Pr. SELIM JAMBARTChef du service d’endocrinologie et des maladies métaboliques

Hôtel-Dieu de France

Stratégies pour atteindre les objectifs de contrôle lipidique Stratégies pour atteindre les

objectifs de contrôle lipidique

The past two decades were

dominated by LDL and statin

therapy.

Substantial residual cardiovascular risk in statin-treated patients

Placebo Statin

Year of follow-up

% p

atie

nts

0 1 2 3 4 5 6

10

20

30

0

Risk reduction=24%(p<0.0001)

The MRC/BHF Heart Protection Study

Heart Protection Study Collaborative Group, 2002

19.8% of statin-treatedpatients had a majorcardiovascular event by 5 years

Residual risk after statin treatment in major intervention trials

37

30

37

24

24

31

24

15

36

63

70

63

76

76

69

76

85

64

0 20 40 60 80 100

CARDS

4S

AFCAPS/TexCAPS

CARE

LIPID

WOSCOPS

HPS

PROSPER

ASCOT-LLA

Risk reduction (%) Residual risk

Risk of primary event (%)

room for improvement

room for improvement

Further events reduction through:

• More aggressive LDL-C lowering

Is Lower Better?

S = statin treated; P = placebo treated.

25

20

15

10

5

0

% w

ith

CH

D e

ven

t

LDL-C (mg/dL)

50 70 90 110 130 150 170 190 210

4S-P

CARE-P

LIPID-P4S-S

WOSCOPS-SWOSCOPS-P

AFCAPS-P

AFCAPS-S

LIPID-S

CARE-S

Secondary prevention

Primary prevention

SimvastatinPravastatinLovastatin

?

Prove It: All-Cause Death or Major CV Events in All Randomized Subjects

00 33 1818 2121 2424 2727 303066 99 1212 1515

% with

Event

Months of Follow-up

Pravastatin 40mg(26.3%)

Atorvastatin 80mgAtorvastatin 80mg(22.4%)(22.4%)

16% RR16% RR

(P = 0.005)(P = 0.005)

3030

2525

2020

1515

1010

55

00

room for improvement

Further events reduction through:

• More aggressive LDL-C lowering• Targeting other lipoproteins

Superko HR. Circulation 1996;94:2351-4

Frequency of different forms of dyslipidemiain men with coronary artery disease

60

50

40

30

20

10

0

Fre

quen

cy (

%)

Lp(a)HomocysHyper CTpolygenic

FCHLLowHDL

FH ALP

ALP: TG, HDL-c + small, dense LDL

Classification Classification desdes ddyslipidyslipidéémimieess

• Une dyslipidémie ne représente pas une seule maladie, mais comprend des situations pathologiques différentes par leur pathogénie et donc par leur traitement

Classification Classification desdes ddyslipidyslipidéémimieess

1/ Dysfonction du récepteur des LDL

LDL-C élevé; CT élevé; TG et HDL-C normaux

IDLIDLIDL

Large VLDL

Large VLDL

SmallVLDLSmallVLDL

LDLreceptor

Liver

LPL Lipoprotein lipaseLPL Lipoprotein lipase

HL Hepatic lipaseHL Hepatic lipase

LDLDLL

LPLLPL

LPLLPL

LPLLPL

HLHL

HLHL

CELLS

receptorLDL

THE LDL RECEPTOR

LDL: an atherogenic lipoprotein

The Framingham Study: Relationship Between Cholesterol and CHD Risk

Adapted from Castelli WP. Am J Med 1984;76:4–12Adapted from Castelli WP. Am J Med 1984;76:4–12

00

2525

5050

7575

100100

125125

150150

<204(<5.3)<204(<5.3)

205-234(5.3–6.1)205-234(5.3–6.1)

235-264(6.1–6.8)235-264(6.1–6.8)

265-294(6.8–7.6)265-294(6.8–7.6)

>295(>7.6)>295(>7.6)

CH

D in

cid

en

ce p

er

1000

CH

D in

cid

en

ce p

er

1000

CH

D in

cid

en

ce p

er

1000

CH

D in

cid

en

ce p

er

1000

Serum total cholesterol, mg/dL (mmol/L)Serum total cholesterol, mg/dL (mmol/L)Serum total cholesterol, mg/dL (mmol/L)Serum total cholesterol, mg/dL (mmol/L)

StatinsMolecular mechanisms of action

SREBP feedback control

S = statin treated; P = placebo treated.

