prof. a. tenenbaum director cardioline heart institute
DESCRIPTION
Dyslipidemia & Evidence-Based Medicine : What have we behind statins monotherapy?. Prof. A. Tenenbaum Director Cardioline Heart Institute Director of Research Cardiac Rehabilitation Institute, Sheba Medical Center 2010. Agenda. Dyslipidemia & Atherogenic Particles - PowerPoint PPT PresentationTRANSCRIPT
Prof. A. TenenbaumProf. A. TenenbaumDirector
Cardioline Heart InstituteDirector of Research Cardiac Rehabilitation Institute,
Sheba Medical Center2010
Dyslipidemia & Evidence-Based Dyslipidemia & Evidence-Based Medicine :Medicine :
What have we behind statins What have we behind statins monotherapy?monotherapy?
AgendaAgenda
Dyslipidemia & Atherogenic ParticlesDyslipidemia & Atherogenic Particles
Cholesterol Metabolism: Absorption, Cholesterol Metabolism: Absorption, De NovoDe Novo Synthesis and Synthesis and their Markerstheir Markers
Clinical Significance of Atherogenic DyslipidemiaClinical Significance of Atherogenic Dyslipidemia
Beyond Statins: Clinical EvidencesBeyond Statins: Clinical Evidences
““Surrogate”-Endpoints EvidencesSurrogate”-Endpoints Evidences
Clinical “Hard”-Endpoints EvidencesClinical “Hard”-Endpoints Evidences
SummarySummary
Dyslipidemia & Atherogenic ParticlesDyslipidemia & Atherogenic Particles
Cholesterol Metabolism: Absorption, Cholesterol Metabolism: Absorption, De NovoDe Novo Synthesis and Synthesis and their Markerstheir Markers
Clinical Significance of Atherogenic DyslipidemiaClinical Significance of Atherogenic Dyslipidemia
Beyond Statins: Clinical EvidencesBeyond Statins: Clinical Evidences
““Surrogate”-Endpoints EvidencesSurrogate”-Endpoints Evidences
Clinical “Hard”-Endpoints EvidencesClinical “Hard”-Endpoints Evidences
SummarySummary
The basic structure of a lipoprotein. The core contains mostly lipids and the shell has a composition similar to cell membranes (protein + phospholipids + cholesterol). The shell protein molecules (apo-proteins) serve to activate surface receptors and enzymes essential for the uptake and metabolism of lipoproteins.
Relative sizes and densities of the four major lipoproteins. Chylomicrons (density < 0.95) are not shown here because of their enormous size (about 100 x the size of VLDL).
LiverLiver
Endogenous and Exogenous Sourcesof Cholesterol
Endogenous and Exogenous Sourcesof Cholesterol
Fecal bile acids and neutral sterols
Exogenous
Extrahepatictissues
Endogenous
DietaryDietarycholesterolcholesterol
(~300–700 mg/day)(~300–700 mg/day) Intestine
Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:728-777; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082-1150.
BiliaryBiliarycholesterolcholesterol(~1000 mg/day)(~1000 mg/day)
~700 mg/day
Synthesis(~800 mg/day)
Cholesterol Metabolism: Uptake
CETP
SR-BI
HDL is believed to protect against atherosclerosis at least in part through the process of reverse cholesterol transport, whereby excess free cholesterol (FC) is removed from cells in peripheral tissues, such as macrophages within the arterial wall, and returned to the liver for excretion in the bile. FC is generated in part by the hydrolysis of intracellular cholesteryl ester (CE) stores. Several key molecules play a role in reverse cholesterol transport, including ATP-binding cassette protein A1 (ABCA1), lecithin:cholesterol acyltransferase (LCAT), and scavenger receptor class-B, type I (SR-BI).
Steps Involved inCholesterol Absorption
Steps Involved inCholesterol Absorption
1000 mg
up to 700mg
NPC1L1
Sterols
Intestinal Sterol Transport In EnterocytesIntestinal Sterol Transport In Enterocytes
NPC1L1
Sterols
PL S
Lymphatic VesselLymphatic Vessel
Apo B 48
ACAT
Chylomicron
NPC1L1 Protein
ABCG5/G8
Intestinal LumenIntestinal Lumen
EnterocyteEnterocyte
Mechanism of Cholesterol Absorption
Lymphatic VesselLymphatic Vessel
Apo B 48
ACAT
CE Poor Chylomicron
NPC1L1 Protein
ABCG5/G8
Intestinal LumenIntestinal Lumen
EnterocyteEnterocyte
XXLess free
cholesterol & sterol
absorption
EZETIMIBEEZETIMIBE
Ezetimibe has specific, high affinity binding to a structural protein on the brush border
Ezetimibe : Mechanism of Action
Cholesterol Metabolism:De Novo Synthesis
HMG-CoA reductase inhibitor
Zymosterol
Lathosterol7-Dehydrocholesterol
www.lbqp.unb.br/.../ aulas2D/sint_de_colest.htm
Absorption and Synthesis MarkersAbsorption and Synthesis Markers
LathosterolCholestanol
Synthesis Absorption
•Lathosterol: is one of precursors of Cholesterol in the Mevalonate pathway thus is a marker of cholestrol synthesis.
