Aggressive Lipid Lowering Treatment

Aggressive Lipid Lowering Treatment

Richard CESKACentre of Preventive Cardiology

University Hospital, Prague, Czech Republic

International Atherosclerosis Society

Chair: Federation for EUROPE

Dyslipidemia Management

Part of the complex approach to decrease CV RISK

Influence all lipid parameters

LDL-C – The first target HDL-C,TGs, apoB…

To lower MACROvascular risk

To lower MICROvascular risk

To lower CV morbidity and mortality

What does it mean? „Agressive Lipid

Lowering“ .

1. LDL-C

2. Residual Risk (DLP risk)

LDL-C

• Killer No 1

• The most important risk factor for CVD

• The first target for lipid lowering treatment

What is an appropriate What is an appropriate therapeutic target for therapeutic target for

LDL-C?LDL-C?

The human evolutionWhat was the LDL-C of our

ancestry?

What is desirable LDL- C ?•Hunter-Gatherer humans•Newborn•Primates•Domestic animals

•Adult Euro/American•(probable physiologic level)

•1,3-1,9 50-75 •0,8-1,8 30-70•1,0-2,1 40-80• > 2,1 >80

•1,3-1,8 50-70•Desirable

LDL-Receptor PathwaySREBP Pathway

Michael BROWN Joseph GOLDSTEIN

LDL-receptor

Nobel Prize 1985SREBP

Familial hypercholesterolemia, positive family history, LDL-C 8,2mmol/l (W

27years)

MERCURY: LDL-C

-31,0

-35,4

-43,7

-37,2

-47,0

-50

-40

-30

-20

-10

0

pp<0.0001<0.0001pp<0.0001<0.0001

% c

han

ge f

rom

base

line

RosuvastatinAtorvastatinSimvastatinPravastatin

10R 10A 20A 20S 40P

MERCURY: TG

-10,5

-13,5

-18,3

-15,9

-18,9

-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

pp=0.0682=0.0682(NS)(NS)pp=0.6891 (NS)=0.6891 (NS)

pp=0.0011=0.0011pp<0.0001<0.0001

% c

han

ge f

rom

base

line

RosuvastatinAtorvastatinSimvastatinPravastatin

10R 10A 20A 20S 40P

*p<0,01 ezetimibe + sdružené dávky statinů vs. sdružené dávky statinů samotné

Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424.

Ezetimibe + statins LDL-C

–60

–50

–40

–20

0

ezetimibe10 mg +

atorvastatin(n=255)

ezetimibe10 mg +

simvastatin(n=274))

ezetimibe10 mg +

lovastatin(n=192)l)

ezetimibe10 mg +

pravastatin(n=204))

–56*–51*

–40*–39*–30

–10

Stř

edn

í ho

dn

ota

% z

měn

y u

vyp

očí

tan

ého

LD

L-C

z v

ých

ozí

hla

din

y p

o 1

2-ti

týd

nec

h

Treatment of Hyperlipidemia

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.

LDL-CLDL-C LDL-CLDL-C

Therapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Drug TherapyDrug TherapyDrug TherapyDrug Therapy

Therapy of Choice: StatinTherapy of Choice: StatinTherapy of Choice: StatinTherapy of Choice: Statin

AlternativeAlternative/combo/combo:: Ezetimibe,r Ezetimibe,resin or niacinesin or niacin

The The Lower Lower = = The The BetterBetter

for LDL-C loweringfor LDL-C lowering

For clinical outcomes reductionFor clinical outcomes reduction

Scandinavian Simvastatin Survival

Study (4S)

Scandinavian Simvastatin Survival

Study (4S)

The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994

Primary Endpoint: Overall Survival

Primary Endpoint: Overall Survival

80828486889092949698

100

0 1 2 3 4 5 6

Simvastatin

Placebo

Years since randomizationYears since randomization

% S

urv

ivin

g%

Su

rviv

ing

30% risk reduction

p = 0.0003


Coronary MortalityCoronary Mortality

111

189

0

50

100

150

200

Placebo imvastatin

42% Risk Reduction42% Risk Reductionp<0.00001p<0.00001

Nu

mb

er

of

de

ath

sN

um

be

r o

f d

ea

ths


Atorvastatin 80 mg n=4,995


Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD) , nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years.

