New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and...

New Concepts in the EvaluationNew Concepts in the Evaluation and and

Treatment of DyslipidemiaTreatment of Dyslipidemia

Nathan D. Wong, PhD, FACCNathan D. Wong, PhD, FACC

Professor and DirectorProfessor and Director

Heart Disease Prevention ProgramHeart Disease Prevention Program

Division of CardiologyDivision of Cardiology

University of California, IrvineUniversity of California, Irvine

Past President, American Society Past President, American Society for Preventive Cardiologyfor Preventive Cardiology

1.20

1.100

1.063

1.019

1.006

0.95

5 10 20 40 60 80 1000

ChylomicronRemnants

VLDL

LDL-R

HDL2

HDL3DL3

Particle Size (nm)

Den

sity

(g/

ml)

Chylomicron

VLDLRemnants

Lipoprotein ParticlesLipoprotein Particles

Lp(a)

IDL

Only these lipoprotein particles found in plaque at biopsy.

1.050

Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention

High Plasma Apo B Lipoprotein High Plasma Apo B Lipoprotein Levels Promote AtherogenesisLevels Promote Atherogenesis

BloodApo B lipoproteinparticles

ModificationMacrophage

Monocytes bind toadhesion molecules

Smooth muscle

Foam cell

Inflammatory response

Lipid Atherogenesis

HDL

Liver

Advancedfibrocalcific

lesion

Oxidativemodification

of LDL

LDL+

VLDL

Cholesterolexcreted

Endothelialinjury

Adherenceof platelets

Releaseof PDGF

High plasmaLDL

LDL infiltrationinto intima

+Macrophages

Foam cells

Fatty streak

LCATAPO-A1

Othergrowthfactors

lipid core

adventitia

adventitia

lipid core

Anti-atherosclerotic therapy

From Davies et al (1998)

Unstablelesion

Stablelesion

Proportion of U.S. Adults at Recommended Proportion of U.S. Adults at Recommended Lipid Levels in NHANES 2003-2004Lipid Levels in NHANES 2003-2004

0

10

20

30

40

50

60

70

80

Percent of Adults

LDL-C HDL-C TG All

Men

Women

CVD

DM

Ghandehari and Wong et al, Am Heart J 2008

Genetic Causes of DyslipidemiaGenetic Causes of Dyslipidemia

Type I – Familial HyperchylomicronemiaType I – Familial Hyperchylomicronemia Fasting triglycerides > 1000 mg/dlFasting triglycerides > 1000 mg/dl Defect in lipoprotein lipase or apo CIIDefect in lipoprotein lipase or apo CII Not necessarily at increased risk of CADNot necessarily at increased risk of CAD

Type II - Familial Hypercholesterolemia (type II)Type II - Familial Hypercholesterolemia (type II) LDL-C > 95LDL-C > 95thth percentile for age and gender percentile for age and gender CAD in men by 3CAD in men by 3rdrd or 4 or 4thth decade decade Defect in LDL receptorDefect in LDL receptor Autosomal dominant inheritanceAutosomal dominant inheritance Prevalence 1:500Prevalence 1:500

Familial Defective apo B 100Familial Defective apo B 100 Defective apo B alters LDLr handlingDefective apo B alters LDLr handling Previously undetecable from FHPreviously undetecable from FH


Type III – HyperlipoproteinemiaType III – Hyperlipoproteinemia Increased TC, VLDL, decreased HDL; Increased VLDL:TG Increased TC, VLDL, decreased HDL; Increased VLDL:TG Defect in apo E results in increased concentration of remnant particlesDefect in apo E results in increased concentration of remnant particles RareRare

Type IV – Familial HypertriglyceridemiaType IV – Familial Hypertriglyceridemia Increased TC (due to VLDL), TG, decreased LDL, HDLIncreased TC (due to VLDL), TG, decreased LDL, HDL Results from hepatic overproduction of VLDLResults from hepatic overproduction of VLDL Prevalence 1:100 – 1:50; Association with CAD not as strong as FHPrevalence 1:100 – 1:50; Association with CAD not as strong as FH Heterogeneous inheritanceHeterogeneous inheritance Very sensitive to diet and EtOHVery sensitive to diet and EtOH

Type VType V Increase in chylomicrons and VLDLIncrease in chylomicrons and VLDL RareRare


Familial Combined HyperlipidemiaFamilial Combined Hyperlipidemia Increased TC, LDL and/or triglycerides; decreased HDL Increased TC, LDL and/or triglycerides; decreased HDL Most common genetic dyslipidemia: prevalence 1:50Most common genetic dyslipidemia: prevalence 1:50 Heterogenous inheritanceHeterogenous inheritance Accounts for 10-20% of patients with premature CADAccounts for 10-20% of patients with premature CAD

Defects in HDL MetabolismDefects in HDL Metabolism Most often low HDL is secondary to other dyslipidemiaMost often low HDL is secondary to other dyslipidemia Not all associated with increased CAD risk (e.g. apo AINot all associated with increased CAD risk (e.g. apo AIMilanoMilano)) Tangier’s DiseaseTangier’s Disease CETP defects result in increased HDLCETP defects result in increased HDL

Total Cholesterol Distribution: Total Cholesterol Distribution: CHD vs Non-CHD PopulationCHD vs Non-CHD Population

Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.1996 Reprinted with permission from Elsevier Science.

35% of CHD 35% of CHD Occurs in Occurs in People with People with TC<200 mg/dLTC<200 mg/dL

150 200

Total Cholesterol (mg/dL)

250 300

No CHD

CHD

Framingham Heart Study—26-Year Follow-up

Low HDL-C Levels Increase CHD Risk Even Low HDL-C Levels Increase CHD Risk Even When Total-C Is NormalWhen Total-C Is Normal

Risk of CHD by HDL-C and Total-C levels; aged 48–83 yCastelli WP et al. JAMA 1986;256:2835–2838

02468

101214

< 40 40–49 50–59 60< 200

230–259200–229

260

HDL-C (mg/dL) Tota

l-C (m

g/dL

)

14

-y in

cid

en

ce

rate

s (%

) fo

r C

HD

11.24

11.91

12.50

11.91

6.56

4.67

9.05

5.53

4.85

4.153.77

2.782.06

3.83

10.7

6.6

Sarwar N, et al. Circulation. 2007;115:450-458.

aIndividuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most)

CHD Risk Ratio* (95% CI)

1.72 (1.56–1.90)

21

Duration of follow-up≥10 years 5902<10 years 4256

SexMale 7728

Female 1994

Fasting statusFasting 7484Nonfasting 2674

Adjusted for HDL Yes 4469 No 5689

N=262,525

Groups CHD Cases

Overall CHD Risk Ratioa

Decreased Risk Increased Risk

CHD=coronary heart diseaseHDL=high-density lipoprotein

Triglyceride Level Is Significant CHD Risk Factor: Triglyceride Level Is Significant CHD Risk Factor: Recent Meta-Analysis of 29 Studies (n=262,525) Recent Meta-Analysis of 29 Studies (n=262,525) (Sarwar et al., Circulation 2007)(Sarwar et al., Circulation 2007)

Triglyceride-rich lipoproteins carry cholesterol and promote Triglyceride-rich lipoproteins carry cholesterol and promote atherosclerosis*atherosclerosis*

Very–low-density lipoprotein (VLDL) is precursor to low-density Very–low-density lipoprotein (VLDL) is precursor to low-density lipoprotein (LDL) lipoprotein (LDL)

Hypertriglyceridemia (HTG) drivesHypertriglyceridemia (HTG) drives Cholesterol esters enrichment of VLDL (more atherogenic)Cholesterol esters enrichment of VLDL (more atherogenic) ↓ ↓ LDL size (small, dense LDL are more atherogenic)*LDL size (small, dense LDL are more atherogenic)* ↓ ↓ LDL-C (small, dense LDL carry less cholesterol)*LDL-C (small, dense LDL carry less cholesterol)* ↓ ↓ High-density lipoprotein (HDL) size (small, dense HDL are unstable)High-density lipoprotein (HDL) size (small, dense HDL are unstable)

HTG is linked to other proatherogenic states*HTG is linked to other proatherogenic states* Insulin resistanceInsulin resistance Proinflammatory stateProinflammatory state Prothrombotic stateProthrombotic state Prooxidative stateProoxidative state Endothelial dysfunctionEndothelial dysfunction

*Reasons why non–HDL-C is stronger than LDL-C as predictor of cardiovascular disease

How Can Hypertriglyceridemia How Can Hypertriglyceridemia be Atherogenic?be Atherogenic?

Apolipoprotein B

LDL=130 mg/dL

Fewer Particles More Particles

Cholesterolester

More apolipoprotein B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

Correlates with: TC 198 mg/dL

LDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dL

Non–HDL-C148 mg/dL

Correlates with: TC 210 mg/dL

LDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dL

Non–HDL-C180 mg/dLTC=total cholesterol, LDL-C=low-density lipoprotein cholesterol, TG=triglycerides, HDL-C=high-density lipoprotein cholesterol

Elevated Triglycerides Are Associated With Elevated Triglycerides Are Associated With Increased Small, Dense LDL ParticlesIncreased Small, Dense LDL Particles

Cholesterol per particle, Cholesterol per particle, BUTBUT

Subendothelial Subendothelial penetrationpenetration

Subendothelial Subendothelial bindingbinding

Oxidized/modifiedOxidized/modified

LDL-receptor clearanceLDL-receptor clearance

LDL=low-density lipoprotein

Why Is Small, Dense LDL Why Is Small, Dense LDL MoreMore Atherogenic?Atherogenic?

