New Concepts in the Evaluation and Treatment of Dyslipidemia

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 Heart Disease Prevention ProgramProgram

Division of CardiologyDivision of Cardiology

University of California, IrvineUniversity of California, Irvine

Learning ObjectivesLearning Objectives

Discuss the role of cholesterol, lipoproteins, and the Discuss the role of cholesterol, lipoproteins, and the metabolic syndrome in coronary heart diseasemetabolic syndrome in coronary heart disease

Examine the results of important cholesterol lowering Examine the results of important cholesterol lowering clinical trials and understand their relevance in clinical clinical trials and understand their relevance in clinical practicepractice

Review current NCEP goals for lipid managementReview current NCEP goals for lipid management

Evaluate the efficacy and safety profiles of various Evaluate the efficacy and safety profiles of various cholesterol lowering strategies including diet and lifestyle cholesterol lowering strategies including diet and lifestyle regimens and pharmacologic agentsregimens and pharmacologic agents

Most Myocardial Infarctions Are CausedMost Myocardial Infarctions Are Causedby Low-Grade Stenosesby Low-Grade Stenoses

Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992.Pooled data from 4 studies: Ambrose et al, 1988; Little et al, 1988; Nobuyoshi et al, 1991; and Giroud et al, 1992.(Adapted from Falk et al.)(Adapted from Falk et al.)

Falk E et al, Circulation, 1995.

LipoproteinsLipoproteins

Water-soluble way to transport hydrophobic lipidsWater-soluble way to transport hydrophobic lipids

• Envelope of phospholipids and free cholesterol

• Triglyceride and cholesteryl ester-rich core

• Vary in size and density

From: Braunwald et al, Heart Disease: A Textbook of Cardiovascular Medicine 6th ed., 2001

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

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

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

Compliance with Lipid Treatment GuidelinesCompliance with Lipid Treatment Guidelines

About half U.S. population has LDL-CAbout half U.S. population has LDL-C >130 >130 mg/dLmg/dL

Less than half those eligible undertake Less than half those eligible undertake treatmenttreatment

Only a third of those treated achieve their LDL-Only a third of those treated achieve their LDL-C goalsC goals

40%40% of patients surveyed who saw a physician of patients surveyed who saw a physician in preceding 2 years were unaware of their in preceding 2 years were unaware of their lipid statuslipid status

Only 20-25% of CVD patients in the U.S. are Only 20-25% of CVD patients in the U.S. are reported to be on treatment for dyslipidemiareported to be on treatment for dyslipidemia

AHA Heart Disease and Stroke Statistics: 2004 UpdateAHA Heart Disease and Stroke Statistics: 2004 Update

NHANES II Behavioral Risk Factor SurveyNHANES II Behavioral Risk Factor Survey

_______________________________________________________________

______________________________________________________________

__________________________________________________________________

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

0

2

4

6

8

10

12

Inci

den

ce (

%)

>4940-49<40<133 133-163 >163 <105 105-166 >166

HDL-CLDL-C TG

Assmann et al. Eur Heart J. 1998;19(suppl A):A2.

mg/dL

Lipid Parameters and Risk of Lipid Parameters and Risk of CAD Over 8 Years (PROCAM) CAD Over 8 Years (PROCAM)

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

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

LDL Particle Size Subclass: LDL Particle Size Subclass:

Fasting triglycerides of 175 mg/dl or greater or TG/HDL Fasting triglycerides of 175 mg/dl or greater or TG/HDL ratio >3 is a good surrogate of small, dense LDL ratio >3 is a good surrogate of small, dense LDL

particle sideparticle side

IDLIDL L3L3 L2L2 L1L1

large, large, buoyantbuoyant

small, densesmall, dense

AA BBABAB

Accumulation of Other Risk Factors Accumulation of Other Risk Factors Compound Effects of Dyslipidemia on Risk Compound Effects of Dyslipidemia on Risk

of CHDof CHD

0

5

10

15

20

25

30

35

40

185 210 235 260 285 310 335

Low HDL

Smoking

Hyperglycemia

Hypertension

No Other Risk Factors

Schaefer EJ, adapted from the Framingham Heart Study

CH

D R

isk

Per

100

0 (i

n 6

yea

rs)

Serum Cholesterol (mg/dL)

Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q.