Secondary Endpoint: Major coronary events, cerebrovascular events, hospitalization for congestive heart failure (CHF), all-cause mortality, peripheral artery disease, any cardiovascular event, any coronary event

Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD) , nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years.

Secondary Endpoint: Major coronary events, cerebrovascular events, hospitalization for congestive heart failure (CHF), all-cause mortality, peripheral artery disease, any cardiovascular event, any coronary event

TNT Trial

Presented at ACC 2005Presented at ACC 2005



10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL

19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period

10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL

19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period

TNT: The Lower the Better

-22%

J. C. LaRosa et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. // N Engl J Med 2005;352:1425-35.

Intensive lipid-lowering therapy with atorvastatin 80 mg/day in patients with stable

CHD provides significant clinical benefit beyond that provided by atorvastatin 10 mg/day

TNT pts after CABG n = 4,654MACE -27%

High-dose High-dose atorvastatinatorvastatin

80 mg/day80 mg/dayIf LDL was <40 mg/dL at 24 wks If LDL was <40 mg/dL at 24 wks

dose could be reduced to 40 dose could be reduced to 40 mg/daymg/day

n=4,439n=4,439

High-dose High-dose atorvastatinatorvastatin

80 mg/day80 mg/dayIf LDL was <40 mg/dL at 24 wks If LDL was <40 mg/dL at 24 wks

dose could be reduced to 40 dose could be reduced to 40 mg/daymg/day

n=4,439n=4,439

IDEAL Trial: Study Design

Presented at AHA 2005Presented at AHA 2005

Standard-dose Standard-dose simvastatinsimvastatin

20 mg/day20 mg/dayIf cholesterol >190 mg/dL at 24 wks If cholesterol >190 mg/dL at 24 wks

dose could be increased to 40 dose could be increased to 40 mg/daymg/day

n=4,449n=4,449

Standard-dose Standard-dose simvastatinsimvastatin

20 mg/day20 mg/dayIf cholesterol >190 mg/dL at 24 wks If cholesterol >190 mg/dL at 24 wks

dose could be increased to 40 dose could be increased to 40 mg/daymg/day

n=4,449n=4,449

8,888 patients 8,888 patients ≤80 years ≤80 years with definite history of with definite history of myocardial infarction and qualified for stain therapy at myocardial infarction and qualified for stain therapy at

time of recruitmenttime of recruitment RandomizedRandomized

8,888 patients 8,888 patients ≤80 years ≤80 years with definite history of with definite history of myocardial infarction and qualified for stain therapy at myocardial infarction and qualified for stain therapy at

time of recruitmenttime of recruitment RandomizedRandomized

IDEAL Trial: Primary Endpoint

9,310,4

0

3

6

9

12

Atorvastatin Simvastatin

9,310,4

0

3

6

9

12


• The primary The primary composite endpoint composite endpoint of major coronary of major coronary event occurred in event occurred in 9.3% of the 9.3% of the atorvastatin group atorvastatin group and 10.4% of the and 10.4% of the simvastatin group.simvastatin group.

Primary Composite of major coronary event * Primary Composite of major coronary event * (%)(%)

p = 0.07p = 0.07


%%

* Major coronary event defined as * Major coronary event defined as coronary death, hospitalization for coronary death, hospitalization for non-fatal acute MI or resuscitated non-fatal acute MI or resuscitated cardiac arrest.cardiac arrest.

IDEAL Trial: Secondary Endpoints

12,0

26,5

13,7

30,8

0

8

16

24

32

Major CV events Any CV event


12,0

26,5

13,7

30,8

0

8

16

24

32

Major CV events Any CV event


• Major Major cardiovascular cardiovascular events, defined as events, defined as any primary event any primary event plus stroke, occurred plus stroke, occurred less often in the less often in the atorvastatin group.atorvastatin group.

•Any cardiovascular Any cardiovascular event, defined as event, defined as major CV event plus major CV event plus hospitalization for hospitalization for CHF and peripheral CHF and peripheral artery disease, also artery disease, also occurred less often in occurred less often in the atorvastatin the atorvastatin group.group.