25

20

15

10

5

0

% w

ith

CH

D e

ven

t

LDL-C (mg/dL)

50 70 90 110 130 150 170 190 210

4S-P

CARE-P

LIPID-P4S-S

WOSCOPS-SWOSCOPS-P

AFCAPS-P

AFCAPS-S

LIPID-S

CARE-S

Secondary prevention

Primary prevention

SimvastatinPravastatinLovastatin

Patient categoryLDL-C target

(mg/dL)

< 160 mg/dL

< 130 mg/dL

< 100 mg/dL

? 70 mg/dl

No CHD, < 2 other risk factors

No CHD, > 2 other risk factors

< 20% 10 year risk

CHD and CHD risk equivalents

JAMA 2001;285:2486-2497.

LDL-C Targets for Therapy

Noncoronary atherosclerosisDiabetes> 20% 10 year CHD risk

Cholesterol Absorptiongood absorbers and bad absorbers

ABCA1=adenosine triphosphate–binding cassette protein; ACAT=acyl-coenzyme A:cholesterol acyltransferase; CM=chylomicronAdapted from Champe PC, Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.

ABCA1ABCA1

BLOOD

Chylomicrons

Remnants

DIET

Micelles

Free cholesterol

Ch

ole

ster

ol

Bile acids

Unstirredwaterlayer

Synthesis

FC biosynthesis

ACAT

Cholesteryl Ester (CE)FC

ENTEROCYTE

Bru

sh

Bor

der

Plaque formation

CE

CE

Sterols/stanols

XX

Cholesterol Absorption Inhibitors (ezetimibe)

X

Ezetimibe Blocks Cholesterol Metabolism at a New Site

Pleiotropic parietal vascular effects of statins

BLOOD

Chylomicrons

Remnants

DIET

Micelles

Free cholesterol

Ch

ole

ster

ol

Bile acids

Unstirredwaterlayer

Synthesis

FC biosynthesis

ACAT

Cholesteryl Ester (CE)FC

ENTEROCYTE

Bru

sh

Bor

der

Plaque formation

CE

CE

StatinsX

Cholesterol Absorption Inhibitors (ezetimibe)

X

Ezetimibe potentializes statins effecton cholesterol

Classification Classification desdes ddyslipidyslipidéémimieess

1/ Dysfonction du récepteur des LDLLDL-C élevé; CT élevé; TG et HDL-C normaux

2/ Dysfonction de la LPL

Triade

Triade

IDLIDLIDL

Large VLDL

Large VLDL

SmallVLDLSmallVLDL

LDLreceptor

Liver

LPL Lipoprotein lipaseLPL Lipoprotein lipase

HL Hepatic lipaseHL Hepatic lipase

LDLDLL

LPLLPL

LPLLPL

LPLLPL

HLHL

HLHL

CELLS

receptorLDL

Diabetes and the metabolic syndrome: a typical atherogenic lipoprotein profile

Small,denseLDL

Small,denseLDL

TG TG

HDL-c HDL-c

Prandiallipemia

Prandiallipemia

In people with the triade profile we should consider the qualityof lipoproteins rather than the quantity of blood lipids

(the busses rather than the passengers)

CHYLO VLDL β VLDL IDL LDL Small dense LDL

TG-rich lipoproteins

Atherogenic apo B-rich particles

C-rich lipoproteins

Sm

all d

ense

LD

LH

yper

TG

, Low

HD

L-C

CORONARY HEART DISEASE

Syndrome X=Polymetabolic syndrome=Deadly quartet=Dyslipidemic hypertension

Hig

h bl

ood

pres

sure

Mic

roal

bum

inur

ia

Sm

all d

ense

LD

LIm

pair

ed g

luco

se

tole

ranc

e; ty

pe 2

DM

Hyp

erur

icem

ia

Vis

cera

l Obe

sity

Ele

vate

d fi

brin

ogen

,

tiss

ue f

acto

r &

P

AI

1

Non

alc

ohol

ic f

atty

live

r P

olyc

isti

c ov

arie

s

HYPERINSULINISMINSULIN RESISTANCEGENES ENVIRONMENT

Hyp

er T

G, L

ow H

DL

-C

GLOBAL CARDIOMETABOLIC RISK

SMOKING LDL-C BPAGEMALE SEX

GLU

Classical risk factorsClassical risk factors

GLOBAL CARDIOMETABOLIC RISK

Metabolic syndromeMetabolic syndrome

AbdominalObesity

HDL-C

TG

TNF IL-6

PAI-1

Glu T2DMSMOKING LDL-C BP

Insulin

BPAGEMALE SEX

GLU

Classical risk factorsClassical risk factors Emerging risk factorsEmerging risk factors

Despite Therapeutic Advances, Prevalence Despite Therapeutic Advances, Prevalence of Risk Factors Remainsof Risk Factors Remains

Gregg EW, et al. JAMA. 2005;293:1868-1874.Ford ES, et al. Obes Res. 2003;11:1223-1231.