Primary and Secondary Prevention Trials With Statins

2° prevention placebo

2° prevention statin

1° prevention placebo

1° prevention statin

0

5

10

15

20

25

30

80 90 100 110 120 130 140 150 160 170 180 190 200

LDL-C Achieved (mg/dL)

AFCAPS

AFCAPS

WOSCOPS

WOSCOPS

CARECARE

LIPID LIPID

4S

4S

Eve

nt

Rat

e (%

)

HPSHPS

Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of Cholesterol Treatment Trialists’ (CCT) Collaboration: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis fo data from cholesterol-lowering treatment: prospective meta-analysis fo data from

90,056 participants in 14 randomized trials of statins 90,056 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 reduction—Over 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 coronary Statin therapy can safely reduce 5-year incidence of major coronary events, revascularization, and stroke by about 20% per mmol/L events, revascularization, and stroke by about 20% per mmol/L (about 38 mg/dl) reduction in LDL-C(about 38 mg/dl) reduction in LDL-C

Meta-analysis of Statin Trials

HDL-C

LaRosa JC et al. JAMA. 1999;282:2340-2346.

5

0

-5

-10

-15

-20

-25

-30

-35

-28

+5

-13

-31-29

-21

LDL-C TGCoronary

EventsFatal CHD

Total Mortality

Ch

an

ge

(%

)

Statin Trials: Therapy Reduces Statin Trials: Therapy Reduces Major Coronary Events in WomenMajor Coronary Events in Women

n = number of women enrolled.* 4S = primarily CHD death and nonfatal MI;

CARE = coronary death, nonfatal MI, angioplasty, or bypass surgery;AFCAPS/TexCAPS = fatal/nonfatal MI, unstable angina, or sudden cardiac death.

Miettinen TA et al. Circulation. 1997;96:4211-4218.Lewis SJ et al. J Am Coll Cardiol. 1998;32:140-146.Downs JR et al. JAMA. 1998;279:1615-1622.

4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997)

2 Prevention 1 Prevention

-50-45-40-35-30-25-20-15-10-505

10

Major coronary events*

-34

-46 -46

%

P=0.012

P=0.001

-15

-32*

-27*

-40

-30

-20

-10

0

Crouse JR et al. Arch Intern Med. 1997;157:1305-1310.

*P=0.001.†95% confidence interval of percentage of relative reduction.

Effects of Statins on Stroke: A Meta-analysis of Effects of Statins on Stroke: A Meta-analysis of Primary- and Secondary-Prevention TrialsPrimary- and Secondary-Prevention Trials

Relativereductionin rates

(%)

1° Prevention (-42 to -27)†

2° Prevention (13-45)†

Combined (11-40)†

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

HPS: Incidence of MI and HPS: Incidence of MI and stroke in diabetic patients stroke in diabetic patients

without prior diseasewithout prior disease

<0.0001<0.0001

p valuep value

369 (18.7%) 369 (18.7%)

Placebo Placebo (n=1976)(n=1976)

28%28%

Relative Relative reduction reduction (adjusted)(adjusted)

279 (13.9%) 279 (13.9%)

Simvastatin Simvastatin (n=2006)(n=2006)

Collins R et al. Presented at the American Heart Association Scientific Sessions. November 13, 2001.

Collaborative Atorvastatin Diabetes Collaborative Atorvastatin Diabetes Study (CARDS)Study (CARDS)

2838 patients aged 40-75 with type 2 diabetes, 2838 patients aged 40-75 with type 2 diabetes, no prior CVD, but at least 1 of the following: no prior CVD, but at least 1 of the following: retinopathy, albuminuria, smoking, or retinopathy, albuminuria, smoking, or hypertensionhypertension

Randomization to 10 mg atorvastatin or placeboRandomization to 10 mg atorvastatin or placebo

Mean follow-up 3.9 yearsMean follow-up 3.9 years

Reduction in all CVD events of 37% (p=0.001), Reduction in all CVD events of 37% (p=0.001), all cause mortality 27% (p=0.059). CHD events all cause mortality 27% (p=0.059). CHD events reduced 36% and stroke 48%.reduced 36% and stroke 48%.