Significance of NonSignificance of Non--HDL-CHDL-C LDL-C levels incompletely measure the total LDL-C levels incompletely measure the total

atherogenic burdenatherogenic burden When serum TG are >200 mg/dL, increased remnant When serum TG are >200 mg/dL, increased remnant

atherogenic lipoproteins heighten risk beyond predicted atherogenic lipoproteins heighten risk beyond predicted by LDL-Cby LDL-C

– Associated with substantially elevated VLDL-CAssociated with substantially elevated VLDL-C VLDL-C and IDL-C are not accounted for by the VLDL-C and IDL-C are not accounted for by the

calculation of LDL-Ccalculation of LDL-C Non-HDL-C = cholesterol concentration of all Non-HDL-C = cholesterol concentration of all

atherogenic lipoproteinsatherogenic lipoproteins

Miller M, et al. Am J Cardiol 2009;101:1003-1008

Non-HDL-Cholesterol and CVD RiskNon-HDL-Cholesterol and CVD Risk

Very–low-density lipoprotein (VLDL)Very–low-density lipoprotein (VLDL) Made in the liverMade in the liver Triglycerides (TG) >> cholesterol esters (CE)Triglycerides (TG) >> cholesterol esters (CE) Carries lipids from the liver to peripheral tissuesCarries lipids from the liver to peripheral tissues

HDL

LDL

IDL

VLDL

Ath

erog

enic

Lip

opro

tein

sN

on-H

DL;

Apo

B-1

00—

cont

aini

ng

Intermediate-density lipoprotein (IDL)• Formed from VLDL due to lipase removal of TG• Also known as a VLDL remnant

Low-density lipoprotein (LDL) • Formed from IDL due to lipase removal of TG• CE >> TG

High-density lipoprotein (HDL)• Removes cholesterol from peripheral tissues

Lp(a)

Lipoprotein (a) • Formed from LDL w/addition of apolipoprotein A • Atherogenic and prothrombotic

Non-HDL Includes Non-HDL Includes AllAll Atherogenic Atherogenic Lipoprotein ClassesLipoprotein Classes

Lp(a) in Atherogenesis: Another Culprit?Lp(a) in Atherogenesis: Another Culprit?

Identical to LDL particle except for addition of apo(a)Identical to LDL particle except for addition of apo(a)

Plasma concentration predictive of atherosclerotic Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although disease in many epidemiologic studies, although not allnot all

Accumulates in atherosclerotic plaqueAccumulates in atherosclerotic plaque

Binds apo B-containing lipoproteins and proteoglycansBinds apo B-containing lipoproteins and proteoglycans

Taken up by foam cell precursorsTaken up by foam cell precursors

May interfere with thrombolysisMay interfere with thrombolysis

Maher VMG et al. JAMA. 1995;274:1771-1774.Stein JH, Rosenson RS. Arch Intern Med. 1997;157:1170-1176.

Lp(a): An Independent CHD Risk Factor in Men of the Lp(a): An Independent CHD Risk Factor in Men of the Framingham Offspring CohortFramingham Offspring Cohort

RR=relative risk; HT=hypertension; GI=glucose intolerance.

Bostom AG et al. JAMA. 1996;276:544-548.

1.9 1.8 1.81.2

2.73.6

RR

0.1

1

10

2

5

0.2

0.5 Lp(a) TC HDL-C HT GI Smoking

Placebo - Statin outcome trialsPlacebo - Statin outcome trials

High-risk CHD patients High-risk CHD patients (high cholesterol) (high cholesterol)

Majority of Majority of CHD patients CHD patients (broad range of (broad range of cholesterol levels) cholesterol levels)

Patients at high risk Patients at high risk of CHD (highof CHD (high cholesterol)cholesterol)

Patients at low Patients at low risk of CHD risk of CHD (low HDL-C)(low HDL-C)

PrimaryPrimarypreventionprevention

SecondarySecondarypreventionprevention

WOSCOPS(pravastatin)

AFCAPS/TexCAPS(lovastatin)

4S(simvastatin)

HPS(simvastatin)

CARE (pravastatin)

LIPID(pravastatin)

Continuum Continuum of riskof risk

22.622.6

12.912.9

8.448.44

7.97.9

2.82.8Pla

ceb

o M

I ra

te p

er 1

00 s

ub

ject

s p

er 5

yea

rs

PROSPER(pravastatin)

Heart failureHeart failureCORONAGISSI-HF(rosuvastatin)

End stageEnd stage53.753.7

JUPITER(rosuvastatin)

LDL-C achieved mg/dL (mmol/L)

WOSCOPS – Placebo

AFCAPS - Placebo

ASCOT - PlaceboAFCAPS - Rx WOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS - Placebo

LIPID - Rx

4S - Placebo

CARE - Rx

LIPID - Placebo

CARE - Placebo

HPS - Rx

0

5

10

15

20

25

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Even

t ra

te (

%)

6

Secondary Prevention

Primary Prevention

Rx - Statin therapyPRA – pravastatinATV - atorvastatin

200(5.2)

PROVE-IT - PRA

PROVE-IT – ATV

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279

LaRosa JC et al. N Engl J Med 2005;352:e-version

TNT – ATV10

TNT – ATV80

LDL cholesterol and benefit in clinical trialsLDL cholesterol and benefit in clinical trialsIs lower better ?Is lower better ?

JUPITERJUPITER

TNTTNT

Cholesterol Treatment Trialists’ (CCT) Collaboration: Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: Efficacy and safety of cholesterol-lowering treatment:

prospective meta-analysis fo data from 90,056 prospective meta-analysis fo data from 90,056 participants in 14 randomized trials of statins participants in 14 randomized trials of statins

(The Lancet 9/27/05)(The Lancet 9/27/05)

Over average 5 year treatment period (per mmol/L reductionOver average 5 year treatment period (per mmol/L reduction—approx 40 mg/dl in LDL-C):—approx 40 mg/dl in LDL-C): 12% reduction in all-cause mortality12% reduction in all-cause mortality 19% reduction in coronary mortality19% reduction in coronary mortality 23% reduction in MI or CHD death23% reduction in MI or CHD death 17% reduction in stroke17% reduction in stroke 21% reduction in major vascular events21% reduction in major vascular events No difference in cancer incidence (RR=1.00).No difference in cancer incidence (RR=1.00).

Statin therapy can safely reduce 5-year incidence of major Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about coronary events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C20% per mmol/L (about 38 mg/dl) reduction in LDL-C

HPS: First Major Coronary Event

0.4 0.6 0.8 1.0 1.2 1.4

Nonfatal MI

Coronary death

Subtotal: MCE

Coronary

Noncoronary

Subtotal: any RV

Any MVE

Coronary events

Revascularizations

Type of Major Vascular Event

Statin-Allocated

(n = 10269)

Placebo-Allocated

(n = 10267)

357 (3.5%) 574 (5.6%)

587 (5.7%) 707 (6.9%)

898 (8.7%) 1212 (11.8%)

513 (5.0%) 725 (7.1%)

450 (4.4%) 532 (5.2%)

939 (9.1%) 1205 (11.7%)

2033 (19.8%) 2585 (25.2%)

0.73 (0.670.79)P < 0.0001

0.76 (0.700.83)P < 0.0001

0.76 (0.720.81)P < 0.0001

Statin Better Placebo Better

Heart Protection Study Collaborative Group. Lancet. 2002;360:722.

HPS—Simvastatin: Vascular Events by Baseline LDL-C

Baseline Baseline

LDL-C (mg/dL)LDL-C (mg/dL)Statin Statin

(n = 10,269)(n = 10,269)Placebo Placebo

(n = 10,267)(n = 10,267)

<100<100 282 (16.4%)282 (16.4%) 358 (21.0%)358 (21.0%)

100–129100–129 668 (18.9%)668 (18.9%) 871 (24.7%)871 (24.7%)

130130 1083 (21.6%)1083 (21.6%) 1356 (26.9%)1356 (26.9%)

All patientsAll patients 2033 (19.8%)2033 (19.8%) 2585 (25.2%)2585 (25.2%)

Event Rate Ratio (95% CI)Statin Better Statin Worse

0.4 0.6 0.8 1.0 1.2 1.4

www.hpsinfo.org

0.76 (0.72–0.81)P < 0.0001

Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study

3 6 9 12 15 18 21 24 27 30

Follow-up (months)

30

25

20

15

10

5

0

P =0.005

Rec

urre

nt M

I or

Car

diac

Dea

th

16% RRRAtorvastatin

Pravastatin

ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction

Cannon CP et al. NEJM 2004;350:1495-1504

HMG-CoA Reductase Inhibitor: HMG-CoA Reductase Inhibitor: Secondary PreventionSecondary Prevention

4,162 patients with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months

0

5

10

15

20

25

30

60 80 100 120 140 160 180 200

TNT: RationaleTNT: Rationale

(1.6)(1.6) (2.1)(2.1) (2.6)(2.6) (3.1)(3.1) (3.6)(3.6) (4.1)(4.1) (4.7)(4.7) (5.2)(5.2)

Atorvastatin 80 mgAtorvastatin 80 mg


ScreeningScreening

TNTTNT

??

