Embed Size (px)
Citation preview
Cholesterol
Myths or facts JDucobu UMons 2013
The International Network of Cholesterol Skeptics
Quelques aphorismes du Prof Even (Inserm Paris )
bull laquo Le cholesteacuterol nrsquoest pas une graisse raquo bull laquo Le cholesteacuterol ne bouche pas les artegraveres raquo bull laquo Il nrsquoy pas de rapport entre le taux de cholesteacuterol et les maladies CV
sauf au-dessus de 500mgdl raquo bull laquo Les patients atteints drsquohypercholesteacuteroleacutemie familiale ne font pas
drsquoatheacuterome mais une maladie qui touche uniquement les orifices des coronaires raquo
bull laquo Il nrsquoy a pas de mauvais cholesteacuterol crsquoest une farce inventeacutee par lrsquoindustrie pharmaceutique raquo
bull laquo Toutes les eacutetudes sont fausseacutees par les firmes et tous les experts sont corrompus raquo
bull laquo Les cardiologues ne connaissent rien en biochimie drsquoailleurs ils ne lisent pas raquo
bull laquo Les statines sont tregraves dangereuses elles provoquent lrsquoeacutepideacutemie de diabegravete actuelle raquo
bull hellip
The cholesterol facts versus the cholesterol myths
Jean Ducobu 2013
bull Causality
bull Ideal target
bull Side effects
of statins
bull Strategy
Causality of LDL-C
laquo Kochrsquos postulat raquo An infectious agent is responsible of a disease
IF
bull ACausal agent is present in typical lesions
bull BDisease occurs if laquo inoculation raquo of agent
bull CAbsence of agent in healthy individuals
bull DEradication or reduction of the agent leads to reversibility
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull ACausal agent is present in typical lesions
Histopathology
bull Numerous animal models
bull Cholesterol is present in human vessels
Diet induced atherosclerosis in animals left rabbits right mice
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
The International Network of Cholesterol Skeptics
Quelques aphorismes du Prof Even (Inserm Paris )
bull laquo Le cholesteacuterol nrsquoest pas une graisse raquo bull laquo Le cholesteacuterol ne bouche pas les artegraveres raquo bull laquo Il nrsquoy pas de rapport entre le taux de cholesteacuterol et les maladies CV
sauf au-dessus de 500mgdl raquo bull laquo Les patients atteints drsquohypercholesteacuteroleacutemie familiale ne font pas
drsquoatheacuterome mais une maladie qui touche uniquement les orifices des coronaires raquo
bull laquo Il nrsquoy a pas de mauvais cholesteacuterol crsquoest une farce inventeacutee par lrsquoindustrie pharmaceutique raquo
bull laquo Toutes les eacutetudes sont fausseacutees par les firmes et tous les experts sont corrompus raquo
bull laquo Les cardiologues ne connaissent rien en biochimie drsquoailleurs ils ne lisent pas raquo
bull laquo Les statines sont tregraves dangereuses elles provoquent lrsquoeacutepideacutemie de diabegravete actuelle raquo
bull hellip
The cholesterol facts versus the cholesterol myths
Jean Ducobu 2013
bull Causality
bull Ideal target
bull Side effects
of statins
bull Strategy
Causality of LDL-C
laquo Kochrsquos postulat raquo An infectious agent is responsible of a disease
IF
bull ACausal agent is present in typical lesions
bull BDisease occurs if laquo inoculation raquo of agent
bull CAbsence of agent in healthy individuals
bull DEradication or reduction of the agent leads to reversibility
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull ACausal agent is present in typical lesions
Histopathology
bull Numerous animal models
bull Cholesterol is present in human vessels
Diet induced atherosclerosis in animals left rabbits right mice
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Quelques aphorismes du Prof Even (Inserm Paris )
bull laquo Le cholesteacuterol nrsquoest pas une graisse raquo bull laquo Le cholesteacuterol ne bouche pas les artegraveres raquo bull laquo Il nrsquoy pas de rapport entre le taux de cholesteacuterol et les maladies CV
sauf au-dessus de 500mgdl raquo bull laquo Les patients atteints drsquohypercholesteacuteroleacutemie familiale ne font pas
drsquoatheacuterome mais une maladie qui touche uniquement les orifices des coronaires raquo
bull laquo Il nrsquoy a pas de mauvais cholesteacuterol crsquoest une farce inventeacutee par lrsquoindustrie pharmaceutique raquo
bull laquo Toutes les eacutetudes sont fausseacutees par les firmes et tous les experts sont corrompus raquo
bull laquo Les cardiologues ne connaissent rien en biochimie drsquoailleurs ils ne lisent pas raquo
bull laquo Les statines sont tregraves dangereuses elles provoquent lrsquoeacutepideacutemie de diabegravete actuelle raquo
bull hellip
The cholesterol facts versus the cholesterol myths
Jean Ducobu 2013
bull Causality
bull Ideal target
bull Side effects
of statins
bull Strategy
Causality of LDL-C
laquo Kochrsquos postulat raquo An infectious agent is responsible of a disease
IF
bull ACausal agent is present in typical lesions
bull BDisease occurs if laquo inoculation raquo of agent
bull CAbsence of agent in healthy individuals
bull DEradication or reduction of the agent leads to reversibility