Colhoun HM et al., The Lancet 2004; 364: 685-696

ASCOT: Primary Endpoint: Nonfatal MI/Fatal CHD

0

1

2

3

4

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Years

Cu

mu

lati

ve I

nci

den

ce (

%)

36% reduction

HR = 0.64 (0.50-0.83)

Atorvastatin 10 mg Number of events 100

Placebo Number of events 154

P = 0.0005

Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

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

Are LDL and HDL Effects Additive?Are LDL and HDL Effects Additive?

R2 = 0.8512

0

20

40

60

80

100

0 10 20 30 40 50 60 70 80

% Absolute Change in LDL+HDL

% C

V E

ven

t R

RR

HATS

FATS

FATS F/U

4SVA HIT DAIS

BIP

AFCAPS/TexCAPS

WOSCOPS

LIPIDCARE, HPS

HHS

CDP

ASCOT

ALLHAT

PROSPER

2nd Order Relationship

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

ARBITER 2: Primary Endpoint ARBITER 2: Primary Endpoint Carotid IMT Across 12 MonthsCarotid IMT Across 12 Months

CIMT at 12 months

• Statin vs ER niacin + statin P = 0.08

• Intent-to-treat analysis of statin vs. ER niacin + statin P = 0.048

• Non-Insulin resistant pts only: statin vs. ER niacin P = 0.026

Taylor AJ, et al. ARBITER 2: A double-blind, placebo-controlled study of extended-release niacin on Atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Ch

ang

e i

n C

IMT

(m

m +

/- S

EM

)

ER Niacin Placebo

68% decrease in progression

How low to go? Recent Findings from How low to go? Recent Findings from PROVE-IT and REVERSALPROVE-IT and REVERSAL

PROVE-IT PROVE-IT (Cannon CP et al., NEJM 2004; 350: 1495-1504)(Cannon CP et al., NEJM 2004; 350: 1495-1504)

randomized 4162 ACS pts to 80 mg atorvastatin vs. 40 randomized 4162 ACS pts to 80 mg atorvastatin vs. 40 mg pravastatinmg pravastatin

median on-treatment LDL-C of 62 mg/dl vs. 95 mg/dl. median on-treatment LDL-C of 62 mg/dl vs. 95 mg/dl. 16% reduction of combined death, MI, unstable angina 16% reduction of combined death, MI, unstable angina

req. hosp., stroke, and revas in 30 days on atorvastatin req. hosp., stroke, and revas in 30 days on atorvastatin

REVERSAL REVERSAL (Nissen SE et al., JAMA 2004; 291: 1071-80)(Nissen SE et al., JAMA 2004; 291: 1071-80)

randomized 654 pts to atorvastatin 80 mg vs. randomized 654 pts to atorvastatin 80 mg vs. pravastatin 40 mg; 502 and evaluable IVUS at pravastatin 40 mg; 502 and evaluable IVUS at baseline and after 18 mos on treatment.baseline and after 18 mos on treatment.

On-treatment LDL-C 79 mg/dl on atorvastatin and 110 On-treatment LDL-C 79 mg/dl on atorvastatin and 110 mg/dl on pravastatin. mg/dl on pravastatin.

Those on atorvastatin showed significantly less Those on atorvastatin showed significantly less progression of atheroma volumeprogression of atheroma volume

Late Breaking Clinical Trial, ACC 3/8/05Late Breaking Clinical Trial, ACC 3/8/05Treating to New Targets (TNT) StudyTreating to New Targets (TNT) Study

10,001 pts with CAD randomized to 10 mg 10,001 pts with CAD randomized to 10 mg atorvastatin (n=5006) vs. 80m mg atorvastatin atorvastatin (n=5006) vs. 80m mg atorvastatin (n=4995) for 4.9 years, reducing LDL-C to 101 (n=4995) for 4.9 years, reducing LDL-C to 101 mg/dl and 77 mg/dl, respectivelymg/dl and 77 mg/dl, respectively

Total major cardiovascular events were 10.9% on Total major cardiovascular events were 10.9% on low dose atorvastatin vs. 8.7% on high dose low dose atorvastatin vs. 8.7% on high dose atorvastatin, representing a 22% reduction in riskatorvastatin, representing a 22% reduction in risk

Provides evidence that treatment to a lower target Provides evidence that treatment to a lower target below the recommended 100 mg/dl goal will below the recommended 100 mg/dl goal will provide additional benefit in preventing provide additional benefit in preventing cardiovascular eventscardiovascular events

N Engl J Med, 3/8/05

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

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%

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 for 10-Year Risk for CADCADRisk ProfileRisk Profile

YesYes10%-20%10%-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

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

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)

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

I have some bad news for you. While your cholesterol has remained the same, the research

findings have changed.