Adapted from LaRosa et al. Adapted from LaRosa et al. N Engl J Med. N Engl J Med. 2005:352:1425-1435. 2005:352:1425-1435.

LDL-C, mg/dL (mmol/L)LDL-C, mg/dL (mmol/L)

Pat

ien

ts W

ith

CH

D E

ven

ts (

%)

Pat

ien

ts W

ith

CH

D E

ven

ts (

%)

0

20

40

60

80

100

120

140

160 Atorvastatin 10 mg (n=5006)

Atorvastatin 80 mg (n=4995)

TNT: Changes in LDL-C by TNT: Changes in LDL-C by Treatment GroupTreatment Group

TNT: Changes in LDL-C by TNT: Changes in LDL-C by Treatment GroupTreatment Group

FinalFinalScreenScreen 00 33 1212 2424 3636 4848 6060

PP<.001<.001

BaselineBaseline

4.04.0

3.53.5

3.03.0

2.52.5

2.02.0

1.51.5

1.01.0

0.50.5

00

Mean

LD

L-C

(mm

ol/L

)M

ean L

DL

-C (m

mo

l/L)

Mean LDL-C level = 101 mg/dL (2.6 mmol/L)Mean LDL-C level = 101 mg/dL (2.6 mmol/L)

Mean LDL-C level = 77 mg/dL (2.0 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L)

LaRosa et al. LaRosa et al. N Engl J Med.N Engl J Med. 2005;352:1425-1435. 2005;352:1425-1435.

Mea

n L

DL

-C (

mg

/dL

)M

ean

LD

L-C

(m

g/d

L)

Study Visit (Months)Study Visit (Months)

TNT: Primary Efficacy Outcome Measure: Major TNT: Primary Efficacy Outcome Measure: Major Cardiovascular Events*Cardiovascular Events*

** CHD death, nonfatal nonCHD death, nonfatal non––procedure-related MI, resuscitated cardiac arrest, procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.fatal or nonfatal stroke.LaRosa et al. LaRosa et al. N Engl J Med.N Engl J Med. 2005;352:1425-1430. 2005;352:1425-1430.

HR=0.78 (95% CI 0.69, 0.89); HR=0.78 (95% CI 0.69, 0.89); PP<.001<.001

Pro

po

rtio

n o

f P

atie

nts

Exp

erie

nci

ng

P

rop

ort

ion

of

Pat

ien

ts E

xper

ien

cin

g

Maj

or

Car

dio

vasc

ula

r E

ven

tM

ajo

r C

ard

iova

scu

lar

Eve

nt

00

0.050.05

0.100.10

0.150.15


Atorvastatin 80 mgAtorvastatin 80 mg Relative Relative risk risk

reduction reduction

22% 22%

00 11 22 33 44 55 66Time (Years)Time (Years)

Mean LDL-C level = 77 mg/dL Mean LDL-C level = 77 mg/dL

Mean LDL-C level = 101 mg/dL Mean LDL-C level = 101 mg/dL

Meta analysis of moderate vs aggressive statin Meta analysis of moderate vs aggressive statin therapytherapy

Cannon et al (2006) JACC 48:438

Coronary death or MI

ACS

Stable CHD

Recent Coronary IVUSRecent Coronary IVUSProgression TrialsProgression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

Med

ian

ch

an

ge in

perc

en

t ath

ero

ma v

olu

me (

%)

Mean LDL-C (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

A-Plusplacebo

ACTIVATEplacebo

Relationship between LDL-C and Progression Rate

ASTEROIDrosuvastatin

Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565

Rosuvastatin 40 mg (n=349 for IVUS analysis; n=292 for QCA analysis)

Patients (≥18 years)

CAD, undergoing coronary angiography

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

≥40 mm segment

Target segment for QCA: all segments >25% at baseline

No cholesterol entry criteria

Visit:Week:

Lipids LipidsTolerability

IVUSQCA

LipidsTolerability

LipidsTolerability

TolerabilityTolerability Tolerability

1–6

20

313

426

539

652

765

878

991

10104

Eligibilityassessment

ASTEROID: Study DesignASTEROID: Study Design

IVUSQCA

Lipids

*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 10-mm

subsegmentMedian normalized TAV

Chang

e f

rom

base

line (

%)

- 9.1%*

*- 6.8%

End Point Analysis: Change in Key IVUS Parameters

n=319 n=346

Adapted from Nissen et al. JAMA 2006;295(13):1556-65.

Example of Regression of Atherosclerosis with Example of Regression of Atherosclerosis with Rosuvastatin in ASTEROID (measured by IVUS)Rosuvastatin in ASTEROID (measured by IVUS)

Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med, 2006; 73:937-944.

Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved.

Diabetes Mellitus:Diabetes Mellitus:Effect of an HMG-CoA Reductase Effect of an HMG-CoA Reductase InhibitorInhibitor

Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;37:117-25

Meta-analysis of 18,686 patients with DM randomized to treatment with a HMG-CoA Reductase Inhibitor

A statin reduces adverse CV events in diabetics

Residual CVD Risk in Statin vs Placebo Residual CVD Risk in Statin vs Placebo TrialsTrials

4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-1307.6 Downs JR et al. JAMA. 1998;279:1615-1622.

14S Group. Lancet. 1994;344:1383-1389.2LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 3Sacks FM et al. N Engl J Med. 1996;335:1001-1009.

LDLN 4444 4159 20 536 6595 66059014

-35% -28% -29% -26% -25%-25%Secondary High Risk Primary

Patie

nts

Expe

rienc

ing

Maj

or C

HD E

vent

s, %

4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/TexCAPS6

PlaceboStatin

19.4

12.310.2 8.7

5.5 6.8

28.0

15.913.2 11.8

7.910.9

Many CHD Events Still Occur in Statin-Treated Patients

25-40% CVD Reduction Leaves High Residual Risk

Antioxidative Activity

AntithromboticActivity

Potential Antiatherogenic Actions of HDL

Anti-infectious Activity

EndothelialRepair

Chapman MJ et al. Curr Med Res Opin. 2004;20:1253-1268.Assmann G et al. Annu Rev Med. 2003;53:321-341.

AntiapoptoticActivity

ReverseCholesterolTransportCellular

CholesterolEfflux

Anti-inflammatoryActivity

VasodilatoryActivity

HDL

Apo A-I

Apo A-II

Should High-Density Lipoprotein Should High-Density Lipoprotein Be a Target of Therapy?Be a Target of Therapy?

-1-0.8-0.6-0.4-0.2

00.20.40.60.8

11.21.4

MARS MAAS

PLAC I LCAS

PLAC ICCAIT

LCASMAAS

MARS

ASTEROID

CCAIT

40 45 50

*ASTEROID rosuvastatin MAAS simvastatin CCAIT lovastatin MARS lovastatin LCAS fluvastatin PLAC I pravastatin

Ch

an

ge in

% s

ten

osis

per

year

On-treatment HDL-C (mg/dL)

Change in Percent Diameter Stenosis Change in Percent Diameter Stenosis vs On-treatment HDL-C in QCA Trialsvs On-treatment HDL-C in QCA Trials

PlaceboStatin*

Ballantyne CM, Nicholls S et al. Circulation 2008; Online

Should High-Density Lipoproteins Be a Should High-Density Lipoproteins Be a Target of Therapy ?Target of Therapy ?

ATP III Guidelines on HDL-C: “Current documentation of ATP III Guidelines on HDL-C: “Current documentation of risk reduction through controlled clinical trials is not sufficient risk reduction through controlled clinical trials is not sufficient to warrant setting a specific goal value for raising HDL-C” to warrant setting a specific goal value for raising HDL-C” (Grundy SM et al. (Grundy SM et al. Circulation. Circulation. 2004;110:227-239)2004;110:227-239)

Failure of ACCORD, FIELD, AIM-HIGH and the experience Failure of ACCORD, FIELD, AIM-HIGH and the experience with torcetrapib and dalcetrapib have raised doubts re: the with torcetrapib and dalcetrapib have raised doubts re: the value of raising HDL-Cvalue of raising HDL-C

Still, Still, The one best study of niacin effects on CVD (HPS-2/THRIVE) The one best study of niacin effects on CVD (HPS-2/THRIVE)

is ongoing—results early in 2013is ongoing—results early in 2013 Investigational CETP inhibitors greatly increase HDL-C and Investigational CETP inhibitors greatly increase HDL-C and

might be shown to reduce CVD—clinical trials ongoing, results might be shown to reduce CVD—clinical trials ongoing, results after 2017after 2017

HDL-C Risk Factor vs Risk Marker?HDL-C Risk Factor vs Risk Marker?

Low HDL-C predicts high CVD RiskLow HDL-C predicts high CVD RiskHigh HDL-C predicts anti-atherogenic effects:High HDL-C predicts anti-atherogenic effects:

Anti-inflammatoryAnti-inflammatory AntioxidantAntioxidant AntithromboticAntithrombotic Pro-endothelialPro-endothelial

But clinical trials of HDL-C-raising agents so far But clinical trials of HDL-C-raising agents so far have failed to prove CVD benefit—suggesting have failed to prove CVD benefit—suggesting that HDL-C may be only a risk markerthat HDL-C may be only a risk marker

• Smoking Cessation− HDL-C levels are lower in smokers (by 7%-20%), and return

towards normal 1-2 months after smoking cessation• Whole Food Plant Based Diet—dietary fiber blunts adverse

carb effect• Weight Reduction

− For every 3 kg (7 lb) of weight loss, HDL-C levels increase by 2-4%, but only after stabilization at new lower weight

• Exercise− Aerobic exercise (40 min, 3-4 x weekly) may increase HDL-

C by 5-10%Rössner S et al. Atherosclerosis. 1987;64:125-130.Wood PD et al. N Engl J Med. 1988;319:1173-1179.Ornish D et al. JAMA. 1998;280:2001-2007.