40

30

20

10

0High Total

Cholesterol(240 mg/dL)

High Blood Pressure(Systolic >140 mm Hg

or Diastolic >90 mm Hg)

Smoking

17%14.9%

26.4%

Pre

vale

nce

(%

)

Total Diabetes(Diagnosed/Undiagnosed)

High-Risk WaistCircumferencein Men (>40 in)

8.1%

36%NHES/

NHANES data

1960-19621971-19751976-19801988-19941999-2000

Metabolic Syndrome Associated With Increased CV Morbidity and Mortality

Isomaa B, et al. Diabetes Care. 2001;24:683-689.

**Cardiovascular mortality was defined using ICD-9 (codes 390-459) before 1997 and ICD-10 (codes 100-199) thereafter.

25

20

15

10

5

0CHD

*P<0.001

No metabolic syndromeMetabolic syndrome

MI Stroke All-CauseMortality

CardiovascularMortality

*P<0.001

*

*

*

*

*

25

20

15

10

5

0

Pre

vale

nce

(%

)

Mo

rtal

ity

Rat

e (%

)

PPAR discovery elucidatesthe mechanism of action of fibrates

A-IA-I

A-IIA-II

LPLLPL

C-IIIC-III

Fibrates

PPAR

Regulation of lipoprotein metabolism by PPAR

HDL HDL particlesparticles

TG rich particlesTG rich particles

PPRE

PPAR

RXR

PPRE

PPAR

RXR

PPRE

PPAR

RXR

PPRE

PPAR

RXR

Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC, Circulation, 1998, 98, 2088-2093

PPAR activators lower small dense LDL

VLDL rich in apo C-III

LDL

PPAR activator

Small dense LDL

TGCholesterylester

Macrophage

Large buoyant LDL

LDL receptor

CETP

VLDL poor in apo C-III

TG

Cholesteryl esterCETP

PPAR activators act on the main factorsinvolved in the onset of atherosclerosis

0

5

10

15

20

25

30

TG ≤ 204 TG > 204 TG ≤ 204 TG > 204

Inci

den

ce o

f ca

rdia

c ev

ents

per

1,0

00 p

erso

n-y

ears

PlaceboGemfibrozil

LDL/HDL >5LDL/HDL ≤5

HHS: CHD events reduced in patients with high TG levels and LDL/HDL ratio

71% reduction

p < 0.005

0 1 2 3 4 5 6

20

16

12

8

4

0

Rat

e (%

)

Triglycerides < 200 mg/dl Triglycerides 200 mg/dl

Placebo

Bezafibrate

p = 0.02

39.5% reduction

BIP: event rate reduction in patients with baseline triglycerides < or > 200 mg/dl (2.3 mmol/L)

0 1 2 3 4 5 6

20

16

12

8

4

0

Placebo

Bezafibrate

p = 0.86

Time (years)

Rat

e (%

)

Time (years)

VA-HIT: CVD risk reduction in diabeticscompared with nondiabetics

Combined endpoint Nonfatal MI

CHD death Stroke

18

21

10

3

No diabetes

p = 0.67

p = 0.88

p = 0.09

p = 0.07

22p = 0.17

32

4041

p = 0.004

p = 0.046p = 0.02

p = 0.26

Diabetes

40

30

20

10

0

Cum

ulat

ive

even

t rat

e ch

ange

(%

)

FIELD: Effects on CHD Events* and Total CVD Risk in Patients With No Prior CVD (n=7664)

(n = 7664)(n = 7664)

p=0.014

p=0.004

* Post-hoc analysis

-25%

-19%

-30

-10

-5

0R

isk

red

uct

ion (

%)

-20

CHD Events* Total CVD

The fibrates patients

in association with statins if necessary

• Visceral obesity

• Insulin resistance, prediabetes or diabetes

• Primary prevention• Lipids goal (NECP ATP III)

• LDL cholesterol <100 mg/dl

• HDL cholesterol > 40 mg/dl• Triglycerides <150 mg/dl

TG + VLDL

Alcohol; fructose

Oral synthetic estrogens

Beta blockers; furosemide

Total cholesterol 200 200HDL cholesterol 50 30Triglycerides 100 350LDL cholesterol 130 100

– Total cholesterol 200 200

– HDL cholesterol 50 30

– Triglycerides 100 350

– LDL cholesterol 130100

– Non HDL cholesterol 150170

Classification Classification desdes ddyslipidyslipidéémimieess

1/ Dysfonction du récepteur des LDLLDL-C élevé; CT élevé; TG et HDL-C normaux

2/ Dysfonction de la LPLTriade

3/ Hypo HDLémies isolées

Peripheraltissuestissues

CellCell

membranemembrane

VLDL, IDL, LDLVLDL, IDL, LDL

LDLLDL receptorreceptor

LPLLPL CETPCETP

FCFC CECECECE

TGTGHDL3HDL3 HDL2HDL2

TGTGCECE

Free cholesterolFree cholesterolTriglyceridesTriglyceridesCholesteryl estersCholesteryl esters