Lipid Management GoalLipid Management Goal

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*

Risk Category LDL-C and non-HDL-C Goal

Initiate TLCConsider

Drug Therapy

High risk: CHD or CHD risk equivalents (10-year risk >20%)

and

<100 mg/dL

if TG > 200 mg/dL,

non-HDL-C should be < 130 mg/dL

100 mg/dL >100 mg/dL (<100 mg/dL: consider drug

options)

Very high risk:

ACS or established CHD

plus: multiple major risk factors (especially diabetes) or severe and poorly controlled risk factors

<70 mg/dL,

non-HDL-C < 100 mg/dL

All patients >100 mg/dL (<100 mg/dL: consider drug

options)

Grundy, S. et al. Circulation 2004;110:227-39.

Lipid Management Goals: NCEPLipid Management Goals: NCEP

ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes

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


If baseline LDL-C > 100 mg/dL, initiate LDL-lowering drug therapy

If on-treatment LDL-C > 100 mg/dL, intensify LDL-lowering drug therapy (may require LDL lowering drug combination)

If baseline is LDL-C 70 to 100 mg/dL, it is reasonable to treat to LDL < 70 mg/dL

Assess fasting lipid profile in all patients, and within 24 hours of hospitalization for those with an acute event. For patients hospitalized, initiate lipid-lowering medication as recommended below prior to discharge according to the following schedule:



When LDL lowering medications are used, obtain at least a 30-40% reduction in LDL-C levels.



If TG are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL

Further reduction of non-HDL to < 100 mg/dL is reasonable

Therapeutic options to reduce non-HDL-C: More intense LDL-C lowering therapy I (B) orNiacin (after LDL-C lowering therapy) IIa (B) orFibrate (after LDL-C lowering therapy) IIa (B)

If TG are > 500 mg/dL, therapeutic options to prevent pancreatitis are fibrate or niacin before LDL lowering therapy; and treat LDL-C to goal after TG-lowering therapy. Achieve non-HDL-C < 130 mg/dL, if possible




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

0.76 (0.72–0.81)P<0.0001

Heart Protection Study (HPS)

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

20,536 patients with CAD, other occlusive arterial disease, or DM randomized to 20,536 patients with CAD, other occlusive arterial disease, or DM randomized to simvastatin (40 mg) or placebo for 5.5 yearssimvastatin (40 mg) or placebo for 5.5 years

CAD=Coronary artery disease, CI=Confidence interval, DM=Diabetes mellitus,

HPS Collaborative Group. Lancet 2002;360:7-22

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


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

LaRosa JC et al. NEJM. 2005;352:1425-1435

LDL-C=Low density lipoprotein cholesterol; TNT=Treating to New Targets; HPS=Heart Protection Study; CARE=Cholesterol and Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study.

30

25

20

15

10

5

00 70 90 110 130 150 170 190 210

LDL-C (mg/dL)

TNT (atorvastatin 80 mg/d)

TNT (atorvastatin 10 mg/d)HPS

CARE

LIPIDLIPID

CAREHPS

Eve

nt (

%) 4S

4SStatinPlacebo

Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD


Therapeutic Lifestyle Changes in Therapeutic Lifestyle Changes in LDL-Lowering Therapy: Major FeaturesLDL-Lowering Therapy: Major Features

Saturated fats <7% of total caloriesSaturated fats <7% of total calories

Dietary cholesterol <200 mg per dayDietary cholesterol <200 mg per day

Plant stanols/sterols (2 g per day)Plant stanols/sterols (2 g per day)

Viscous (soluble) fiber (10–25 g per day)Viscous (soluble) fiber (10–25 g per day)

Weight reduction Weight reduction Increased physical activityIncreased physical activity

Plant Sterol and Stanol EstersPlant Sterol and Stanol Esters

Low absorptionLow absorption

Reduce LDL-C by 10%-15%Reduce LDL-C by 10%-15%

May interfere with absorption of lipid-soluble May interfere with absorption of lipid-soluble vitaminsvitamins

Plant stanol estersPlant stanol esters Saturated derivatives of plant sterol estersSaturated derivatives of plant sterol esters Very low absorptionVery low absorption

Nguyen. J Nutr. 1999;129:2109.