Lifestyle Modifications to Raise HDL-C Lifestyle Modifications to Raise HDL-C LevelsLevels

Cullen P et al. Eur Heart J. 1998;19:1632-1641.Kokkinos PF et al. Arch Intern Med. 1995;155:415-420.Kodama S et al. Arch Intern Med. 2007;167:999-1008.

Available Agents for HDL-C RaisingAvailable Agents for HDL-C Raising

AgentAgent HDL-CHDL-C ↑↑ Primary UsePrimary Use

Nicotinic acidNicotinic acid 15-35%15-35% HDL HDL ↑↑

FibratesFibrates 5-20% 5-20% TG ↓ TG ↓

StatinsStatins 5-15% 5-15% LDL ↓ LDL ↓

Prescr. Om-3*Prescr. Om-3* 2-10% 2-10% TG ↓TG ↓

Bile-acid resins*Bile-acid resins* 2-5% 2-5% LDL ↓LDL ↓

Ezetimibe*Ezetimibe* 1-3% 1-3% LDL ↓LDL ↓

Pioglitazone*Pioglitazone* 5-20% 5-20% Glucose ↓Glucose ↓

Estrogens*Estrogens* 10-25% 10-25% Hot flashesHot flashes

-blockers*-blockers* 10-20% 10-20% BPHBPH

Alcohol*Alcohol* 5-15% 5-15% Social, etc.Social, etc.

*Lacking FDA-approved indication for HDL-raising.Belalcazar LM, Ballantyne CM. Prog Cardiovasc Dis. 1998;41:151-174.Insull W et al. Mayo Clin Proc. 2001;76:971-982.McKenney JM et al. Pharmacother. 2007;27:715-728.

Risk Reduction for CHD EventsRisk Reduction for CHD EventsAs a Function of Changes in TC, LDL-C, and As a Function of Changes in TC, LDL-C, and

HDL-CHDL-C

*4S, CARE, LIPID, WOSCOPS**HELSINKI, VA-HIT,AFCAPS/TexCAPS

PERCENT CHD EVENTCHANGE RATE

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)

CH

D D

eath

or

Nonfa

tal M

I (%

)

Placebo

5.9

Fenofibrate

9

6

3

0

5.2

P=0.16

11% RRR

9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 years

A fibrate does not provide significant additional benefit* in diabetics

Source: Keech A et al. Lancet 2005;366:1849-61

*Unadjusted for concomitant statin use

CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction

Fibrate Evidence:Fibrate Evidence:Primary PreventionPrimary Prevention

ACCORD Lipid Study Results ACCORD Lipid Study Results (NEJM 2010; 362: 1563-74)(NEJM 2010; 362: 1563-74)

5518 patients with type 2 DM treated with open 5518 patients with type 2 DM treated with open label simvastatin randomly assigned to label simvastatin randomly assigned to fenofibrate or placebo and followed for 4.7 years.fenofibrate or placebo and followed for 4.7 years.

Annual rate of primary outcome of nonfatal MI, Annual rate of primary outcome of nonfatal MI, stroke or CVD death 2.2% in fenofibrate group stroke or CVD death 2.2% in fenofibrate group vs. 1.6% in placebo group (HR=0.91, p=0.33).vs. 1.6% in placebo group (HR=0.91, p=0.33).

Pre-specified subgroup analyses showed Pre-specified subgroup analyses showed possible benefit in men vs. women and those possible benefit in men vs. women and those with high triglycerides and low HDL-C.with high triglycerides and low HDL-C.

Results support statin therapy alone to reduce Results support statin therapy alone to reduce CVD risk in high risk type 2 DM patients.CVD risk in high risk type 2 DM patients.

Fibrate Evidence:Fibrate Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention

Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial5,518 diabetic patients on statin therapy randomized to fenofibrate (160 mg) or placebo for 4.7 years

On a background of statin therapy, a fibrate does not reduce CV events in diabetics

CV

death

, nonfa

tal st

roke

or

nonfa

tal M

I (%

/year)

Placebo

2.4

Fenofibrate

3

2

1

0

2.2

P=0.32

8% RRR

Source: ACCORD study group. NEJM 2010;Epub ahead of print

CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction

Is Niacin Useful in Low HDL-C?Is Niacin Useful in Low HDL-C?

HATS: Percent Change in StenosisHATS: Percent Change in Stenosis

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Ch

ang

e (%

)

*P = 0.16 for comparison with placebo; †P < 0.001; ‡P = 0.004.HATS = HDL-Atherosclerosis Treatment Study.

Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.

Placebo Antioxidant Simvastatin/ Simvastatin /Vitamins* Niacin† Niacin/

Antioxidants‡

Simvastatin-niacin97%

All placebos

76%RR = 0.10P = 0.03

0 1 2 30

70

80

90

100

HATS = HDL-Atherosclerosis Treatment Study.Adapted from Brown BG et al. N Engl J Med. 2001;345:1583-1592.

HATS: Patients Free of EventsHATS: Patients Free of Events

Pa

tie

nts

Fre

e o

f E

ven

ts (

%)

Years

StudyTreatme

ntn/N

Controln/N

Peto OR95% Cl

Peto OR 95% Cl

ARBITER-6-HALTS 2/187 9/176 0.25 (0.08,

0.84)

Guyton JR et al 1/676 1/272 0.35 (0.02, 7.56)

AFREGS 0/71 1/72 0.14 (0.00, 6.92)

ARBITER-2 2/87 2/80 0.92 (0.13, 6.65)

HATS 1/38 5/38 0.24 (0.05, 1.26)

UCSF_SCOR 0/48 1/49 0.14 (0.00, 6.96)

STOCKHOLM 72/279 100/276 0.61 (0.43, 0.88)

CLAS 1/94 5/94 0.25 (0.05, 1.29)

CDP 287/1119 839/2789 0.81 (0.69, 0.94)

Total Test for heterogeneity: P = 0.24, I2 = 23.0% Test for overall effect: P <0.0001

0.75 (0.65, 0.86)

Subtotal excluding CDP 0.53 (0.38, 0.73)

0.1 0.2 0.5 1 2 5 10Log scale

Meta-Analysis: Effects of Nicotinic AcidMeta-Analysis: Effects of Nicotinic AcidPre-AIM-HIGH Trials: Major Coronary EventsPre-AIM-HIGH Trials: Major Coronary Events

Many of these trials were tests of drug combinations that included niacin.Bruckert E et al. Atherosclerosis. 2010;210:353-361.

AIM-HIGHAIM-HIGHDesign Design

Purpose: “Rigorous test of the HDL hypothesis…” Purpose: “Rigorous test of the HDL hypothesis…” ((notnot designed to be a test of niacin) designed to be a test of niacin)

Subjects: n=3414 men/women (85%/15%) w/ prior CVD event Subjects: n=3414 men/women (85%/15%) w/ prior CVD event and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 (100-and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 (100-400) [median (range)] 400) [median (range)]

Randomized TherapyRandomized Therapy Extended-release niacin (1500-2000 mg hs) vsExtended-release niacin (1500-2000 mg hs) vs

““Placebo” (immediate-release niacin 100-150 mg hs)Placebo” (immediate-release niacin 100-150 mg hs)

Open-label titration/addition (keep LDL-C in 40-80 mg/dL)Open-label titration/addition (keep LDL-C in 40-80 mg/dL) Simvastatin 5-80 mg/dSimvastatin 5-80 mg/d

Ezetimibe 10 mg/d + extended release niacin (1500-2000 mg)Ezetimibe 10 mg/d + extended release niacin (1500-2000 mg)

AIM-HIGH Investigators. N Engl J Med. 2001;365:2255-267.AIM-HIGH Investigators. Am Heart J. 2011;161:471-477.e2.

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGH — ResultsHDL-C at Baseline and Follow-up

1o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization

Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.

AIM-HIGH — ResultsPrimary Outcome

Fate of Niacin Beyond AIM-HIGH: HPS2-Fate of Niacin Beyond AIM-HIGH: HPS2-THRIVE : December 2012 UpdateTHRIVE : December 2012 Update

HPS2-THRIVE evaluated extended-release HPS2-THRIVE evaluated extended-release niacin/laropiprant plus statin therapy versus statin niacin/laropiprant plus statin therapy versus statin therapy alone in patients at high risk for therapy alone in patients at high risk for cardiovascular eventscardiovascular events

HPS2-THRIVE did not reach the primary endpoint HPS2-THRIVE did not reach the primary endpoint to reduce coronary deaths, non-fatal heart attacks, to reduce coronary deaths, non-fatal heart attacks, strokes, or revascularizationsstrokes, or revascularizations

This finding, supportive of AIM-HIGH, suggests This finding, supportive of AIM-HIGH, suggests that niacin may not provide additional benefit to that niacin may not provide additional benefit to reduce CVD risk when patients are well-treated with reduce CVD risk when patients are well-treated with statinsstatins

Emerging HDL-C TherapiesEmerging HDL-C Therapies

CETP AntagonismCETP Antagonism

Role of CETP in AtherosclerosisRole of CETP in Atherosclerosis

Human CETP deficiency is usually associated with marked ↑ in HDL-CHuman CETP deficiency is usually associated with marked ↑ in HDL-C CETP activity is inversely correlated with plasma HDL-CCETP activity is inversely correlated with plasma HDL-C Decreasing CETP activity has consistently inhibited atherosclerosis in Decreasing CETP activity has consistently inhibited atherosclerosis in

animal modelsanimal models

Barter PJ et al. Arterioscler Thromb Vasc Biol. 2003;23:160-167.Contacos C et al. Atherosclerosis. 1998;141:87-98. Guerin M et al. Arterioscler Thromb Vasc Biol. 2008;28:148-154.