Major cardiovascular events and Major cardiovascular events and any cardiovascular event (%)any cardiovascular event (%)


%%

p=0.02

p<0.001

UK Switching Study: Impact of Switching From Atorvastatin to Simvastatin

Patients Switched from Atorvastatin to

Simvastatin (n=2511)

Atorvastatin(n=9009)D

ea

th o

r C

V E

ven

t (%

)

Years after Index Date

12

10

8

6

4

2

0

0.0 0.5 1.0 1.5 2.0 2.5 3.0

33%Increase in death

or CV events with switch to

Simvastatin (P=0.007)

PHILLIPS B, et al. Poster accepted for presentation at the European Society of Cardiology Congress, Sep 1-5, 2007

Primary end point: Primary end point: time to death or first time to death or first major CV event (MI, major CV event (MI,

stroke, and stroke, and revascularization)revascularization)

Primary end point: Primary end point: time to death or first time to death or first major CV event (MI, major CV event (MI,

stroke, and stroke, and revascularization)revascularization)

PHILLIPS B, et al. Poster accepted for presentation at the European Society of Cardiology Congress, Sep 1-5, 2007

LDL-C lowering with statins: reduced CHD events

Events

(%

)

50

Secondary PreventionPrimary Prevention

CARE-Rx

4S-Rx

LIPID-Rx

CARE-PL

LIPID-PL

4S-PL

AFCAPS-RxAFCAPS-PL

WOSCOPS-RxWOSCOPS-PL

70 90 110 130 150 170 190 2100

5

10

15

20

25

LDL Cholesterol (mg/dL)The Lower The Better

AVERT

Aggressive lipid-lowering therapy isas effective as angioplasty

Treatment with atorvastatin, as compared with angioplasty, was associated with a significantly longer time to a first ischemic

event and with a reduction in risk of 36%Pitt B.et al. AGGRESSIVE LIPID-LOWERING THERAPY COMPARED WITH ANGIOPLASTY IN STABLE CORONARY ARTERY DISEASE. // New Engl. J. Med. 1999;341:70-76.

PROVE IT–TIMI 22(2-Year Trial)

0

1

LogCHDRisk

100 LDL-C Level60

Pravastatin40 mg

16% Reduction in CVD

Atorvastatin80 mg

Cannon CP et al. N Engl J Med 2004;350:1495-1504.

High dose atorvastatin after strokeor trasient ischemic attack (SPARCL)

SPARCL

-16%

P. Amarenco et al. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack.// N Engl J Med 2006;355:549-59.

CHD Event Rates in Secondary Prevention and ACS Trials

Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

y = 0.1629x · 4.6776R² = 0.9029p < 0.0001

LDL Cholesterol (mg/dl)

CH

D E

ven

ts (

%)

PROVE-IT-PR

PROVE-IT-AT CARE-S

LIPID-S

HPS-S4S-S

HPS-P

CARE-P

LIPID-P

4S-P

0

5

10

15

20

25

30

30 50 70 90 110 130 150 170 190 210

TNT 80TNT 10A2Z 80

A2Z 20

IDEAL S20/40IDEAL A80

High-dose statin betterHigh-dose statin worse

Odds Reduction

Event Rates

No./Total (%)

High Dose Std Dose

-16%3972/13798

(28.8)4445/13750

(32.3)

-16%1097/13798

(8.0)1288/13750

(9.4)

-12%462/13798

(3.3)520/13750

(3.8)

+3%340/13798

(2.5)331/13750

(2.4)

-6%808/13798

(5.9)857/13750

(6.2)

-18%316/13798

(2.3)381/13750

(2.8)

Coronary Death or Any Cardiovascular Event

Coronary Death or MI

Cardiovascular Death

Non-Cardiovascular Death

Total Mortality

Stroke

0.5 1 2.5

OR 0.8295% CI, 0.71-0.96p=0.012

Odds Ratio (95% CI)

Meta-Analysis of Intensive Statin Therapy All Endpoints

Cannon CP, et al.

OR, 0.9495% CI, 0.85-1.04P=0.20

OR, 1.0395% CI, 0.88-1.20p=0.73

OR, 0.8895% CI, 0.78-1.00p=.054

OR, 0.8495% CI, 0.77-0.91p=0.00003

OR, 0.8495% CI, 0.80-0.89p<0.0001

Cannon CP, et al. JACC 2006; 48: 438 - 445.