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull ACausal agent is present in typical lesions
Histopathology
bull Numerous animal models
bull Cholesterol is present in human vessels
Diet induced atherosclerosis in animals left rabbits right mice
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
The cholesterol facts versus the cholesterol myths
Jean Ducobu 2013
bull Causality
bull Ideal target
bull Side effects
of statins
bull Strategy
Causality of LDL-C
laquo Kochrsquos postulat raquo An infectious agent is responsible of a disease
IF
bull ACausal agent is present in typical lesions
bull BDisease occurs if laquo inoculation raquo of agent
bull CAbsence of agent in healthy individuals
bull DEradication or reduction of the agent leads to reversibility
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull ACausal agent is present in typical lesions
Histopathology
bull Numerous animal models
bull Cholesterol is present in human vessels
Diet induced atherosclerosis in animals left rabbits right mice
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Causality of LDL-C
laquo Kochrsquos postulat raquo An infectious agent is responsible of a disease
IF
bull ACausal agent is present in typical lesions
bull BDisease occurs if laquo inoculation raquo of agent
bull CAbsence of agent in healthy individuals
bull DEradication or reduction of the agent leads to reversibility
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull ACausal agent is present in typical lesions
Histopathology
bull Numerous animal models
bull Cholesterol is present in human vessels
Diet induced atherosclerosis in animals left rabbits right mice
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull ACausal agent is present in typical lesions
Histopathology
bull Numerous animal models
bull Cholesterol is present in human vessels
Diet induced atherosclerosis in animals left rabbits right mice
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Diet induced atherosclerosis in animals left rabbits right mice
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
No cholesterol no atheroma
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Atherogenesis
Heinecke J N Engl J Med 2011364170-171
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull BDisease occurs if laquo inoculation raquo of agent
Epidemiology correlation of cholesterol and CVD incidence
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Seven-countries study 1970
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Framingham 1971
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
MRFIT 1986
IS RELATIONSHIP BETWEEN SERUM CHOLESTEROL AND RISK OF PREMATURE DEATH FROM CORONARY HEART DISEASE CONTINUOUS AND GRADED FINDINGS IN 356 222 PRIMARY SCREENEES OF THE MULTIPLE RISK FACTOR INTERVENTION TRIAL (MRFIT)
The relation is more evident in patients with high cholesterol( gt200) than in patients with lower cholesterol (lt160) because they have other diseases than CV pathology
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Framingham 1988 Importance of LDL and HDL fractions
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
LIPOPROTEIN METABOLISM
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
MRFIT 1993 Stamler Diabetes Care
Importance of other Risk Factors
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull CAbsence of agents in healthy individuals
Genetic PCSK9 mutants ( very low LDL-C from birth) develop very few CVD
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
1 Brown MS et al Proc Natl Acad Sci U S A 1979763330-3337 2 Steinberg D et al Proc Natl Acad Sci U S A 20091069546-9547 3 Goldstein JL et al Arterioscler Thromb Vasc Biol 200929431-438
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for Lysosomal Degradation
1 Qian YW et al J Lipid Res 2007481488-1498 2 Horton JD et al J Lipid Res 200950S172-S177 3 Zhang DW et al J Biol Chem 200728218602-18612
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Gain-of-Function Mutations in PCSK9 Cause Autosomal-Dominant Hypercholesterolemia (ADH)
bull Associated with ndash High serum LDL-C2
ndash Premature CHD and MI2
ndash In vitro testing in many identified mutations show decreased levels of LDLRs3
For a full list of ADH mutations please see refer to Abifadel reference
1 Abifadel M et al Hum Gen 200930520-529 2 Horton JD et al J Lipid Res 200950S172-S177 3 Cameron J et al Hum Mol Genet 2006151551-1558
PCSK9 Variant Population Clinical Characteristics
D374Y British Norwegian
families 1 Utah family
Premature CHD
Tendon xanthomas
Severe hypercholesterolemia
S127R French South African
Norwegian families Tendon xanthomas CHD early MI
stroke
R215H Norwegian family Brother died at 31 from MI strong
family history of CVD
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Loss-of-Function Mutations in Human PCSK9 are Associated with Lower LDL-C Levels
bull Found in 1 to 3 of population1
bull Associated with
ndash Lower serum LDL-C1
ndash Lower incidence of coronary heart disease1