LIVER PERIPHERAL TISSUE

CE

TG

Bile

Foamcells

RCT HDL

ABC-A1

VLDL LDL

PLASMA

LDL-R

ABC-G1

Free cholesterol

CETP

Athero-sclerosisLDL

CETP Inhibitors: 2 Down, 2 RemainCETP Inhibitors: 2 Down, 2 Remain

CETP

Evacetrapib

↑CVD (25%) but OK HDL

function(off-target eff.?)

*No ↓CVD,but OK HDL

function, +/- anti athero?

--------------------↑HDL-C----------------------~80% ~80% ~138% ~30%

Lipid Effects of CETP Lipid Effects of CETP Inhibitors/ModulatorsInhibitors/Modulators% Change from Baseline% Change from Baseline

CETP AgentDose

(mg/day)HDL-C

(%)LDL-C

(%)TG (%)

Torcetrapib 60 61 -24 -9

Anacetrapib 100 138 -40 -7

Evacetrapib 500 129 -36 -11

Dalcetrapib 600 31 -2 -3

Adapted from Cannon C et al. JAMA. 2011;306:2153-2155. Nicholls SJ et al. JAMA. 2011;306:2099-2109.

Is the toxicity of torcetrapib related to the mechanism or the molecule?

Atorvastatin only

Torcetrapib plus atorvastatin

0 90 180 270 360 450 540 630 720 810

Days After Randomization

Patie

nts

With

out E

vent

(%)

10098969492900

Barter PJ et al. N Engl J Med. 2007;357:2109-2122.

Torcetrapib: Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality Torcetrapib: Increased Cardiovascular and Non-cardiovascular Morbidity and Mortality

HR = 1.25P = 0.0001

Torcetrapib Caused Off-target Torcetrapib Caused Off-target HyperaldosteronismHyperaldosteronism

Torcetrapib arm of ILLUMINATE trial showed significant:Torcetrapib arm of ILLUMINATE trial showed significant:11

↑ ↑ Systolic BSystolic Blood Pressure:lood Pressure: Mean ↑Mean ↑5.4 mmHg5.4 mmHg >15 mmHg >15 mmHg ↑ ↑ SBP: 19.5% torcetrapib arm (vs 9.4% placebo SBP: 19.5% torcetrapib arm (vs 9.4% placebo

arm, arm, PP<0.001)<0.001) ↓ ↓ serum potassiumserum potassium ↑ ↑ serum bicarbonateserum bicarbonate ↑ ↑ serum sodiumserum sodium ↑ ↑ serum aldosteroneserum aldosterone

Inverse relationship of CVD and on-Rx-HDL-C Inverse relationship of CVD and on-Rx-HDL-C preservedpreserved Conclusion: ↑ CVD Conclusion: ↑ CVD in ILLUMINATE likely due to off-target actions of in ILLUMINATE likely due to off-target actions of

torcetrapib, not related to CETP inhibitiontorcetrapib, not related to CETP inhibition1,21,2

1. Barter PJ et al. N Engl J Med. 2007;357:2109-2122.2. Rosenson RS. Curr Athero Rep. 2008;10:227-229.

dal-OUTCOMES Results: Isolated ↑HDL-C

LDL

Chol

este

rol

(mg/

dL)

HDL

Chol

este

rol

(mg/

dL)

Schwartz GG et al. N Engl J Med. 2012 Nov 5. [Epub ahead of print].

No. at riskPlacebo 7907 7685 7498 7272 6959 6436 3650Dalcetrapib 7910 7663 7402 7196 6871 6333 3599

No. at riskPlacebo 7907 7679 7473 7265 6947 6427 3640Dalcetrapib 7910 7657 7382 7191 6863 6324 3591

Months

dal-OUTCOMES Results: No ↓CVD


Year

Cum

ulat

ive In

ciden

ce o

f Prim

ary

Out

com

e (%

of p

atie

nts)

No. at riskPlacebo 7933 7386 6551 1743Dalcetrapib 7938 7372 6495 1736

dal-OUTCOMES Results: HDL STILL Functional


Change in HDL Cholesterol (mg/dL) from Baseline to Month 1, According to Quintile

Annu

alize

d Ev

ent R

ate

(%)

Revisiting the HDL HypothesisRevisiting the HDL HypothesisWhere do we go Next?Where do we go Next?

Residual CVD risk exists despite intense statin Residual CVD risk exists despite intense statin monotherapymonotherapy

Low HDL-C predicts high CVD risk; high HDL-C is Low HDL-C predicts high CVD risk; high HDL-C is protective protective

Existing HDL raising therapies have inconsistent effectsExisting HDL raising therapies have inconsistent effects Clinical trials have not yet answered the following:Clinical trials have not yet answered the following:

Is HDL a Is HDL a causal factorcausal factor or a or a biomarkerbiomarker of risk? of risk? Does raising HDL-C reduce CVD risk?Does raising HDL-C reduce CVD risk?

Investigational drugs to raise HDL-C and reduce CVD Investigational drugs to raise HDL-C and reduce CVD riskrisk

Continued need for multifactorial approaches to reduce Continued need for multifactorial approaches to reduce CVD riskCVD risk

Current Investigational Approaches to Current Investigational Approaches to Reduce Residual CVD Risk via Enhanced Reduce Residual CVD Risk via Enhanced

HDL, etc.HDL, etc. Additional CETP inhibitors: anacetrapib, evacetrapibAdditional CETP inhibitors: anacetrapib, evacetrapib

Apolipoprotein A1 (Apo A1) Milano; Apo A1 agonistApolipoprotein A1 (Apo A1) Milano; Apo A1 agonist

Delipidated HDL; rHDLDelipidated HDL; rHDL

Selective LXRSelective LXRβ (β (liver X receptor) agonist liver X receptor) agonist

DMHCA; GW 3965DMHCA; GW 3965

PPAR (peroxisome proliferator-activated receptor PPAR (peroxisome proliferator-activated receptor αα//γγ agonistagonist

aleglitazar, muraglitazar, tesaglitazaraleglitazar, muraglitazar, tesaglitazar

DPP-4 (dipeptidyl peptidase-4) antagonistDPP-4 (dipeptidyl peptidase-4) antagonist

alogliptin, linagliptin, saxagliptin, sitagliptinalogliptin, linagliptin, saxagliptin, sitagliptin

MTP (microsomal transport protein) antagonistMTP (microsomal transport protein) antagonist

Lp-PLALp-PLA22 and vascular disease and vascular disease

LpPLA2 Studies Collaboration (2010) Lancet 375; 1536-1544

Effects of Lp-PLA2 inhibition by darapladib in diabetic, hypercholesterolemic pigs

Wilensky et al (2008) Nature Medicine (in press)

Novel anti-atherosclerotic agentsDarapladib in animal models and clinical trials

STABILITY Stabilization of Atherosclerotic Plaque by Initiation of Darapladib TherapyEstimated enrolment 15,500• Darapladib vs placebo in well treated patients with CHD plus other risk.• 1ary endpoint major coronary event

SOLID – TIMI52 Stabilization of plaques using darapladib.• Incidence of major coronary events in patients with ACS•Darapladib 160 mg vs placebo started within 30 days of index ACS event.

NCEP ATP III: Evaluation—NCEP ATP III: Evaluation—Major Risk Factors for CADMajor Risk Factors for CAD

Age (men Age (men 45 y; women 45 y; women 55 y)55 y)

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

Cigarette smokingCigarette smoking

Hypertension (BP Hypertension (BP 140/90 mm Hg or 140/90 mm Hg or antihypertensive medication)antihypertensive medication)

HDL-C <40 mg/dLHDL-C <40 mg/dL

Family history of premature CADFamily history of premature CAD <55 y in first-degree male relative<55 y in first-degree male relative <65 y in first-degree female relative<65 y in first-degree female relative

Revised ATP III (AHA/NHLBI) Metabolic Syndrome Revised ATP III (AHA/NHLBI) Metabolic Syndrome Definition 2005Definition 2005

*Diagnosis is established when 3 of these risk factors are present.†Abdominal obesity is more highly correlated with metabolic risk factors than is BMI. ‡Some men develop metabolic risk factors when circumference is only marginally increased.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497; Updated AHA/NHLBI Statement Oct 18, 2005: Grundy et al. Circulation 2005; 112 (epub).