20

40

30

0

10

0 30 months 5 years

Summary: 5 Years Of Follow-Up In IDEAL Is The Longest Period Of Follow-Up Of ACS Patients On Statin TherapyC

ard

iac

Eve

nt

(%) 50

60

Atorvastatin 80 mgPravastatin 40 mg

Simvastatin 20-40 mg

16% RRRP=0.005

PROVE IT

MI or UA

18% RRRP=0.04

IDEAL

All MI

Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

PCSK9 (proprotein convertase subtilisin/kexin type 9) Enzyme - associated with plasma levels of LDL –C(expressed in the liver, intestine and kidney)

Overexpression of gene for PCSK9 more PCSK9 enzyme LDLreceptors reduction (LDL-Receptor enable removal of LDL-C from the plasma) increase in circulating LDL-C

High levels of PCSK9 = high LDL-C levels

Conversely, lacking Pcsk9 leads to increased levels of hepatic LDL receptors,and they remove LDL from the plasma at an accelerated rate)

Low levels of PCSK9 = low LDL- C levels

1.Brown, M.S.,Science, Vol 311, March 24, 2006

2. Cohen J.C. et al.,New England Journal of Medicine, Volume 354, 2006 Number 12

Cohens et al. study

• Studied patients with lifelong low LDL-C levels, due to loss of- function mutations in the gene encoding PCSK9 = they have low level of PCSK9 = low level of LDL-C

• Severe mutation: LDL-C was reduced by 1 mmol/l (38 mg/dl)

prevalence of CHD declined by a remarkable 88%.

• Less severe mut.:LDL-C was reduced by only 0,52 mmol/l (21 mg/dl)

CHD incidence declined by 47%.

Cohen et al., N Engl J Med 2006;354:1264-72.

Brown, M.S.,Science, Vol 311, March 24, 2006

The Longer The Better

Why does lowering of LDL-C concentration by 40 mg/dl

by a PCSK9 mutation reduce CHD incidence by 88%,

whereas a 40-mg/dl lowering with a statin reduces CHD

prevalence by only 23% on average ???




Cohen et al. study

The most likely answer is

DURATION




Cohens et al. study

• People with mutations in PCSK9 likely have

maintained relatively low LDL levels

throughout their lives.

• People in statin trials have had their LDL levels

lowered for only 5 years.

• Atherosclerosis is a chronic disease that

begins in the teenage years




Cohens et al. study

Recent Coronary IVUS Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

MedianChange

In PercentAtheromaVolume

(%)

Mean Low-Density Lipoprotein Cholesterol (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

A-Plusplacebo

ACTIVATEplacebo

Relationship between LDL-C and Progression Rate

ASTEROIDrosuvastatin

r2= 0.95p<0.001

Nissen S. JAMA 2006

Rosuvastatin 40 mg (n=349 evaluated serial IVUS examinations)

Patients

CAD, undergoing coronary angiography

Target coronary artery: ≤50% reduction in lumen diameter of

≥40 mm segment

No cholesterol entry criteria

≥18 years

Visit:Week:

Lipids LipidsTolerability

IVUSLipids

Tolerability

LipidsTolerability

TolerabilityTolerability Tolerability

1–6

20

313

426

539

652

765

878

991

10104

Eligibilityassessment

CAD=coronary artery disease; PCI=percutaneous coronary intervention; IVUS=intravascular ultrasound

ASTEROID: study design

IVUSLipids

IVUS Objem atero plátu

Precise Planimetry of EEM and Lumen Bordersallows calculation of Atheroma Cross-sectional Area

EEM = External Elastic Membrane

EEM Area

LumenArea

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

(EEM area — Lumen Area)

ASTEROID Trial: Principal Findings

• LDL Levels were LDL Levels were reduced from reduced from 130.4 mg/dL at 130.4 mg/dL at baseline to a baseline to a mean of 60.8 mean of 60.8 mg/dL at 2 year mg/dL at 2 year follow-up follow-up (p<0.001), with (p<0.001), with 75% of patients 75% of patients achieving an LDL achieving an LDL <70 mg/dL. <70 mg/dL.