•Cholestanol and plant sterols: are positively correlated with the intestinal cholesterol (dietary plus endogenous) flux. *
*Metabolism. 1989 Feb;38(2):136-40
LathosterolCholestanol
Ratio Bigger More Synthesis
LathosterolCholestanol Ratio Smaller More
Absorption
Absorption and Synthesis MarkersAbsorption and Synthesis Markers
Patients with high cholesterol absorption presented a higher risk of MACE
Patients with high cholesterol absorption presented a higher risk of MACE
Relative risk of MACE in the 4S
00.20.40.60.8
11.21.41.61.8
Cholestanol (10²mmol/cholestrol)
1st Q
Cholestanol (10²mmol/cholestrol)
2nd Q
Cholestanol (10²mmol/cholestrol)
3ed Q
Cholestanol (10²mmol/cholestrol)
4th Q
Absorption Quartile
Rel
ativ
e ri
sk 2.2 fold increase p<0.012.2 fold increase p<0.01
Data from the Finnish cohort of the 4S study: Miettinen TA et al BMJ Vol 316 11 April 1998
Simvastatin Did Not Reduce Major Coronary Events in the Highest Quartiles of Cholesterol Absorption - 4S Sub-
Study
Simvastatin Did Not Reduce Major Coronary Events in the Highest Quartiles of Cholesterol Absorption - 4S Sub-
Study
4S = Scandinavian Simvastatin Survival Study. Miettinen et al. BMJ. 1998;316:1127
0
5
10
15
20
25
30
35
40
% M
ajo
r C
oro
nar
y e
ven
ts
1 2 3 4
Placebo (n=434)
Simvastatin 20-40 mg (n=434)
17% Relative Risk 25%34%38%
High Cholesterol Absorption
Low Cholesterol Absorption
<4.2 4.2 – 4.6 4.7 – 5.1 >5.1LDL-C/ Quartile(mmol/l)
Low response to simvastatin
Dual Inhibition conceptDual Inhibition concept
Assman G, Kannenberg F,Weng W et al. Effects of ezetimibe, simvastatin, and ezetimibe-simvastatin on non-cholesterol sterols. Poster presented at the American Collegeof Cardiology meeting, New Orleans, Louisiana, USA, March 7–10, 2004.
25
20
15
10
5
0
% o
f p
atie
nts
wit
h C
HD
eve
nt
LDL-C, mmol/L (mg/dL)
2.3(90)
2.8(110)
3.4(130)
3.9(150)
4.4(170)
4.9(190)
5.4(210)
4S-P
CARE-P
LIPID-P4S-S
WOSCOPS-S
WOSCOPS-P
AFCAPS-PAFCAPS-S
LIPID-S
CARE-S
Adapted from – - The Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better. O’Keefe, JR et al. J Am Coll Card. 2004; 2;43(11):2142-6
S=Statin; P=Placebo
1.8(70)
HPS-P
HPS-S
Secondary
prevention
Primary
prevention
Simvastatin
Pravastatin
Lovastatin
Atorvastatin
1.8(50)
1.8(30)
PROVE-IT-AT
PROVE-IT-PR
ASCOT-SASCOT-P
TNT IDEAL
LDL-C Levels vs Events inLDL-C Levels vs Events in Statin Trials: How Low to Go?Statin Trials: How Low to Go?LDL-C Levels vs Events inLDL-C Levels vs Events in
Statin Trials: How Low to Go?Statin Trials: How Low to Go?
% o
f P
aien
ts w
ith
CH
D E
ven
t
LDL Cholesterol (mg/dL)
0
5
10
15
20
25
90 110 130 150 170 190 210
CARE-RxLIPID-Rx
4S-Rx
CARE-PILIPID-PI
4S-PI
WOS-PIWOS-Rx
AFCAPS-Rx
AFCAPS-PI
PI = Placebo Rx = Treatment
70
TNT-Entry
50
Kastelein. Atherosclerosis 1999;143:S17-S21
Secondary Prevention
Primary Prevention
Relation Between CHD Events and LDL Cholesterol in Statin Trials
Relation Between CHD Events and LDL Cholesterol in Statin Trials
AFCAPS: Lovastatin; 4S: SimvastatinWOS, LIPID, CARE: Pravastatin
TNT
Jupiter-PiJupiter-Rx
11
Lower LDL-C Reduces Risk for CHDLower LDL-C Reduces Risk for CHD
Adapted from Grundy SM et al Circulation 2004;110:227–239.
1
3.7
2.9
2.2
1.3
1.7
40 70 100 130 160 190
LDL-C (mg/dl)
Rel
ativ
e ri
sk f
or
CH
D(l
og
sca
le)
–30 mg/dl
–30% CHD risk
Multiple Studies Showed a Relationship BetweenLDL-C Reduction and CHD Relative Risk
Multiple Studies Showed a Relationship BetweenLDL-C Reduction and CHD Relative Risk
MI = myocardial infarction.
Adapted with permission from Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.
15 20 25 30 35 40
–20
0
20
40
60
80
100
LDL-C reduction, %
No
nfa
tal
MI
and
CH
D d
eath
re
lati
ve r
isk
red
uct
ion
, %
4S CARDSPOSCH ASCOT-LLANHLBI PROSPERLRC ALERTUpjohn HPSLos Angeles AF/TexCAPSMRC LIPIDOslo CARELondon WOSCOPS
Relationship between LDL-C levels and change in percent atheroma volume for several IVUS trials
Median change in Percent AtheromaVolume(%)
ASTEROID rosuvastatin
50 60 80 90 100 110
0.6
1.2
1.8
Mean LDL-C (mg/dL)
0
-1.2
-0.6
70 120
A-Plus placebo
CAMELOT placebo
REVERSAL pravastatin
REVERSAL atorvastatin
R2 = 0.97 P<0.001
Progression
Regression
Ref: Nissen S et al. JAMA 2006; 295:
REVERSAL
The Need for Intensive LDL-C Lowering:The Need for Intensive LDL-C Lowering:Relationship Between Degree of LDL-C Reduction Relationship Between Degree of LDL-C Reduction and Change in Atheroma Volumeand Change in Atheroma Volume
The solid blue line indicates the relationship between mean change in LDL-C and change in atheroma volume from linear regression analysis. The dashed green lines indicate the upper and lower 95% confidence limits for the mean values.