<40 mg/dL<40 mg/dL<50 mg/dL <50 mg/dL or Rx for or Rx for ↓ HDL↓ HDL

MenMenWomenWomen

>>102 cm (102 cm (>>40 in)40 in)>>88 cm (88 cm (>>35 in)35 in)

MenMenWomenWomen

100 mg/dL 100 mg/dL or Rx for or Rx for ↑ glucose↑ glucoseFasting glucoseFasting glucose130/130/85 mm Hg 85 mm Hg or on HTN Rxor on HTN RxBlood pressureBlood pressure

HDL-CHDL-C150 mg/dL 150 mg/dL or Rx for or Rx for ↑ TG↑ TGTGTG

Abdominal obesityAbdominal obesity†† (Waist circumference(Waist circumference‡‡))

Defining LevelDefining LevelRisk FactorRisk Factor

NCEP ATP III: EvaluationNCEP ATP III: Evaluation——Need for Framingham CalculationNeed for Framingham Calculation


NoNo>20%>20%CAD or CAD risk CAD or CAD risk equivalentequivalent

YesYes0%-10%0%-10%2 RF2 RF

NoNo<10%<10%1 RF1 RF

Need for Need for Framingham Framingham CalculationCalculation

10-Year Risk 10-Year Risk for CADfor CADRisk ProfileRisk Profile

YesYes10%-20%10%-20%

NCEP ATP III: Evaluation—NCEP ATP III: Evaluation—CAD Risk EquivalentsCAD Risk Equivalents

DiabetesDiabetes


Atherosclerotic diseaseAtherosclerotic disease Peripheral artery diseasePeripheral artery disease Abdominal aortic aneurysmAbdominal aortic aneurysm Symptomatic carotid artery diseaseSymptomatic carotid artery disease

CAD 10-year risk >20%CAD 10-year risk >20%

Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.

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

Assessing CHD Risk in MenAssessing CHD Risk in MenStep 1: Age

YearsPoints

20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 13

Step 2: Total CholesterolTC Points at Points at Points at Points at

Points at(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69

Age 70-79 <160 0 0 0 0

0160-199 4 3 2 1

0200-239 7 5 3 1

0240-279 9 6 4 2

1280 11 8 5 3

1

HDL-C(mg/dL) Points

60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-Cholesterol

Systolic BP PointsPoints

(mm Hg) if Untreated if Treated

<120 0 0120-129 0 1130-139 1 2140-159 1 2160 2 3

Step 4: Systolic Blood Pressure

Step 5: Smoking Status

Points at Points at Points at Points atPoints at

Age 20-39 Age 40-49 Age 50-59 Age 60-69Age 70-79

Nonsmoker 0 0 0 00

Smoker 8 5 3 11

Age

Total cholesterol

HDL-cholesterol

Systolic blood pressure

Smoking status

Point total

Step 6: Adding Up the Points

Point Total 10-Year Risk Point Total 10-Year Risk

<0 <1% 118%

0 1% 1210%

1 1% 1312%

2 1% 1416%

3 1% 1520%

4 1% 1625%

5 2% 1730%

6 2%7 3%8 4%9 5%

10 6%

Step 7: CHD Risk

ATP III Framingham Risk Scoring

© 2001, Professional Postgraduate Services®

www.lipidhealth.org

Point Total 10-Year Risk Point Total 10-Year Risk

<9 <1% 2011%

9 1% 2114%

10 1% 2217%

11 1% 2322%

12 1% 2427%

13 2% 25 30%

14 2%15 3%16 4%17 5%18 6%19 8%

Assessing CHD Risk in WomenAssessing CHD Risk in Women

Note: Risk estimates were derived from the experience of the Framingham Heart Study, a predominantly Caucasian population in Massachusetts, USA.

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

Step 1: Age

YearsPoints

20-34 -735-39 -340-44 045-49 350-54 655-59 860-64 1065-69 1270-74 1475-79 16

TC Points at Points at Points at Points atPoints at(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69

Age 70-79 <160 0 0 0 0

0160-199 4 3 2 1

1200-239 8 6 4 2

1240-279 11 8 5 3

2280 13 10 7 4

2

HDL-C(mg/dL) Points

60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-Cholesterol

Systolic BP PointsPoints

(mm Hg) if Untreated if Treated

<120 0 0120-129 1 3130-139 2 4140-159 3 5160 4 6

Step 4: Systolic Blood Pressure

Step 5: Smoking Status

Points at Points at Points at Points atPoints at

Age 20-39 Age 40-49 Age 50-59 Age 60-69Age 70-79

Nonsmoker 0 0 0 00

Smoker 9 7 4 21

Age

Total cholesterol

HDL-cholesterol

Systolic blood pressure

Smoking status

Point total

Step 6: Adding Up the Points

Step 7: CHD Risk

Step 2: Total Cholesterol

ATP III Framingham Risk Scoring

© 2001, Professional Postgraduate Services®

www.lipidhealth.org

hs-CRP Adds to Predictive Value of TC:HDL Ratio in hs-CRP Adds to Predictive Value of TC:HDL Ratio in Determining Risk of First MIDetermining Risk of First MI

0.0

1.0

2.0

3.0

4.0

5.0

High Medium Low Low

Medium

High

Total Cholesterol:HDL RatioTotal Cholesterol:HDL Ratio

Ridker et al, Circulation. 1998;97:2007–2011.

hs-CRP

hs-CRP

Rel

ativ

e R

isk

Rel

ativ

e R

isk

JUPITERWhy Consider Statins for Low LDL, high hsCRP Patients?

However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.

Ridker et al, New Engl J Med 2001;344:1959-65

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

[A]

[B]

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

AFCAPS/TexCAPS Low LDL Subgroups

RR

Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke

UnstableUnstable AnginaAngina

CVD DeathCVD DeathCABG/PTCACABG/PTCA

JUPITERJUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of Multi-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular EventsRosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRPAmong Individuals With Low LDL and Elevated hsCRP

4-week 4-week run-inrun-in

Ridker et al, Circulation 2003;108:2292-2297.

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060

LDL <130 mg/dL hsCRP >2 mg/L

JUPITERTrial Design

Placebo (N=8901)Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

Number Needed to Treat (NNT5) = 25

- 44 %

0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lati

ve In

cid

ence

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Ridker et al NEJM 2008

JUPITER population – high CRP (>2mg/l), low LDLDual Target Analysis: LDL-C <70 mg/dL, hsCRP <2 mg/L

LDL >70 mg/dLand / or

hsCRP >2 mg/LHR 0.64 (0.49-0.84)

LDL <70 mg/dL and hsCRP <2 mg/LHR 0.35 (0.23-0.54)

placebo HR 1.0 (referent)

P <0.0001

0 1 2 3 40.00

0.02

0.04

0.06

0.08

Cu

mu

lati

ve I

nci

den

ce

Number at RiskFollow-up (years)

rosuvastatinplacebo

7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 1457,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168

Ridker PM et al. Lancet 2009;373:1175–1182

1 RF

2 RFs

equivalent

CAD or CAD risk


Risk Category

<160

<130

<100

<130

LDL-C Goal

(mg/dL)

160

130

100

130

LDL-C Level to Initiate

TLC (mg/dL)

LDL-C Level to Initiate

Drug Therapy(mg/dL)

190

160

130

130

(10-year risk0%-10%)

(10-year risk10%-20%)

NCEP ATP III Guidelines: TreatmentNCEP ATP III Guidelines: Treatment

Statins in ACS - GuidelinesStatins in ACS - Guidelines

• Who - Initiate therapy regardless of baseline LDL.

• When – Pre-discharge; but no difference in benefit

when initiated immediately or days post event (ESC

<4 days).

• What – Evidence base is for high dose statin (but

not 80mg simvastatin).

• Goal - <70 mg/dl (2.0 mmol/l) LDL cholesterol.

ACC/ AHA 2007 in JACC (2008) 51; 210-47ESC 2007 in Eur Heart J (2007) 28; 1598-1660

Lipid Management Goal: Persons Lipid Management Goal: Persons with Pre-existing CHDwith Pre-existing CHD

LDL-C should be less than 100 mg/dL

Further reduction to LDL-C to < 70 mg/dL is reasonable

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

*Non-HDL-C = total cholesterol minus HDL-C


If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*

1 RF <190

2 RFs(CAD risk 20%) <160

CAD or CAD risk equivalent <130

(CAD risk >20%)

NCEP ATP III: Setting Goals—NCEP ATP III: Setting Goals—SecondarySecondary––Non-HDL-CNon-HDL-C


Risk Category Non–HDL-C Goal (mg/dL)

(Patients With TG (Patients With TG 200)200)

Level Level (mg/dl)(mg/dl)

ClassificationClassification

<200<200 DesirableDesirable

200-239200-239 Borderline HighBorderline High

>>240240 HighHigh



>40>40 Minimum goal*Minimum goal*

40-5040-50 Desired goal*Desired goal*

>50>50 HighHigh



<150<150 NormalNormal

150-199150-199 Borderline HighBorderline High

200-499200-499 HighHigh

>>500500 Very HighVery High

Total Cholesterol HDL-Cholesterol

Triglyceride

Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97

ATP III Classification of Other Lipoprotein ATP III Classification of Other Lipoprotein LevelsLevels

*These goals apply to men. For women, the minimum goal is >50 mg/dL

HDL=High density lipoprotein

NCEP ATP III Guidelines: TreatmentNCEP ATP III Guidelines: Treatment

TherapeuticLifestyle Change (TLC)

Improve diet

Weight reduction

Physical activity


PharmacologicTreatment

Statins (HMG-CoA reductase inhibitors)

Fibrates

Niacin

Bile acid sequestrants

Lipid Management Lipid Management RecommendationsRecommendations

Start dietary therapy (<7% of total calories as saturated fat and <200 mg/d cholesterol)

Adding plant stanol/sterols (2 gm/day) and viscous fiber (>10 mg/day) will further lower LDL

Promote daily physical activity and weight management.