• HDL levels were HDL levels were

increased from increased from 43.1 mg/dL at 43.1 mg/dL at baseline to a baseline to a mean of 49.0 mean of 49.0 mg/dL at follow-mg/dL at follow-up (p<0.001).up (p<0.001).

LDL/

HD

L LD

L/H

DL

mg/

dLm

g/dL

Mean LDL level decrement and HDL level increment

(mg/dL)

43,1

60,849,0

130,4

0

22

44

66

88

110

132

LDL Levels HDL Levels

Baseline Follow-up

43,1

60,849,0

130,4

0

22

44

66

88

110

132

LDL Levels HDL Levels

Baseline Follow-up

p<0.001p<0.001

p<0.001p<0.001

Presented at ACC 2006Presented at ACC 2006

*p<0.001 for difference from baseline. Wilcoxon signed rank test

-10-9-8-7-6-5-4-3-2-10

Median Atheroma Volume in themost diseased 10mm

subsegmentMedian Normalised Total

Atheroma Volume

Chang

e f

rom

base

line (

%)

- 9.1%

*

*- 6.8%

Endpoint analysis: Change in key IVUS parameters

Ref: Nissen S et al. JAMA 2006;295 (13):1556-1565.

Regression of atherosclerosis in ASTEROID

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

ACS Patients: Major Coronary Events MI + CHD Death +

Resuscitated Cardiac Arrest

Years Since Randomization

Cu

mu

lati

ve H

azar

d (

%)

0 1 2 3 4 50

4

8

12

16

20

HR = .66 (95% CI = 0.46, 0.95), P=.02

34% RRR

SimvastatinAtorvastatin

Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

Odds ratio

0.5 1 3.0

Study (n)

Treatment Achieved LDL (mg/dl)

Odds ratio (95% CI)

0.74 (0.58,0.94) TNT (10,001) Atorvastatin 8077

0.72 (0.52,0.98) A to Z (4497) Simvastatin 8063

0.54 (0.34,0.85) PROVE-IT (4162) Atorvastatin 8062

0.80 (0.61,1.05) IDEAL (8888) Atorvastatin 8081

0.73 (0.63,0.84), p<0.001 Overall (95% CI)

Intensive statintherapy better

Moderate statintherapy better

Atorvastatin 10101

Simvastatin 2077

Pravastatin 4095

Simvastatin 20104

Intensive Moderate

Scirica BM, et al. AHA 2005

Meta-Analysis of Intensive Statin Therapy CHF

Residual Cardiovascular Risk in Major Statin Trials: Standard Doses

Adapted from Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.

62%69%73%75%

62%

75%

0

20

40

60

80

100

4S LIPID CARE HPS WOS AFCAPS /TexCAPS

LDL

N 4444 4159 20 536 6595 66059014

-35% -28% -29% -26% -25%-25%

Secondary High Risk Primary

Pat

ien

ts E

xper

ien

cin

g

Maj

or

Co

ron

ary

Eve

nts

, %

Residual CVD Risk in Patients Treated With Intensive Statin Therapy

Pa

tie

nts

Ex

pe

rie

nc

ing

M

ajo

r C

VD

Ev

en

ts, % Standard statin therapy

Intensive high-dose statin therapy

PROVE IT-TIMI 222 IDEAL3 TNT4

N

LDL-C,*mg/dL

1Superko HR. Br J Cardiol. 2006;13:131-136. 2Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.3Pedersen TR, et al. JAMA. 2005;294:2437-2445. 4LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.

4162 8888 10 001

95

*Mean or median LDL-C after treatment

62 104 81 101 77

Statistically significant, but clinically inadequate CVD reduction1

Reduction in rate of first major coronary events

per each 39 mg/dL reduction in LDL-C*

ResidualRisk

Atherogenicdyslipidemia

Metabolicsyndrome

Diabetes

Hypertension

Smoking

It is time to treat the Residual CVD Risk in Patients With Dyslipidemia

23%23%

*Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet. 2005;366:1267-1278.