Adapted from Nissen S et al JAMA 2004;291:1071–1080.
% Change in LDL-C
Ch
ang
e in
ath
ero
ma
volu
me
(mm
3 )
–15
–10
–5
0
5
10
15
20
–80 –70 –60 –50 –40 –30 –20 –10 0 10 20
N=502
0%
20%
40%
60%
80%
100%
Total Hadassah Rambam Soroka Sheba
Target LDL - 100 mg/dL Under-dosageReached
65.4%65.4%
Holem: Harats D. et al ; Dr Giluts: 4C - Computerized Community Cholesterol Control
Lipid Profile at Baseline n=1928
Normal
10%
LDL>100+HDL<40
11%
Only LDL>10025%Only HDL<40
11%
Only TG>1505%
TG>150+HDL<40
8% LDL>100+TG>150 + HDL<40
12%
LDL>100+TG>150
18%
2798ALL1928Screened
652LDL>124
66%LDL>100
66%LDL>100
Holem Study Clalit 4C Project
In Israel, ~ 65% of CHD or/and Diabetic patients do not reach LDL levels < 100 mgIn Israel, ~ 65% of CHD or/and Diabetic patients do not reach LDL levels < 100 mg
LDL-C Lowering Compared Statins Across Dose Range
Dual inhibition using Ezetrol and Statin provides greater Atherogenic burden relief
In add on trials Vs Atrovaststin Vs Rosuvastatin
In add on trials Vs Atrovaststin Vs Rosuvastatin
Mea
n %
ch
ang
e fr
om
bas
elin
e to
wee
k 12
0
–20
–30
–40
–50
–10
–70
–60
Eze+Simva 10 mg
(n=87)
–46%*
Simva10 mg(n=79)
–31%
Eze+Simva 20 mg
(n=86)
–51%*
Simva20 mg(n=89)
–35%
Eze+Simva 40 mg
(n=89)
–55%*
Simva40 mg(n=90)
–42%
Eze+Simva 80 mg
(n=91)
–61%*
Simva80 mg(n=87)
–46%
*p<0.001 vs. corresponding dose of simvastatin
Adapted from Goldberg AC et al. Poster presentation at the 53rd ACC, March 7–10, 2004.
Ezetrol with Any Statin at Any Dose gives Incremental LDL-c Reduction of 25%25%Ezetrol with Any Statin at Any Dose gives Incremental LDL-c Reduction of 25%25%
More than 70% of HR Patients* Attaining NCEP ATP III LDL-C Goal w/ Eze Vs. 20% w/ statinsMore than 70% of HR Patients* Attaining NCEP ATP III LDL-C Goal w/ Eze Vs. 20% w/ statins
*Patients not at goal at baseline
p<0.001 for all between-treatment differences
% o
f p
atie
nts
at
tain
ing
go
al
Allpatients
CHD or CHDrisk equivalent
Placebo + statin Ezetimibe + statin100
40
80
0
60
20
71.0
20.6
69.5
17.3
75.1
32.2
90.7
52.4
(n=1584)(n=783) (n=1276)(n=641) (n=265)(n=121) (n=43)(n=21)
No CHD and <2
risk factors
No CHD and <2
risk factors
Pearson et al. Mayo Clin. Proc. - May 2005;80(5):587-595.
Ezetimibe/Simvastatin vs. Atorvastatin Efficacy Study
Ezetimibe/Simvastatin vs. Atorvastatin Efficacy Study
-65
-60
-55
-50
-45
-40
-35 Atorva 10 mg Start Dose Group
EZE 10 mg + Simva 10 mg Start Dose Group
EZE 10 mg + 20 mg Start Dose Group
Combined EZE 10 mg + Simva Dose Groups
Per
cen
t R
edu
ctio
n F
rom
Un
trea
ted
B
asel
ine
in L
DL
-C
* * PP<0.001<0.001
Week 24
80 mg
10/80 mg-59%*
-52%
Week 18
40 mg
10/40 mg-56%*
-49%
Week 12
20 mg
10/20 mg
10/40 mg
-50%*
-54%*
-44%-46%*
Week 6
10 mg
10/10 mg
10/20 mg-50%*
-37%
Christie M. Ballantyne et al. Am J Cardiol 2004;93:1487–1494
Reduction in LDL-C across dosesReduction in LDL-C across doses
***p<0.001 for the indicated between-treatment differenceTreatment by subgroup interaction not significant, indicating treatment effect consistent with whole cohort
-60
-50
-40
-30
-20
-10
0
All RAll E/S
-51.6-54.2
-51.8 -51.0
-55.8***-58.5
-55.0 -55.6
% c
han
ge
fro
m b
asel
ine
Whole MS w/oCohort T2DM T2DM Neither
-70
Proportions of patients attaining recommendedProportions of patients attaining recommendedLDL-C levels of <100 and <70 mg/dLLDL-C levels of <100 and <70 mg/dL
<100 mg/dL† <70 mg/dL‡
All R
All E/S
All R
All E/S
0
20
40
60
80
100
81.9
89.0
81.3 80.9
88.2*** 91.486.8 87.9
% p
atie
nts
att
ain
ing
LD
L –
C <
100
mg
/dL
WholeCohort
T2DM MS w/o NeitherT2DM
0
10
20
30
40
50
60
29.5
35.9
32.2
26.8
45.3***
54.8
37.0
44.1
% p
atie
nts
att
ain
ing
LD
L–C
<70
mg
/dL
WholeCohort
T2DM MS w/o NeitherT2DM
All RAll E/SAll RAll E/S
***p<0.001 for the indicated between-treatment difference†Treatment by subgroup interaction not significant for LDL-C <100 mg/dL, indicating treatment effect consistent with whole cohort‡There was a statin by subgroup interaction for LDL-C <70 mg/dL (p=0.012)
CRPCRP
Significantly Greater % Reductions in CRP Were Achieved With Eze/Simva Compared With Each Corresponding Dose of Simva MonotherapySignificantly Greater % Reductions in CRP Were Achieved With Eze/Simva Compared With Each Corresponding Dose of Simva Monotherapy
Pearson T et al. Am J Cardiol 2007;99:1706–1713
METABOLIC SYNDROMEMETABOLIC SYNDROME
The evolution of mankind…The evolution of mankind…
2.5 mil. years 100 years
0
100
Relative risk of type 2 diabetes80
60
40
20
<22
BMI (kg/m2)
22.0–22.9
23.0–23.9
24.0–24.9
25.0–26.9
27.0–28.9
3529.0–30.9
31.0–32.9
33.0–34.9
Colditz et al.Ann Intern Med 1995; 122: 481-6
The relative risk of type 2 diabetes is clearly linked to overweight and obesity
1.0 2.9 4.3 5.0 8.115.8
27.6
40.3
54.0
93.2
What is an Atherogenic lipid profile?