Encourage increased consumption of omega-3 fatty acids in fish or 1 g/day omega-3 fatty acids in capsule form for risk reduction.




For all patients

Therapeutic Lifestyle ChangesTherapeutic Lifestyle ChangesNutrient Composition of TLC DietNutrient Composition of TLC Diet

NutrientNutrient Recommended IntakeRecommended Intake

Saturated fatSaturated fat Less than 7% of total calories Less than 7% of total calories

Polyunsaturated fatPolyunsaturated fat Up to 10% of total caloriesUp to 10% of total calories

Monounsaturated fat Monounsaturated fat Up to 20% of total calories Up to 20% of total calories

Total fatTotal fat 25–35% of total calories25–35% of total calories

CarbohydrateCarbohydrate 50–60% of total calories50–60% of total calories

FiberFiber 20–30 grams per day20–30 grams per day

ProteinProtein Approximately 15% of total calories Approximately 15% of total calories

CholesterolCholesterol Less than 200 mg/dayLess than 200 mg/day

Total calories (energy)Total calories (energy) Balance energy intake and expenditure Balance energy intake and expenditure to maintain desirable body weightto maintain desirable body weight

Possible Benefits From Other TherapiesPossible Benefits From Other Therapies

Therapy Result

• Soluble fiber in diet (2–8 g/d) (oat bran, fruit, and vegetables)

• Soy protein (20–30 g/d)

• Stanol esters (1.5–4 g/d) (inhibit cholesterol absorption)

• Fish oils (3–9 g/d) (n-3 fatty acids)

LDL-C 1% to 10%

LDL-C 5% to 7%

LDL-C 10% to 15%

Triglycerides 25% to 35%

Jones PJ. Curr Atheroscler Rep. 1999;1:230-235.Lichtenstein AH. Curr Atheroscler Rep. 1999;1:210-214.Rambjor GS et al. Lipids. 1996;31:S45-S49.Ripsin CM et al. JAMA. 1992;267:3317-3325.

Dietary AdjunctsDietary Adjuncts

TLC for patients with LDL-C = 160TLC for patients with LDL-C = 160

Walden CE et al. Arterioscler Thromb Vasc Biol 1997;17:375-382.Jenkins DJ et al. Curr Opin Lipidol 2000;11:49-56.Cato N. Stanol meta-analysis. Personal communication, 2000.

Dietary ComponentDietary Component LDL-C LDL-C (mg/dL) (mg/dL)

Low saturated fat/dietary cholesterolLow saturated fat/dietary cholesterol ––1212

Viscous fiber (10–25 g/d)Viscous fiber (10–25 g/d) – –88

Plant stanols/sterols (2 g/d)Plant stanols/sterols (2 g/d) ––1616

TotalTotal – –36 mg/dl36 mg/dl

Moderate physical activity at least 30-60 minutes 5 days a week or longer will help to raise HDL-C, lower total and LDL-C, lower TG, lower glucose, insulin, and blood pressure levels.

Questran® Prescribing Information, Colestid ® Prescribing Information, WelChol ® Prescribing information, Niaspan ® Prescribing Information, Lopid ® Prescribing Information, TriCor ® Prescribing Information, Lipitor ® Prescribing Information, Zocor ® Prescribing Information, Mevaco ® r Prescribing Information, Lescol ® Prescribing Information, Pravacol ® Prescribing Information; Zetia ® Prescribing Information.

Effect of Lipid-modifying Therapies

TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin.

TherapyTherapy TCTC LDLLDL HDLHDL TGTG Patient Patient tolerabilitytolerability

Bile acid Bile acid sequestrantssequestrants

7-10%7-10% 10-18%10-18% 3%3% Neutral or Neutral or PoorPoor

Nicotinic acidNicotinic acid 10-20%10-20% 10-20%10-20% 14-35%14-35% 30-70%30-70% Poor to Poor to reasonablereasonable

Fibrates Fibrates (gemfibrozil)(gemfibrozil)

19%19% 4-21%4-21% 11-13%11-13% 30%30% GoodGood

Statins*Statins* 19-37%19-37% 25-50%25-50% 4-12%4-12% 14-29%14-29% GoodGood

EzetimibeEzetimibe 13%13% 18%18% 1%1% 9%9% GoodGood

When LDL-lowering drug therapy When LDL-lowering drug therapy

is employed in high-risk or is employed in high-risk or

moderately high risk patients, moderately high risk patients,

intensity of therapy should be intensity of therapy should be

sufficient to achieve a 30–40% sufficient to achieve a 30–40%

reduction in LDL-C levels.reduction in LDL-C levels.

Effect of Statin Therapy on LDL-C Effect of Statin Therapy on LDL-C Levels: “The Rule of 6”Levels: “The Rule of 6”

Illingworth DR. Med Clin North Am. 2000;84:23-42.

37

19

35

27

28

18

12

12

6

12

0 10 20 30 40 50 60

Atorvastatin 10/80

Fluvastatin 20/80

Simvastatin 20/80

Pravastatin 20/40

Lovastatin 20/80

Reduction of LDL Cholesterol (%)

Starting dose LDL-C

Highestrecommended dose

AtorvastatinAtorvastatin

PravastatinPravastatin

RosuvastatinRosuvastatin

SimvastatinSimvastatin

10 mg10 mg 20 mg20 mg 40 mg40 mg 80 mg80 mg

DoseDose

*P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg**P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg† P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg1.Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. 2.Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.

*P<.002 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg**P<.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg† P<.002 vs atorvastatin 40 mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg1.Jones PH, Davidson MH, Stein EA, et al. Am. J. Cardiology 2003; 93: 152-160. 2.Data on file, DA-CRS-02 AstraZeneca Pharmaceuticals LP, Wilmington, DE.

*

**†

–60–60

–50–50

–40–40

–30–30

–20–20

–10–10

00

Mean

Perc

en

t C

han

ge F

rom

B

ase

line in

LD

L-C

(

SE

)M

ean

Perc

en

t C

han

ge F

rom

B

ase

line in

LD

L-C

(

SE

)Percentage Change From Baseline in Percentage Change From Baseline in

LDL-C at Week 6 by Dose (ITT)LDL-C at Week 6 by Dose (ITT)1,21,2

Grundy et al. Circulation. 2004;110:227-239.

Doses of Statins Required to Attain 30-40% Reduction of LDL-C

Dose, mg/dDose, mg/d LDL Reduction, LDL Reduction, %%

AtorvastatinAtorvastatin 1010 3939

Lovastatin Lovastatin 4040 3131

Pravastatin Pravastatin 4040 3434

Simvastatin Simvastatin 20-4020-40 35-4135-41

Fluvastatin Fluvastatin 40-8040-80 25-3525-35

Rosuvastatin 5-10 39-45

Source: Kashani A et al. Circulation 2006;114:2788-97

• 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm)

• Dose-dependent phenomenon that is usually reversible

• 15.4% incidence of myalgias* (18.7% incidence in control arm)

• 0.9% incidence of myositis (0.4% incidence in control arm)

• 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm)

74,102 subjects in 35 randomized clinical trials with statins

*The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively.

HMG-CoA Reductase Inhibitor:HMG-CoA Reductase Inhibitor:Adverse EffectsAdverse Effects

Hepatocyte

Skeletal myocyte

Why combination therapy?Why combination therapy?

Few patients achieve LDL-C goal on Few patients achieve LDL-C goal on monotherapymonotherapy

Uptitration of dosage is rareUptitration of dosage is rare

LDL-C goals are getting more aggressiveLDL-C goals are getting more aggressive

High-dose statins increase risk of side effectsHigh-dose statins increase risk of side effects

Can address mixed dyslipidemia (e.g., few pts Can address mixed dyslipidemia (e.g., few pts achieve adequate control of HDL-C and achieve adequate control of HDL-C and triglycerides on monotherapy)triglycerides on monotherapy)

Options for Patients who Fail to Reach Options for Patients who Fail to Reach LDL-C Goal on Statin MonotherapyLDL-C Goal on Statin Monotherapy

• Niacin• Bile acid sequestrant• Cholesterol absorption inhibitor

Addition of:Addition of:

Pharmacologic Therapy: NiacinPharmacologic Therapy: Niacin

Reduces HDL catabolism and VLDL productionReduces HDL catabolism and VLDL production

Primarily used to treat low HDL-C (15%-35%Primarily used to treat low HDL-C (15%-35%) ) and elevated TG (20%-50% and elevated TG (20%-50% ))

LDL-C LDL-C 5%-25% 5%-25%

Side effectsSide effects Hepatotoxicity, hyperglycemia, hyperuricemia,Hepatotoxicity, hyperglycemia, hyperuricemia,

upper GI distress, flushing, itchingupper GI distress, flushing, itching

Contraindicated in patients with liver disease,Contraindicated in patients with liver disease,gout, peptic ulcergout, peptic ulcer


Mean c

hang

e f

rom

Base

line

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

500

HDL-C

LDL-C

TG

–9%

–14%

–22% –21%–17%

30%30%26%

22%15%

10%

–28%

–35%

–44%–39%

–11%

–5%

1000 1500 2000 2500Dose (mg) 3000

Nicotinic Acid Evidence:Nicotinic Acid Evidence:Effect on Lipid ParametersEffect on Lipid Parameters

-50

-40

-30

-20

-10

0

10

20

30

HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride

Bile Acid SequestrantsBile Acid Sequestrants

Major actionsMajor actions Reduce LDL-C 15%-30%Reduce LDL-C 15%-30% Raise HDL-C 3%Raise HDL-C 3%-5%-5% May increase TGMay increase TG

Side effectsSide effects GI distress/constipationGI distress/constipation Decreased absorption of other drugs (1st generation)Decreased absorption of other drugs (1st generation)

ContraindicationsContraindications DysbetalipoproteinemiaDysbetalipoproteinemia Elevated TG (especially >400 mg/dL)Elevated TG (especially >400 mg/dL)

New Bile Acid SequestrantNew Bile Acid Sequestrant: : ColesevelamColesevelam

Lower dose for effectLower dose for effect

Fewer GI complaints than with other bileFewer GI complaints than with other bileacid sequestrantsacid sequestrants

Reduces absorption of Reduces absorption of -carotene-carotene

Requires 4-6 tablets/dayRequires 4-6 tablets/day

Davidson et al. Expert Opin Investig Drugs. 2000;9:2663.

