Prof. A. Tenenbaum Director Cardioline Heart Institute

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