Atherogenic triad(?):TG HDL, Small, dense LDL,
Remnants
Atherogenic triad(?):TG HDL, Small, dense LDL,
Remnants
Apo B48Apo B48
Apo B100Apo B100Apo B100Apo B100
Apo AApo A
Risk of Major CHD Event Associated With Risk of Major CHD Event Associated With High Insulin Levels in Nondiabetic MenHigh Insulin Levels in Nondiabetic Men
Q1 TO Q5 = quintiles of area under the curve (AUC) insulin (Q1 = lowest quintile; Q5 = highest quintile).
1.00
0.95
0.90
0.85
0.80
0.75
00 5 10 15 20 25
Years
Proportion without major CHD event
Kaplan-Meier Survival Curve
Pyorala M et al. Circulation 1998: 98: 398-404.
Log rank:Overall P=.001Q5 vs Q1 P<.001
Q1
Q2
Q3Q4
Q5
10
15
20
25
30
35
Tertile I Tertile II Tertile III
Major cardiovascularevents
p<0.0001
Figure 1. The Bezafibrate Infarction Prevention (BIP) study primary endpoint (major major cardiovascular events:cardiovascular events: combined fatal or non-fatal myocardial infarction or sudden death) in accordance with tertiles of HOMA-IR at baseline, age-adjusted rate/1000 person-years.
Age-adjusted rate/1000 person-years
A.Tenenbaum et al, AHJ, 2007
Metabolic syndromeMetabolic syndrome
A consistent relationship of metabolic syndrome with cardiovascular disease has been demonstrated
Cardiovascular disease mortalityC
um
ula
tive
Ha
zard
(%
)
Follow-up (yrs)
Lakka HM et al. JAMA 2002: 288: 2709-2716.
RR (95% CI), 3.55 (1.98-6.43)
15
10
5
0
0 2 4 6 8 10 12
Metabolic Syndrome
Yes
No
Current therapeutic use of statins as monotherapy is still leaving many patients with metabolic syndrome and mixed atherogenic dyslipidemia at high risk for coronary events.
Combined atherogenic dyslipidemia in metabolic syndrome and type Combined atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: Pharmacological options in addition to statin2 diabetes: Pharmacological options in addition to statin
Nicotinic acid (or niacin)
Fibrates
Bile acid sequestrants
CETP inhibition (Torcetrapib)
Ezetimibe
BezafibrateInfarction
P reventionStudy
20
18
16
14
( % )
0 1 2 3 4 5 6
12
10
8
6
4
2
0
22
39.5%p=0.02
Circulation 102: 21-27, 2000
Combined Primary EndpointCombined Primary EndpointBaseline Triglycerides Baseline Triglycerides 200 mg/dl 200 mg/dl
Placebo
Bezafibrate
Time (Year)
BezafibrateInfarction
P reventionStudy
FASTING GLUCOSE CHANGEFASTING GLUCOSE CHANGE TRIGLYCERIDES CHANGETRIGLYCERIDES CHANGE
HDL-C CHANGEHDL-C CHANGE BMI CHANGEBMI CHANGE
Fibric Acid Derivative Bezafibrate in Fibric Acid Derivative Bezafibrate in Patients with Patients with Metabolic SyndromeMetabolic Syndrome
Years
Placebo
Bezafibrate
95
100
105
110
115
120
0 1 2 3 4 5 6
(mg/dL)
60
80
100
120
140
160
180
(mg/dL)
0 1 2 3 4 5 6 Years
(mg/dL)
30
32
34
36
38
40
0 1 2 3 4 5 6
Placebo
Bezafibrate
Placebo
Bezafibrate
Years25
26
27
28
29
30
31
0 1 2 3 4 5 6
(kg/m2)
Years
125
Placebo
Bezafibrate
A.Tenenbaum et al, Arch. Inter. Med,2005
BezafibrateInfarction
P reventionStudy
Kaplan-Meier curves of MI incidence (in accordance with the time of diagnosis; 6.2 years mean follow-up) and of cardiac mortality rate (8.1 years mean follow-up) for the study groups (bezafibrate vs. placebo).