Insull et al. Mayo Clin Proc. 2001;76:971.

*P<0.001 vs placebo.†P=0.04 vs placebo.

5

-1

0

10

3

-15

-20

-15

-10

-5

0

5

10

15

% C

han

ge

fro

m b

asel

ine

at w

k 24

TGHDL-CLDL-C

*

†

Placebo (n=88)

Colesevelam 3.8 g/d (n=95)

Colesevelam Monotherapy: EfficacyColesevelam Monotherapy: Efficacy

Pharmacologic Therapy: FibratesPharmacologic Therapy: Fibrates

Inhibit hepatic TG production and increase HDL productionInhibit hepatic TG production and increase HDL production

Used to treat elevated TG (20%-50% Used to treat elevated TG (20%-50% ) ) and low HDL-C (10%-20% and low HDL-C (10%-20% ))

Variable effect on LDL-CVariable effect on LDL-C

Side effectsSide effects Dyspepsia, gallstones, myopathyDyspepsia, gallstones, myopathy Increased with statinsIncreased with statins

Contraindicated in patients with severe renal or hepatic Contraindicated in patients with severe renal or hepatic diseasedisease


Limitations of Current Limitations of Current Intestinal-Acting AgentsIntestinal-Acting Agents

Bile acid sequestrantsBile acid sequestrants NoncomplianceNoncompliance GI tolerabilityGI tolerability Reduced absorption of lipid-soluble vitaminsReduced absorption of lipid-soluble vitamins May increase TG in patients with hypertriglyceridemiaMay increase TG in patients with hypertriglyceridemia

Plant stanol and sterol estersPlant stanol and sterol esters Lack of selectivityLack of selectivity Some patients may find difficult to incorporate into Some patients may find difficult to incorporate into

dietdiet May reduce absorption of lipid-soluble vitaminsMay reduce absorption of lipid-soluble vitamins

Ezetimibe — Ezetimibe — Localizes at Brush Border of Small IntestineLocalizes at Brush Border of Small Intestine

Ezetimibe, a selective cholesterol absorption Ezetimibe, a selective cholesterol absorption inhibitor, localizes and appears to act at the inhibitor, localizes and appears to act at the brush border of the small intestine and inhibits brush border of the small intestine and inhibits cholesterol absorptioncholesterol absorption

This results inThis results in A decrease in the delivery of intestinal cholesterol to A decrease in the delivery of intestinal cholesterol to

the liverthe liver A reduction of hepatic cholesterol stores and an A reduction of hepatic cholesterol stores and an

increase in clearance of cholesterol from the bloodincrease in clearance of cholesterol from the blood

Ezetimibe and StatinsEzetimibe and StatinsComplementary MechanismsComplementary Mechanisms

Ezetimibe reduces the delivery of cholesterol to the liverEzetimibe reduces the delivery of cholesterol to the liver

Statins reduce cholesterol synthesis in the liverStatins reduce cholesterol synthesis in the liver

The distinct mechanism of ezetimibe is complementary to The distinct mechanism of ezetimibe is complementary to that of statinsthat of statins

The effects of ezetimibe, either alone or in addition to a The effects of ezetimibe, either alone or in addition to a statin, on cardiovascular morbidity or mortality have not statin, on cardiovascular morbidity or mortality have not been establishedbeen established

Knopp RH. N Engl J Med. 1999;341:498–511.

Mea

n P

erce

nt

Ch

ang

e in

L

DL

-C F

rom

Bas

elin

e

Placebo(n = 11)

-30

-20

-10

0

SIMVA 10 mg(n = 12)

SIMVA 10+EZE 10 mg

(n = 11)

-34.9*

-51.9*†

-3.2

-40

-50

-60

Coadministration:Simvastatin + Ezetimibe

*P < 0.01 vs placebo

†P < 0.01 vs simvastatin 10 mg

Stein, E. Eur Heart J. 2001;3(suppl E):E14.

17%

% R

ed

uct

ion

Triglyceride

*P<0.05

-10 -20 -30 -40 -50

0

-46*

-21*

Total Cholesterol

Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731

27 patients with hypertriglyceridemia and low HDL-C treated with -3 fatty acid (4 grams/day) for 7 months

-3 Fatty Acids Evidence:-3 Fatty Acids Evidence:Effect on Lipid ParametersEffect on Lipid Parameters

HDL-C=High-density lipoprotein cholesterol

Source: Yokoyama M et al. Lancet. 2007;369:1090-8

Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS)

*Composite of cardiac death, myocardial infarction, angina, PCI, or CABG

Years

-3 Fatty Acids Evidence:-3 Fatty Acids Evidence:Primary and Secondary PreventionPrimary and Secondary Prevention

18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years

-3 fatty acids provide CV benefit, particularly in secondary prevention CV=Cardiovascular, EPA=Eicosapentaenoic acid

-3 Fatty Acids -3 Fatty Acids Evidence:Evidence:Secondary Secondary PreventionPrevention

**p<0.05

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

-3 Fatty Acids

Placebo

Source: Burr ML et al. Lancet 1989;2:757-761

Diet and Reinfarction Trial (DART)

All

cause

mort

alit

y

(%)

*Corresponds to 2.5 grams of EPA (PUFA)

EPA=Eicosapentaenoic acid, MI=Myocardial infarction

2,033 men with a history of a MI randomized to a diet of reduced fat with an increased ratio of polyunsaturated to saturated fat,

increased fatty fish intake*, or increased fiber intake for 2 years

-3 fatty acids reduce all cause mortality** after a MI

11,324 patients with a history of a MI randomized to -3 polyunsaturated fatty acids [PUFA] (1 gram), vitamin E (300 mg),

both or none for 3.5 years

-3 fatty acids provide significant CV benefit after a MI

Source: GISSI Investigators. Lancet 1999;354:447-455

-3 Fatty Acids -3 Fatty Acids Evidence:Evidence:Secondary Secondary PreventionPreventionGruppo Italiano per lo Studio della Sopravvivenza

nell’Infarto miocardico (GISSI-Prevenzione)

CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal, PUFA=Polyunsaturated fatty acids

Perc

ent

of

pati

ents P=0.04

8P=0.053 P=0.023 P=0.00

8

stroke stroke

02468

10121416

Death,NF MI,

NF stroke(2 way)

CVdeath,NF MI,and NF

Death,NF MI,

NF stroke(4 way)

CVdeath,NF MI,and NF

-3 PUFAPlacebo

3,827 patients 3-14 days following a MI randomized to -3 fatty acids (460 mg EPA + 380 mg DHA) or placebo for 1 year

-3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies

OMEGA Trial

Source: Senges J et al. Presented at the Annual Scientific Sessions of the American College of Cardiology, March 2009, Orlando, FL

Placebo

8.8

Fatty acids

12

8

4

0

10.4

P=0.10

Rate

of

rein

farc

tion,

stro

ke, or

death

* (%

)

DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid, MI=Myocardial infarction

*This is a secondary endpoint

-3 Fatty Acids Evidence:-3 Fatty Acids Evidence:Secondary PreventionSecondary Prevention

CONCLUSIONSCONCLUSIONS

Many persons with normal total or LDL-C levels still Many persons with normal total or LDL-C levels still suffer CHD events.suffer CHD events.

While statin-based clinical trials significantly reduce risk While statin-based clinical trials significantly reduce risk of CHD, residual risk still exists.of CHD, residual risk still exists.

Non-HDL-C, which reflects all the atherogenic lipid Non-HDL-C, which reflects all the atherogenic lipid fractions, appears to be a stronger predictor of CHD fractions, appears to be a stronger predictor of CHD events than LDL-C.events than LDL-C.

The measurement of non-HDL-C and its use as a The measurement of non-HDL-C and its use as a secondary therapeutic target is warranted to better secondary therapeutic target is warranted to better address residual CHD risk. address residual CHD risk.

Lifestyle therapies as well as pharmacologic approaches, Lifestyle therapies as well as pharmacologic approaches, particular combination therapy with statins and other particular combination therapy with statins and other agents, are important for optimizing the entire lipid agents, are important for optimizing the entire lipid profile.profile.

New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and...

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Transcript of New Concepts in the Evaluation and Treatment of Dyslipidemia Nathan D. Wong, PhD, FACC Professor and...