bull Inhibiting LDL-R PCSK9 interaction may lower plasma LDL-C levels4
PCSK9 Variant Population LDL-C CHD Risk
R46L ARIC DHS darr 151 darr 471
Y142X or C679X ARIC DHS darr 28-4012 darr 881
R46L CGPS darr 113 darr 463
1 Cohen JC Boerwinkle E Mosley TH Hobbs HH N Engl J Med 2006 3541264-1272
2 Cohen J Pertsemlidis A Kotowski IK et al Nat Genet 2005 37161-165
3 Benn M Nordestgaard BG Grande P Schnohr P Tybjaeligrg-Hansen A J Am Coll Cardiol 2010552833-2842
4 Steinberg D Witztum JL Proc Natl Acad Sci U S A 20091069546-9547
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
PCSK9 a convertase that coordinates LDL catabolism Jay D HortonJonathan C Cohen and Helen H Hobbs1
J Lipid Res 2009 April 50(Supplement) S172ndashS177
Two young women with total PCSK9 deficiency have been identified Both subjects had very low plasma levels of LDL-C (14 mgdl and 16 mgdl) No adverse clinical sequellae were reported in either individual Determining the long-term consequences of PCSK9 deficiency will require careful clinical assessment of additional older PCSK9-deficient individuals
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
LDL too low
bullNative hunter ndash gatherers bullFree living primates bullNeonates bullAnd some genetic groups ( PCSK9 hypoApoB) with very low LDL( lt40 mgdl and lesshellip) are free from CVD
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
LDL too low
bullCholesterol is produced by every cell and well regulated bullLDL is only necessary to carry lipophilic Vitamins (EDhellip) bull10 ndash 15 mgdl of LDL is enough for this function
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Evidence from epidemiology
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Causality of LDL-C
laquo Kochrsquos postulat raquo
An agent is responsible of a disease IF
bull DEradication or reduction of the agent leads to reversibility
Intervention trials LDL reduction prevent CVD
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
CTT COLLABORATION ( 26 trials 170000 participants) Effect of Statins on Cardiovascular Event Rates
Goldfine AB N Engl J Med 20123661752-1755
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
J Am Coll Cardiol 2012 Dec 2560(25)2631-9
Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian
randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L
Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine
Detroit Michigan 48202 USA
OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD) METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
J Am Coll Cardiol 2012 Dec 2560(25)2631-9 Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease a Mendelian randomization analysis Ference BA Yoo W Alesh I Mahajan N Mirowska KK Mewada A Kahn J Afonso L Williams KA Sr Flack JM Division of Translational Research and Clinical Epidemiology Wayne State University School of Medicine Detroit Michigan 48202 USA
All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C with no evidence of heterogeneity of effect (I(2) = 00) In a meta-analysis combining nonoverlapping data from 312321 participants naturally random allocation to long-term exposure to lower LDL-C was associated with a 545 (95 confidence interval 488 to 595) reduction in the risk of CHD for each mmoll (387 mgdl) lower LDL-C This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 843 times 10(-19)) CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life
54 versus 22 risk reduction per mmoll
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Robinson et al JACC 2005 46 1855-62
Meta-Regression LDL-C Reduction by any means amp CHD
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Evidence Pyramid
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Controversy in primary preventionhellip
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Search strategy In the Cochrane Central Register of Controlled Trials (Issue 1 2007) MEDLINE (2001
to March 2007) and EMBASE (2003 to March 2007) Fourteen randomised control trials (16 trial arms 34272 participants) were included
Main results All-cause mortality was reduced by statins (RR 083 95 CI 073 to 095) as was combined fatal and non-fatal CVD endpoints (RR 070 95 CI 061 to 079) in high risk primary prevention Benefits were also seen in the reduction of revascularisation rates (RR 066 95 CI 053 to 083)
Statins for the high risk primary prevention of cardiovascular disease COCHRANE Library 2011
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Causality conclusions
bull All criteria are met suggesting that LDL- cholesterol is the cause ( the laquo fuel raquo) of CVD Other risk factors play as laquo accelerators raquo
bull Consequence of the model
Lower LDL-C as low as possible is the logical strategy
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Adapteacute drsquoapregraves Kastelein JJP Atherosclerosis 1999143(suppl 1)S17-S21
Pravastatine
Preacutevention secondaire
Preacutevention primaire
Simvastatine
Lovastatine
Atorvastatine
0
5
10
15
20
25
Pat
ien
ts a
vec
1 eacute
veacuten
em
en
t C
V (
)
Reduction of LDL-C with statins
Lower is better
Statine ASCOT AFCAPS