Placebo
BezafibratePlacebo
Bezafibrate
0 1 2 3 4 5 6 7 8 9TIME (YEARS)
CA
RD
IAC
MO
RTA
LITY (
%)
15
10
5
00 1 2 3 4 5 6
MI (%
)
20
15
10
5
0
Plog-rank = 0.02Plog-rank = 0.07
MI incidenceMI incidence cardiac mortality ratecardiac mortality rate
Fibric Acid Derivative Bezafibrate in Fibric Acid Derivative Bezafibrate in Patients with Patients with Metabolic SyndromeMetabolic Syndrome
A.Tenenbaum et al, Arch. Inter. Med,2005
TIME (YEARS)
BezafibrateInfarction
P reventionStudy
Influence of bezafibrate treatment on main outcomes Influence of bezafibrate treatment on main outcomes in patients with 4-5 risk factors for metabolic in patients with 4-5 risk factors for metabolic syndrome (augmented features of metabolic syndrome (augmented features of metabolic syndrome)syndrome)
Patients with augmented features of metabolic syndrome
(n = 575)
Outcomes HR CI
Non-fatal myocardial infarction 0.66 0.41-1.04
Any myocardial infarction 0.65 0.42-1.01
Cardiac deathCardiac death 0.440.44 0.25-0.800.25-0.80
Total death 0.76 0.52-1.12
BezafibrateInfarction
P reventionStudy
0 0.5 1.51.0BEZAFIBRATE BETTERBEZAFIBRATE BETTER PLACEBO BETTERPLACEBO BETTER
9292 men, coronary events, p<0.05men, coronary events, p<0.05
164164 pts, definitive coronary events, p<0.05pts, definitive coronary events, p<0.05
15681568 men, non fatal coronary events, p=0.01men, non fatal coronary events, p=0.01
31223122 pts, the primary endpoint, p=0.26pts, the primary endpoint, p=0.26
subgroup with triglycerides > or =200 mg/dL,subgroup with triglycerides > or =200 mg/dL,459459 pts, the primary endpoint*, p=0.02pts, the primary endpoint*, p=0.02
subgroup with metabolic syndrome,subgroup with metabolic syndrome,14701470 pts, non fatal MI, p=0.01pts, non fatal MI, p=0.01
Meta-analysis of outcomesMeta-analysis of outcomes studies with studies with bezafibrate bezafibrate
BECAITBECAIT
SENDCAPSENDCAP
LEADERLEADER
BIPBIP
BIPBIP
BIPBIP
Hazard ratio
MRI images at baseline and after 1 year of bezafibrate treatment.
Using MRI, the effects of bezafibrate on aortic plaques in 22 dyslipidemic patients was investigated .
Ayaori et al. Atherosclerosis. 2006 Dec 29; [Epub ahead of print]
Bezafibrate induced plaque Bezafibrate induced plaque regression in thoracic and regression in thoracic and abdominal aortasabdominal aortas
Ezetimibe
LYMPH ENTEROCYTE INTESTINALLUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Ezetimibe
X
Ezetimibe
LYMPH ENTEROCYTE INTESTINALLUMEN
ABCG5/G8
Cholesterol
CholesterylEster
ACAT
NPC1L1
Ezetimibe
X
Cholesterol Absorption Inhibitors
LYMPH ENTEROCYTE INTESTINALLUMEN
CholesterylEster
TriglycerideCM
apoB48
Duodenum
Jejunum
Ileum
Colon
CMapoB48
CM RemnantapoB48
VLDLapoB100
LDLapoB100
Liver
XEzetimibe
Cholesterol Absorption Inhibitors
CM Cholesterol Ester
TR
Dujovne, AJC 2002;90:1092-1097Knopp, IJCP 2003;57:363-368
Ezetimibe + Statin Studies: Efficacy on TG Pooled Ezetimibe + Statin Studies: Efficacy on TG Pooled ResultsResults
Ezetimibe + Statin Studies: Efficacy on TG Pooled Ezetimibe + Statin Studies: Efficacy on TG Pooled ResultsResults
-24
-14
-20
-12
-33
-21
-29
-25
-40
-35
-30
-25
-20
-15
-10
-5
0
AtorvastatinPravastatinSimvastatinLovastatin
StatinStatin + EZE Statin
Statin + EZE
StatinStatin + EZE
StatinStatin + EZE
Med
ian
% C
han
geM
edia
n %
Ch
ange
* p<0.01 combination therapy versus statin alone
**
**
**
**
Davidson M et al. J Am Coll Cardiol 2002;40:2125-34 Ballantyne C et al. Circulation 2003;107:2409-2415 Melani L et al. Eur H J 2003;24:717-725Kezzner B et al AJC 2003;91:418-42412
AtorvastatinPravastatinSimvastatinLovastatin
StatinStatin + EZE
Statin Statin + EZE
Statin Statin + EZE
Statin Statin + EZE
4
7 7
4
9* 9**8
7*
0
2
4
6
8
10
Mea
n %
Ch
ange
* p<0.01 combination therapy versus statin alone** p=0.03 combination therapy versus statin alone
Davidson M et al. J Am Coll Cardiol 2002;40:2125-34 Ballantyne C et al. Circulation 2003;107:2409-2415 Melani L et al. Eur H J 2003;24:717-725Kezzner B et al AJC 2003;91:418-42412
Ezetimibe + Statin Studies: Efficacy on HDL-C Pooled ResultsEzetimibe + Statin Studies: Efficacy on HDL-C Pooled ResultsEzetimibe + Statin Studies: Efficacy on HDL-C Pooled ResultsEzetimibe + Statin Studies: Efficacy on HDL-C Pooled Results
EASE TrialEASE Trial
p<0.001 for all between-treatment differencesp<0.001 for all between-treatment differences
-1,6 -0,8-2,9 -3,1
-12,8
1,3
-23,5
-19,4
-30
-25
-20
-15
-10
-5
0
5
TG HDL-C Non-HDL-C apo BL
S M
ea
n P
erc
en
t (±
SE
) C
ha
ng
e
Placebo + Statin
Ezetimibe + Statin
-1,6 -0,8-2,9 -3,1
-12,8
1,3
-23,5
-19,4
-30
-25
-20
-15
-10
-5
0
5
TG HDL-C Non-HDL-C apo BL
S M
ea
n P
erc
en
t (±
SE
) C
ha
ng
e
Placebo + Statin
Ezetimibe + Statin
Pearson et al. Mayo Clin Proc. • May 2005;80(5):587-595Pearson et al. Mayo Clin Proc. • May 2005;80(5):587-595
Ezetimibe Clinical Trials Update
In a California zoo, a mother tiger gave birth to a rare set of triplet tiger cubs, but they died shortly after birth.