Residual Risk: Definitions

1. CVD incidence in patients on statin treatment

• Standard dose, e.g. simvastatin 20-40 mg• Intensive dose, e.g. atorva 80, rosuva 40

2. CVD incidence in patients treated to LDL goal

3. CVD incidence in patients on optimal treatments to prevent CVD, including anti-hypertensive, anti-platelet, LDL, smoking, nutrition, lifestyle

30% of adults in CZ: Metabolic Syndrome

RFs in abdominal obesity

Patients with abdominal

obesity (high waist

circumference) often

present with one or

more additional

CV risk factors

(104 cm)(1.8 mmol/L)

(0.9 mmol/L)

(6.0 mmol/L)

HypertensionCentral obesity

Smoking , Depression

Cardiometabolic risk in MS patient

• Hypertriglyceridemia• Low HDL-C• Elevated apolipoprotein B• Small, dense LDL particles• Postprandial hyperlipidaemia

• Hyperinsulinemia• Glucose intolerance• Insulin resistance• Impaired fibrinolysis• Endothelial dysfunction

Intra-abdominIntra-abdominalal (viscer (visceralal) ) fat fat examinationexamination

The dangerous inner fat!

BackBack

Visceral AT

Subcutaneous AT

FrontFront

Intra-abdominal fat examination

Atherogenity: The role of particle size

HDL

LDL

VLDL

Atherogenic Nonatherogenic

HDL

25,5nm –A profil25,5nm – B profilLDL

Small dense Large

Large

VLDL

Large Small

Small

Particle size and CV risk

< >

How to decrease residual risk?

• Treatment of HLP/ DLP• (part of the complex approach)

Focused on:

HDL-C

TGs•

TGs, (HDL-C) Fibrates

Statin + Fibrate

COMBO

-60

-50

-40

-30

-20

-10

0

Elevated TGs identify patients in whom fibrate therapy reduces CV risk (1)

• HHS1,2: Fibrates reduced the incidence of CV events by 56% in patients with TG levels >2.3 mmol/L (200 mg/dL) compared with a 34% reduction in the overall population

Rel

ativ

e ri

sk r

educ

tion

in t

ota

l C

VE

s/1

000

(%)

Overall(n=4,081)

TG >200 mg/dL(n=1,046)

1 Frick MH et al. N Engl J Med 1987;317:1237-45.2 Barter PH, Rye KA. Arterioscler Thromb Vasc Biol 2008;28:39-46.

p<0.02

p not available

-56%

-34%

Elevated TGs identify patients in whom fibrate therapy reduces CV risk

• BIP1: Fibrate treatment significantly reduced the risk of CV events by 39.5% in patients with TG ≥2.3 mmol/L (200 mg/dL) vs. a 7.3% reduction in the overall population

*CV events: fatal or nonfatal MI or sudden death (primary endpoint)1 The BIP Study Group. Circulation 2000;102:21-7.

-40

-30

-20

-10

0

Rel

ativ

e ri

sk r

educ

tion

in C

V e

vent

s (%

)*

Overall(n=3,090)

TG 200 mg/dL(n=459)

p=0.24

p=0.02

-39.5%

-7.3%

High TGs /low HDL-C identify patients in whom fibrate reduces

CV risk

1 Keech A et al. Lancet 2005;366:1849-61.2 Scott R et al. Diabetes Care 2009;31:493-98.

-30

-20

-10

0R

elat

ive

risk

red

uctio

n (%

)

p=0.035

Low HDL-C (<1.03 mmol/L or 40 mg/dL for men and <1.29 mmol/L or 50 mg/dL for women) and elevated TG (≥2.3 mmol/L or 200 mg/dL) defined according to ATP III criteria

p=0.030

p=0.010

p<0.005

Overall(n=9,795)

Low HDL-C(n=5,820)

Low HDL-C + elevated TG

(n=2,014)Elevated TG

(n=2,517)

Total CVD

-27%-23%

-14%-11%

Small dense LDL reduction Small dense LDL reduction - 56%after statin + fenofibrate combo

Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and Tolerability of Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (The SAFARI Trial) Am J Cardiol 2005;95:462–468

0%

20%

40%

60%

80%

100%

simvastatin 20 mg+ fenofibrát 160 mg

simvastatin 20 mg simvastatin 20 mg+ fenofibrát 160 mg

simvastatin 20 mg

malé denzní střední velké lehké

n=61812 týdnů

Before Before afterafterLDL particlesLDL particles

-56%-56%

SAFARI

Studies with fibrates: Comparison of general population and subgroups ith lo HDL and high Tgs

