch Intern Med. 20061662307-2313.
61
Primary Prevention
Total Mortality
Arch Intern Med. 20061662307-2313.
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Meta-Analysis of Statins in Primary Prevention
Statins
Placebo
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Gender Differences in Heart Disease
64
SIMVASTATIN MAJOR VASCULAR EVENT by AGE SEX
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Baseline
feature
(10269)
(10267)
STATIN better
PLACEBO better
Age
831
1091
(16.9)
(22.1)
lt 65
512
665
(20.9)
(27.2)
65 - 69
548
620
(23.8)
(27.7)
70 - 74
142
209
(23.1)
(32.3)
³
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Sex
1666
2135
(21.6)
(27.6)
Male
367
450
(14.4)
(17.7)
Female
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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The risk for total mortality was not lower in
women treated with lipid-lowering drugs,
regardless of whether they had prior
cardiovascular disease or not
Walsh JME Pignone M. Drug treatment of
hyperlipidemia in women. JAMA. 20042912243-2252.
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The Elderly
Afilalo J et al. JACC 2008
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End-Stage Renal Failure
Conclusions Atorvastatin had no statistically
significant effect on the composite primary end
point of cardiovascular death, nonfatal
myocardial infarction, and stroke in patients
with diabetes receiving hemodialysis
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CORONA - Primary Endpoint CV death or non-fatal
MI or non-fatal stroke
Placebo
Rosuvastatin 10 mg
Percent of patients with primary endpoint
Hazard ratio 0.92 (95 CI 0.83 to 1.02) p0.12
0
36
30
24
18
12
6
Months of follow-up
No. at risk Placebo 2497 2315 2156 2003 1851 1431
811 Rosuvastatin 2514 2345 2207 2068 1932 1484 855
Kjekshus J et al. N Eng J Med 2007 357 2248-61
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Statins _at_ 21

• Annoying (un)believers
• CADTH/Therapeutics Initiative
• THINCS
• Provincial Formularies
• Common sense physicians
• Marketing folks

70
CADTH
2008 report Statins are useless In Primary
Prevention
71
The risk for total mortality was not lower in
women treated with lipid-lowering drugs,
regardless of whether they had prior
cardiovascular disease or not
Walsh JME Pignone M. Drug treatment of
hyperlipidemia in women. JAMA. 20042912243-2252.
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THINCS
Opposed to Statins. Period.
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Statins _at_ 21

• The future
• New drugs
• Indications
• Who benefits
• Statins for all?

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New drugs Squalene SynthaseInhibitors
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New drugs
76
Statins Who Benefits?

• Determined by
• Baseline risk
• Magnitude of Cholesterol reduction
• Genetic Lipoprotein disorders

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Statins Who Benefits?

• Concerns in
• Many low-moderate risk subjects
• Pre-menopausal women
• Weak statins

• Probably not indicated in
• Low-risk subjects
• End-stage renal disease
• End-stage cardiac failure

78
Risk Reduction as a function of Time(25
reduction in LDL-C)
0
40
50
60
70
0
-25
CHD Risk Reduction
-50
-75
-100
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Conclusions

• Statins prevent CAD.