The veterinarians felt that the loss of her litter hadcaused the tigress to fall into a depression.
The veterinarians decided to try something that had never been tried in a zooenvironment. The only "orphans" that could be found quickly, were a litter of wiener pigs.
In a California zoo, a mother tiger gave birth to a rare set of triplet tiger cubs, but they died shortly after birth.
The veterinarians felt that the loss of her litter hadcaused the tigress to fall into a depression.
The veterinarians decided to try something that had never been tried in a zooenvironment. The only "orphans" that could be found quickly, were a litter of wiener pigs.
Surrogate cubs Surrogate cubs
““Surrogate”-endpoints EvidencesSurrogate”-endpoints Evidences
Carotid IMT Trials Examining Clinical Efficacy
of Statin & Ezetimibe
““Surrogate”-endpoints EvidencesSurrogate”-endpoints Evidences
Carotid IMT Trials Examining Clinical Efficacy
of Statin & EzetimibeTrial Patient
populationN Endpoint Treatment regimen
ENHANCE Heterozygote Familial Hyperchol.
720 Carotid IMT 10/80 vs Simvastatin
SANDS Diabetes 499 Carotid IMT Statins / statins + EZE
Touboul et al. Cerebrovasc Dis 23:75-80;2007
Normal Carotid IMT
Normal Carotid IMT
AgeAge
IMT (mm)IMT (mm)
Weeks Months
Timeperiod
–10 to –7
–6 –1 0 3 12 156 9 18 21 24
Placebo/drug
washout
Ezetimibe/simvastatin 10/80 mg/d
Simvastatin 80 mg/d
Screening/fibrate
washout
Period I
Period IIPrerandomization Double-blind treatment
(N~725)
CA IMT
23.8
HETERO-ZYGOUS FH PATIENTS
LDL>210
N Engl J Med 2008;358:1431
MonthsENHANCE
SimvaEze-Simva
-40
0 6 12 18 24
-50
-60
-70
0
-10
-20
-30
10
Perc
enta
ge c
hang
e fr
om b
asel
ine
P<0.01
-16.5 % incremental reduction
LDL-cholesterol
ENHANCESimva
Eze-Simva
Med
ian
perc
ent c
hang
e fr
om B
asel
ine
p < 0.01
3 6 12 18 24
Months
10
-10
-20
-30
-40
-50
-60
-70
-80
0
-26 % incremental reduction
Baseline 24 months (mg/L) (mg/L)
Simva 1.7(0.8-4.1) 1.2(0.6-2.4) Eze-Simva 1.7(0.8-3-9) 0.9(0.5-1.9)
hs-CRP
N Engl J Med 2008;358:1431
SANDS(Stop Atherosclerosis in Native Diabetics Study)
(JAMA 2008;299:1678-89)
SANDS(Stop Atherosclerosis in Native Diabetics Study)
(JAMA 2008;299:1678-89)
Effect of Statins Alone versus Statin plus Ezetimibe on Effect of Statins Alone versus Statin plus Ezetimibe on Carotid Atherosclerosis in Type 2 DiabetesCarotid Atherosclerosis in Type 2 Diabetes
(J Am Coll Cardiol 2008(J Am Coll Cardiol 2008
499 men and womenwith diabetes and no CVD
40 yrs oldSBP>130, LDL>100
Standard TargetsLDL-C <100; SBP <130
non-HDL-C <130N=247
Aggressive Targets LDL-C <70; SBP <115
non-HDL-C <100N=252
Measure CVD using carotid and cardiac ECHO at baseline
18 months and after 3 yrs interventionPrimary outcome—change in CIMT
Trial Design
Mean Changes in LipidsMean Changes in Lipids
-35
-30
-25
-20
-15
-10
-5
0
5
TOT-C LDL-C HDL-C TG non-HDL C
Aggressive Standard
-35
-30
-25
-20
-15
-10
-5
0
5
TOT-C LDL-C HDL-C TG non-HDL C
Aggressive Standard
mg/dL
Change in IMT by Ezetimibe +/-Change in IMT by Ezetimibe +/-
-0.03
-0.02
-0.01
0
0.01
0.02
0.03
0.04
E+ (N=69) E- (N=154)
Aggressive Standard
-0.03
-0.02
-0.01
0
0.01
0.02
0.03
0.04
E+ (N=69) E- (N=154)
Aggressive Standard
* p<0.001 for both E + and E- compared to Standard
mm
102 mg/dL
102mg/dL
108 to 78mg/dL
-31%
101 to68mg/dL
-32%
Baseline cIMT = 0.81
Aggressive target: Group difference between:
CIMT measure
Standard group
Statin/ ezetimibe group
Statin alone
Ezetimibe/statin and statin alone(p)
Ezetimibe/statin and standard therapy (p)
Statin alone and standard therapy (p)
Mean change, 36 mo
0.039 -0.025 -0.012 0.01 (0.999) 0.06 (0.001) 0.05(0.001)
Fleg JL et al. J Am Coll Cardiol 2008; available at: http://content.onlinejacc.org.