Trial(Drug)

Primary Endpoint: Entire Cohort (P-value)

Lipid Subgroup Criterion

Primary Endpoint: Subgroup

HHS (Gemfibrozil)

-34%

TG > 200 mg/dlLDL-C/HDL-C > 5.0 -71%

BIP (Bezafibrate)

-7.3%

TG > 200 mg/dl -39.5%

FIELD(Fenofibrate)

-11%

TG > 204 mg/dlHDL-C < 42 mg/dl

-27%

ACCORD(Fenofibrate)

-8% TG > 204 mg/dlHDL-C < 34 mg/dl -31%

HDL-C (LDL,TG)

Niacin

Statin + Niacin (laropiprant)

-50

-40

-30

-20

-10

0

10

20

30

Efficacy of Extended-Release NiacinEfficacy of Extended-Release NiacinC

han

ge f

rom

Base

line

2500 mg

3000 mg

Goldberg A et al. Am J Cardiol 2000;85:1100-1105.

2000 mg

1500 mg

1000 mg

500mg

HDL-C

LDL-CLp(a)

TG

–9%–14%

–22% –21%–17%

29.5%30%26%

22%15%

10%

–28%

–35% –44%–39%

–11%

–5%

–26%

–3%

–12%

–30%

–24%–17%

0

5

10

15

20

25

30

35

Coronary Drug Project:Coronary Drug Project:Clinical Outcomes*Clinical Outcomes*

Even

t R

ate

(%

)

Coronary Drug Project Research Group. JAMA 1975;231:360–381.

CV SurgeryStroke/TIANonfatal MINonfatal MI/CHD Death

*Total follow-up, adjusted for baseline characteristics, †p<0.05, ‡5-year rate

MI=myocardial infarction; CHD=coronary heart disease; TIA=transient ischemic attack; CV=cardiovascular

Placebo

Niacin

−14†

−27†

−26†

−47†‡

ARBITER 2: Secondary Efficacy Endpoint—Clinical Events

• Composite clinical event endpoint

– Unstable angina/MI hospitalization

– Stroke

– Sudden cardiac death

– Percutaneous coronary revascularization, CABG, or peripheral revascularization

Pati

en

ts w

ith

Even

t (%

)

P = .20

9.6

3.8

60%

0

2

4

6

8

10

12

Statin +Placebo

Statin +Niacin ER

Taylor AJ et al. Circulation 2004;110:3512-3517.

HDL-CNew experimental approach

ApoA-I Milano

Normal Apo A1 and Apo A1 Milano Dimer

A1m/A1m

A1

1 1

243243

173173ss

1

25

35

66 121 165209 220

243

18714399

Lipid Binding In Vivo Catabolism

LCAT Activation Cholesterol Efflux

“Receptor” Binding

Franceschini G. Eur J Clin Invest 1996;26:733–746.

A1=apolipoprotein A1A1m=apolipoprotein A1 MilanoLCAT=lecithin cholesterol acyl- transferase

Evaluation of Plaque Changes in Rabbits by Apo A1 Milano

Infusion: Plaque Lipid ContentApo A1 Milano (1g)Apo A1 Milano (1g)SalineSaline

Unpublished data from Chiesa G et al. Circ Res 2002;90:974–980.

HDL-CNew experimental approach

CETP inhibitors

Background: CETP inhibition

HDLHDL

LDL / LDL / VLDLVLDL

LiverLiver

BileBile

CECE

LDL-RLDL-R

FCFC

FFCC

LCATLCAT

CETPCETP

CCEESR-B1SR-B1

X X inhibitioninhibition

Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the transfer of CE from HDL to apoB-containing lipoproteins (VLDL and LDL-C) in exchange for Trig.