CETPCETP Cholesteryl ester transfer proteinCholesteryl ester transfer proteinLCATLCAT Lecithin cholesterol acyltransferaseLecithin cholesterol acyltransferase

SRB1SRB1

FCFC

ABCA1ABCA1

LiverLiver

The reverse cholesterol transport

LCATLCAT

Therapy of low HDL-C levels

Lifestyle changes PPAR α agonists: fibrates PPAR γ agonists: glitazones Statins Nicotinic acid CETP inhibitors ? Sibutramine ? Rimonabant Apo A 1 Milano

Peripheraltissuestissues

CellCell

membranemembrane

VLDL, IDL, LDLVLDL, IDL, LDL

LDLLDL receptorreceptor

LPLLPL CETPCETP

FCFC CECECECE

TGTGHDL3HDL3 HDL2HDL2

TGTGCECE

Free cholesterolFree cholesterolTriglyceridesTriglyceridesCholesteryl estersCholesteryl esters

CETPCETP Cholesteryl ester transfer proteinCholesteryl ester transfer proteinLCATLCAT Lecithin cholesterol acyltransferaseLecithin cholesterol acyltransferase

SRB1SRB1

FCFC

ABCA1ABCA1

LiverLiver

Reverse cholesterol transportis a three steps process

LCATLCAT

Relationship between cholesteryl ester transfer protein (CETP) and

atherosclerosis

CONFUSING AND CONFLICTING REPORTS

CETP: pro-atherogenic role: rationale

Reduction in the amount of cholesterol per HDL particle, in HDL particle size, and in the number of Apo A-I molecules per HDL particle

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: pro-atherogenic role: rationale

Cholesteryl ester redistribution from HDL to the Apo B lipoproteins

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: pro-atherogenic role: rationale

Reduction in HDL-mediated antioxydant and antiinflammatory effects

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: pro-atherogenic role: the facts

Inhibition of CETP in rabbits is consistently and powerfully anti-atherogenic

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: pro-atherogenic role: the facts

Expression of CETP gene in atherosclerosis-prone mice enhance atherosclerosis

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: anti-atherogenic role: rationale

CETP promotes the formation of a population of lipid-poor apo A1 particles, acting as initial acceptors of cell cholesterol

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: anti-atherogenic role: rationale

Cholesterol-enriched HDL, resulting from CETP inhibition, may be dysfunctional in promoting cell cholesterol efflux

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: anti-atherogenic role: the facts

Japanese with CETP deficiency have a 50% increase in CHD, unless HDL-C is > 60 mg/dl

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

CETP: anti-atherogenic role: the facts

Treatment with probucol

* PQRST study

* Prevention of restenosis (Multivitamins and probucol trial)

* FH

HL

CHYLO

N-HDL

HDL 3

CELLCELL

LDL

HDL 2 a

HDL 2 bCETPCETP

TG

CE

REMNANTS VLDL IDL

LPLLPL

LCATLCAT

LCATLCAT

ABC1

PLTPPLTP

After a one-year treatment with probucol

After a one-year treatment with probucol

After a one-year treatment with probucol

Cardiometabolic Risk Factors Tend to Cluster

Combination therapy is the key

We have to target both LDL and HDL.

We‘re not going to abandon LDL and

the statins but we need to add in

HDL-raising therapy

HDL-C: the next target in the battle against heart disease!

The coming decade will belong to HDL

EUROASPIRE II: Achieving Joint European TC goal

EUROASPIRE II: Achieving Joint European TC goal

00

2020

4040

6060

8080

100100

Perc

en

tag

e o

f p

ati

en

tsP

erc

en

tag

e o

f p

ati

en

tsP

erc

en

tag

e o

f p

ati

en

tsP

erc

en

tag

e o

f p

ati

en

ts

61%

of high-risk patients* received

lipid-modifying therapy

61%

of high-risk patients* received

lipid-modifying therapy

51%

of patients reached Joint European TC

goal**

51%

of patients reached Joint European TC

goal**

*CABG, PTCA, MI or ischaemia, ** TC<5 mmol/L (190 mg/dL) *CABG, PTCA, MI or ischaemia, ** TC<5 mmol/L (190 mg/dL)

Adapted from EUROASPIRE II. Euro Heart J 2001;22:554–772 Adapted from EUROASPIRE II. Euro Heart J 2001;22:554–772

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