SANDS: Follow-up carotid IMT measuresSANDS: Follow-up carotid IMT measures
ARBITER 6ARBITER 6
Carotid Atorvastatin Study in Hyperlipidemic Post-MEnopausal Women: a Randomised Evaluation of Atorvastatin Versus Placebo
(CASHMERE)- Results
Carotid Atorvastatin Study in Hyperlipidemic Post-MEnopausal Women: a Randomised Evaluation of Atorvastatin Versus Placebo
(CASHMERE)- Results
Evidence-Based Medicine:
Cardiovascular Outcome Trials
Evidence-Based Medicine:
Cardiovascular Outcome Trials
Niacin use leads to reductions in cardiovascular events. One of the oldest placebo-controlled clinical trials of lipid treatment, the Coronary Drug Project studied a number of agents including niacin. At a dose between 2 and 3 g/d in men with prior myocardial infarction (MI), niacin led to significant reductions in nonfatal MI and long-term reductions in overall mortality. This trial is the only sufficiently powered clinical trial comparing niacin to placebo in secondary prevention.
Niacin use leads to reductions in cardiovascular events. One of the oldest placebo-controlled clinical trials of lipid treatment, the Coronary Drug Project studied a number of agents including niacin. At a dose between 2 and 3 g/d in men with prior myocardial infarction (MI), niacin led to significant reductions in nonfatal MI and long-term reductions in overall mortality. This trial is the only sufficiently powered clinical trial comparing niacin to placebo in secondary prevention.
JAMA 1975;231:360-381. J Am Coll Cardiol
1986;8:1245-1255.
JAMA 1975;231:360-381. J Am Coll Cardiol
1986;8:1245-1255.
Lipid Research Clinics Coronary Primary Prevention Trial. This trial of 3,806 hypercholesterolemic men without CHD found a 19% reduction in the incidence of CHD in the men treated with cholestyramine.
Lipid Research Clinics Coronary Primary Prevention Trial. This trial of 3,806 hypercholesterolemic men without CHD found a 19% reduction in the incidence of CHD in the men treated with cholestyramine.
JAMA 1984;251:365–374. JAMA 1984;251:365–374.
p< 0.05p< 0.05
LRC-CPPT LRC-CPPT
Proving the lipid hypothesis:
Reduced CV events loweringcholesterol absorption
Proving the lipid hypothesis:
Reduced CV events loweringcholesterol absorption
Cardiovascular Outcome Trials Examining
Clinical Efficacy of Statin & Ezetimibe
Cardiovascular Outcome Trials Examining
Clinical Efficacy of Statin & EzetimibeTrial Patient
populationN Endpoint Treatment regimen
SEAS
(2008)
AS 1,800 MACE 10/40 vs placebo
SHARP
(2010)
CKD 9,000 MACE 10/20 vs placebo
IMPROVE-IT
(2012)
ACS 18,000 MACE 10/40 vs Simvastatin 40/80
All >29,000
HPS2-THRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) To assess the effect of ER niacin/laropiprant 2 g/40 mg vs placebo on CV events, on a background of
simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg 25,000 high-risk atherosclerosis patients
• Randomized, double-blind trial involving 1873 patients with mild-to-
moderate, asymptomatic aortic stenosis. • Randomized, double-blind trial involving 1873 patients with mild-to-
moderate, asymptomatic aortic stenosis.
The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily.
The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily.
The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement,
nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary
intervention, and nonhemorrhagic stroke.
The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement,
nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary
intervention, and nonhemorrhagic stroke.
Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events.
Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events.
Aortic Stenosis Progression: ASTRONOMER Trial. Cholesterol lowering with rosuvastatin 40 mg did not reduce the progression of AS
Aortic Stenosis Progression: ASTRONOMER Trial. Cholesterol lowering with rosuvastatin 40 mg did not reduce the progression of AS
Intensive lipid-lowering therapy with atorvastatin 80 mg does not halt the progression of calcific aortic stenosis Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE).
Intensive lipid-lowering therapy with atorvastatin 80 mg does not halt the progression of calcific aortic stenosis Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression (SALTIRE).
160
170
180
190
200
210
220
0 1 2 3
No LLT
LLT
400
500
600
700
800
900
1000
0 2-year 4-year Lastvisit
No LLT
LLT
Total cholesterol
Total calcium score
Changes of mean total cholesterol level (mg/dl, Panel A) and mean total coronary calcium score (Panel B)
A
B
Tenenbaum et al, ESC 2009IJC, 2010 in pressTenenbaum et al, ESC 2009IJC, 2010 in press
22% RR 22% RR
Number Needed to Treat (NNT) Number Needed to Treat (NNT)
DefinitionThe NNT is the number of patients who need to be treated in order to prevent one additional bad outcome. It is the inverse of the Absolute Risk Reduction
(ARR)
DefinitionThe NNT is the number of patients who need to be treated in order to prevent one additional bad outcome. It is the inverse of the Absolute Risk Reduction
(ARR)
How to Calculate NNTsNNT = 1/ARR
ARR = |CER - EER|
How to Calculate NNTsNNT = 1/ARR
ARR = |CER - EER|
- 22% RR- 22% RR
LDL-C: 108-55LDL-C: 108-55LDL-C: 140-53LDL-C: 140-53
ARR=CER-IER=20.1-15.7=4.4Mean follow-up 4.3 yearARR/year = 1.02NNT/year=98
NNT/5years=20
ARR=CER-IER=20.1-15.7=4.4Mean follow-up 4.3 yearARR/year = 1.02NNT/year=98
NNT/5years=20
ARR=CER-IER=2.8-1.6=1.2Mean follow-up 1.9 yearARR/year = 0.63NNT/year=159
NNT/5years=32
ARR=CER-IER=2.8-1.6=1.2Mean follow-up 1.9 yearARR/year = 0.63NNT/year=159
NNT/5years=32
NNT? NNT?