Free Cholesterol (FC) Free Cholesterol (FC) in Extrahepatic in Extrahepatic tissuestissues

Effects on LDL-C and HDL-C

HDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

HD

L-C

(m

g/d

L) (

SE

)

0

20

40

60

80

100

120

AnacetrapibPlacebo

Anacetrapib n =Anacetrapib n =776 757 718 687 647 607 572 543

Placebo n =Placebo n =766 761 741 744 736 711 691 666

LDL-C

Study Week

BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76

LDL-

C (

mg/

dL)

(SE

)

0

20

40

60

80

100

AnacetrapibPlacebo

Anacetrapib n = 804 771 716 687 646 604 568 540

Placebo n = 803 759 741 743 735 711 691 666

-39.8% (p<0.001) +138.1% (p<0.001)

Lipid Parameters

Parameter

LS Mean Percent (95% CI) Placebo-Adjusted

Change from Baseline

Week 24 Week 76

Non-HDL-C -31.7* (-33.6, -29.8) -29.4* (-31.6, -27.3)

Apo B -21.0* (-22.7, -19.3) -18.3* (-20.2, -16.4)

Apo A-1 44.7* (42.8, 46.5) 42.3* (40.5, 44.1)

TC 13.7* (12.0, 15.3) 15.6* (13.8, 17.3)

TG -6.8 (-9.9, -3.9) -5.3 (-8.9, -1.7)

Lp(a) -36.4 (-40.7, -32.3) -38.8 (-44.5, -33.9)

ApoE 29.2* (24.7, 33.7)35.3* (30.6, 40.1)

*p<0.001; means for all variables except for triglycerides, lipoprotein(a), for which medians are shown

Pioglitazone

No. of ObservationsGlimepiridePioglitazone

-2

0

2

4

6

8

Week

Glimepiride Pioglitazone

206201

203198

206201

206201

724824Baseline

Mazzone T et al. JAMA 2006;296:2572−2581.

HDL Cholesterol ChangesLS

Mean

Ch

an

ge f

rom

Baselin

e,

HD

L-C

(m

g/d

L)

−1.1%

12.8%

*p<0.0001

PROactive Trial: Significant Reduction in Secondary

Outcome

0

5

10

15

20

25

Even

ts,

%

0 6 18 24 3612 30Time from randomization (months)

*Excluding silent myocardial infarction (MI)

All-cause mortality, nonfatal MI*, stroke

Dormandy JA et al. Lancet 2005;366:1279–1289.

Pioglitazone301 events

Placebo358 events16% RRR

HR 0.84 (0.72–0.98) P = 0.027

16% RRRHR 0.84 (0.72–0.98)

P = 0.027

CHICAGO: Mean Change in CIMT

-0,010

-0,005

0,000

0,005

0,010

0,015

0,020

Glimepiride

Pioglitazone

LS M

ean C

hange f

rom

Base

line

Post

eri

or

Wall

CIM

T (

mm

)

Treatment group difference, Final Visit

−0.013 (95% CI: −0.024,−0.002)

Baseline CIMTLS Mean (SE)

GLM (N=186)0.779 (0.0085) mm

PIO (N=175)0.771 (0.0085) mm

p=0.017

0.012

−0.001

Adapted from Mazzone T et al. JAMA 2006;296:2572–2581.

CIMT=carotid intima-media thickness

Telmisartan Improves cholesterol and

lipids

-35

-30

-25

-20

-15

-10

-5

0Total cholesterol LDL-cholesterol Triglycerides

Change f

rom

baseline (

mg/d

L)

Eprosartan

Telmisartan

* P<0.05 vs Eprosartan

*

Derosa et al. Hypertens Res 2004;27:457–464

*

*

How to influence Residual Risk???

What is the priority

???

Lifestyle changes,

Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle

changes, Lifestyle changes , Lifestyle changes, lifestyle changes,

BUT!!!???

Complex treatment of the patient with „CARDIOMETABOLIC RISK“

CMRDiet &

Physical Activity

ACE-IARBsCCBs

Anti-ThromboticAgents

???

NiacinFenofibrate

StatinsResins,eze,niacin

SulfonylureaInzulin

Metformin

GlitazonesGliptines

…..

Dyslipidemia Managementas a part of complex approach

Use therapy which is effective, safe, well tolerated, supported by EBM data in appropriate dose.

Decrease of CV RISK

Hypolipidemic treatment

LDL-C - main targetof treatment, than RR

„The Lower The Better“

„The Earlier The Better“

„The Longer The Better“

Highers doses(higher prices)

More patients(not at desired goal)

Longer treatment

Longer treatment

Thank you!!!

Documents

Aggressive Lipid Lowering Treatment