WOSCOPS
CARE LIPID
4S
HPS
HPS
CARDS
TNT
IDEAL
Placebo Comparateur
TNT WOSCOPS
LIPID
4S
CARE
AFCAPS
ASCOT
HPS
HPS
CARDS
IDEAL
210 70
110 130 150 170 190 90
LDL-C (mgdL)
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
IVUS Studies
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
IVUS Study Less Cholesterol less progression
and hellipeven regression
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
The NCEP Update Sets an Optional Goal of lt70 mgdL for High Risk Patients
ldquoIn terms of absolute risk an LDL-C of 70 mgdL seems preferable for high risk patients compared to a level of 100 mgdLrdquo
Grundy S et al Circulation 2004110227-39
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
ndash Myalgias
ndash Diabetes
ndash Cataracts
ndash Deaths
bull Strategy
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
50 Adapted from Rowland M et al Clin Pharmacokin Concepts and Applications 2nd Ed Philadelphia Lea amp Febiger 1989
Statin dose-effect relationship Myalgias = 15- 20 100
Rhabdomyolysis =lt 110000
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
Lack of effect
Desired pharmacological effect
Minor to
xicity
Major toxicity
Therapeutic effectivness
Dose of Statin (mgday)
Inci
den
ce (
)
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
SLCO1B1 Variants and Statin-Induced Myopathy mdash A Genomewide Study
The SEARCH Collaborative Group
nejm July 23 2008
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
The SEARCH Collaborative Group N Engl J Med 2008101056NEJMoa0801936
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Statin use amp diabetes Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-dose to Moderate-Dose
Statin Therapy
18 Preiss et al JAMA 20113052556-64 CA
RD
-10
56
08
1-0
00
0
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Statin use amp cataracts
CONTROVERSIAL
Dr Jessica Leuschen (Wilford Hall Ambulatory Surgery Center
San Antonio TX) and colleagues point out a 15 increased risk
of cataracts with statin use in a military healthcare system
published in october 2013 (JAMA Ophthalmology)
At the recent European Society of Cardiology(ESC) 2013
Congress Dr John B Kostis (Rutgers Robert Wood Johnson
Medical School New Brunswick NJ) presented the results of
a random-effects meta-analysis showing a 20 lower rate of
cataracts with statin use compared with no statin use with a
more pronounced benefit seen when statins were started in
younger patients
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
CTT statin use amp deaths
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
The cholesterol facts versus the cholesterol myths
bull Causality
bull Ideal target
bull Side effects of statins
bull Strategy
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
TexCaps
WOS
HPS
LIPID
4S
CARE
Relation between NNT and absolute risk in placebo groups
NNT
Absolute
risk in
placebo
group
40-
30-
20-
10-
0-
5 10 15 20 25 30
ASCOT
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Message
bull The treatment must be started according to the risk profile of the
patient rather than to the lipid values
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Belgium
Population 40-65 y 35 millions
bull 2ary Prev (CV diseases diabetes very high Chol or HTA)= 10
bull 1ary Prev = 90
ndash Low risk = 5
ndash Intermediate risk = 70
ndash High Risk = 15
GDeBacker 2006
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
bull Primary prevention
ndash Need to evaluate the global CV risk of the
patient from SCORE tables
ndash Modulation of the result if intermediate
risk by detection of biological (CRPLp(a)hellip) genetic or imaging markers(Calcif IMTMRI hellip)
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
61
On ne traite pas exclusivement des chiffres
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Descamps OS et al Louvain Med 2012 131 (4) 166 (adapteacute de De Bacquer D De Backer G Int J Cardiol2010 143 385 et Descamps OS Cooney MT De Backer G et al Atherosclerosis June 2012 (In print)
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
bull Healthy eating bullMediterranean diet bullVegetables and fruits bullFish and fish oil
bull Physical activity ( gt30 min 5 days a week) bull Weight reduction bullSmoking cessation bullCombinations
First change lifestyle
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Health Number 0530
every day
0 cigarettes
5 fruits amp vegetables
30 min physical activity
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Haut risque sans diabegravete de type 2 SM TG HDL-C
Statine
Statine + Ezeacutetimibe
Statine + Niacine
Statine + CETP-I
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
Haut risque avec diabegravete de type 2 SM TG HDL-C
Statine ou Feacutenofibrate
Statine + Feacutenofibrate
Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Feacutenofibrate
Statine + Ezeacutetimibe + Niacine
Statine + CETP-I
hellip
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
TOUT MEDECIN CONVAINCU DE PRATIQUER LA DIETETIQUE SERA
CONDAMNE POUR EXERCICE ILLEGAL DE LA CUISINE
Pierre Dac