“Post-SEAS” Summary:
1. Can lipid-lowering therapy stop progression of aortic stenosis?
No
2. Does ezetimibe associated with increase risk of cancer?No
3. Does ezetimibe/simvastatin combination significantly reduced the incidence of the ischemic cardiovascular events?
Yes
“Post-SEAS” Summary:
1. Can lipid-lowering therapy stop progression of aortic stenosis?
No
2. Does ezetimibe associated with increase risk of cancer?No
3. Does ezetimibe/simvastatin combination significantly reduced the incidence of the ischemic cardiovascular events?
Yes
Combined treatment more successfully target the therapeutic goals in metabolic syndrome: a) low high-density lipoprotein (HDL)-cholesterol, b) high triglyceride levels) c) small dense LDL-cholesterol d) remnant-like particles cholesterol (RLP-C) d) ApoB
A proper co-administration of statin and other lipid-lowering agent (Bezafibrate, Ezetimibe, Niacin) could be more effective in achieving a comprehensive lipid control as compared with monotherapy.
Conclusions (1)Conclusions (1)Cardiovascular disease is a major health problem world-wide.
Epidemiologic and clinical evidences proved that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases cardiovascular disease.
Therefore, hypercholesterolaemia is a major target for primary and secondary prevention.
Cholesterol homeostasis is regulated by both absorption and production. Each pathway may compensate for changes in the other.
The LRC-CPPT have shown that lowering LDL-C levels follow diminishing cholesterol absorption by cholestyramine leads to reduce the incidence of CHD morbidity and mortality.
Cardiovascular disease is a major health problem world-wide.
Epidemiologic and clinical evidences proved that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases cardiovascular disease.
Therefore, hypercholesterolaemia is a major target for primary and secondary prevention.
Cholesterol homeostasis is regulated by both absorption and production. Each pathway may compensate for changes in the other.
The LRC-CPPT have shown that lowering LDL-C levels follow diminishing cholesterol absorption by cholestyramine leads to reduce the incidence of CHD morbidity and mortality.
Conclusions (2)Conclusions (2)Inhibiting both cholesterol absorption and production, ezetimibe together with a statin provide superior LDL-C lowering vs statin monotherapy. Ezetimibe/simvastatin provides beneficial effect on those parameters beyond LDL-C, such as HDL-C, TG, CRP, endothelial function, oxidized and small dense LDL, platelet aggregation. Statin plus Ezetimibe can attenuate progression of carotid IMTin compare with natural history of carotid atherosclerosis. This combination was equal (ENHANCE) or better (SANDS) than statin alone in this Issue, but less effective than Niacin/Statin combination (ARBITER 6).
In the completed clinical outcomes-based trial (SEAS), statin plus ezetimibe combination leads to significant 22% reduction of the ischemic cardiovascular events.This is first large randomised prospective controlled trial which proved the beneficial effect of ezetimibe/simvastatin on cardiovascular events risk reduction.
Inhibiting both cholesterol absorption and production, ezetimibe together with a statin provide superior LDL-C lowering vs statin monotherapy. Ezetimibe/simvastatin provides beneficial effect on those parameters beyond LDL-C, such as HDL-C, TG, CRP, endothelial function, oxidized and small dense LDL, platelet aggregation. Statin plus Ezetimibe can attenuate progression of carotid IMTin compare with natural history of carotid atherosclerosis. This combination was equal (ENHANCE) or better (SANDS) than statin alone in this Issue, but less effective than Niacin/Statin combination (ARBITER 6).
In the completed clinical outcomes-based trial (SEAS), statin plus ezetimibe combination leads to significant 22% reduction of the ischemic cardiovascular events.This is first large randomised prospective controlled trial which proved the beneficial effect of ezetimibe/simvastatin on cardiovascular events risk reduction.
Conclusions (3)Conclusions (3)Even on optimal statin monotherapy, many patients fail to achieve all the desired lipid targets and remain at high residual risk of cardiovascular events. Targeting multiple lipid pathways can provide greater reductions in LDL cholesterol as well as improvements in other lipid parameters like low plasma levels of HDL cholesterol, as well as elevated triglycerides, both of which are associated with increased cardiovascular risk.
Therefore, a proper co-administration of statins with other agents – fibrates, niacin or ezetimibe – selected on the basis of their safety and effectiveness, could be useful in patients with combined dyslipidemia. Tenenbaum, EVIDENCE-BASED MEDICINE , 2010, in press
Even on optimal statin monotherapy, many patients fail to achieve all the desired lipid targets and remain at high residual risk of cardiovascular events. Targeting multiple lipid pathways can provide greater reductions in LDL cholesterol as well as improvements in other lipid parameters like low plasma levels of HDL cholesterol, as well as elevated triglycerides, both of which are associated with increased cardiovascular risk.
Therefore, a proper co-administration of statins with other agents – fibrates, niacin or ezetimibe – selected on the basis of their safety and effectiveness, could be useful in patients with combined dyslipidemia. Tenenbaum, EVIDENCE-BASED MEDICINE , 2010, in press