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

Effect of Mediterranean-style diet in the Effect of Mediterranean-style diet in the metabolic syndromemetabolic syndrome

180 pts with metabolic syndrome randomized to 180 pts with metabolic syndrome randomized to Mediterranean-style vs. prudent diet for 2 yearsMediterranean-style vs. prudent diet for 2 years

Those in intervention group lost more weight (-4kg) than Those in intervention group lost more weight (-4kg) than those in the control group (+0.6kg) (p<0.01), and those in the control group (+0.6kg) (p<0.01), and significant reductions in CRP and Il-6.significant reductions in CRP and Il-6.

After 2 years, 40 pts in intervention group still had After 2 years, 40 pts in intervention group still had features of metabolic syndrome compared to 78 pts in features of metabolic syndrome compared to 78 pts in the control groupthe control group

Esposito K et al. JAMA 2004; 292(12): 1440-6.

Dietary Approaches to Stop Dietary Approaches to Stop Hypertension (DASH)Hypertension (DASH)

Diet high in fruits and Diet high in fruits and vegetables and low-fat dairy vegetables and low-fat dairy products lowers blood products lowers blood pressure more than a pressure more than a sodium-restricted dietsodium-restricted diet

7-8 servings/day of grain/grain 7-8 servings/day of grain/grain products, 4-5 vegetable, 4-5 products, 4-5 vegetable, 4-5 fruit, 2-3 low- or non-fat dairy fruit, 2-3 low- or non-fat dairy products, 2 or less meat, products, 2 or less meat, poultry, and fish.poultry, and fish.

NEJM 1997; 366: 1117-24.NEJM 1997; 366: 1117-24.

Comparison of Atkins, Ornish, Weight Watchers, and Zone diets Comparison of Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized for weight loss and heart disease risk reduction: a randomized

trialtrial

160 subjects randomized, 40 to each diet, for 2 160 subjects randomized, 40 to each diet, for 2 months of maximum adherence, and self-selected months of maximum adherence, and self-selected adherence for rest of yearadherence for rest of year

After 1 year, mean wt loss 2.1 kg for Atkins, 3.2 kg After 1 year, mean wt loss 2.1 kg for Atkins, 3.2 kg for Zone, 3.0 kg for Weight Watchers, and 3.3 kg for Zone, 3.0 kg for Weight Watchers, and 3.3 kg for Ornish.for Ornish.

Dansinger et al., JAMA 2005; 293: 43-53.

Comparison of diets (cont.)Comparison of diets (cont.)

53% completed Atkins, 65% Zone, 65% Weight 53% completed Atkins, 65% Zone, 65% Weight Watchers, and 50% OrnishWatchers, and 50% Ornish

Each diet significantly reduced LDL-C/HDL-C ratio by Each diet significantly reduced LDL-C/HDL-C ratio by about 10%, no sig effects on blood pressure or glucose. about 10%, no sig effects on blood pressure or glucose.

Weight loss related to self-reported dietary adherence or Weight loss related to self-reported dietary adherence or type of diet; decreases in total/HDL-C, CRP, and insulin type of diet; decreases in total/HDL-C, CRP, and insulin significantly related to weight losssignificantly related to weight loss

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

• Reinforce reductionin saturated fat andcholesterol

• Consider addingplant stanols/sterols

• Increase fiber intake

• Consider referral toa dietitian

• Initiate Tx forMetabolicSyndrome

• Intensify weightmanagement &physical activity

• Consider referral

to a dietitian

6 wks 6 wks Q 4-6 mo

• Emphasize

reduction insaturated fat &cholesterol

• Encouragemoderate physicalactivity

• Consider referral toa dietitian

Visit IBegin LifestyleTherapies

Visit 2Evaluate LDLresponse

If LDL goal notachieved, intensifyLDL-Lowering Tx

Visit 3Evaluate LDLresponse

If LDL goal notachieved, consideradding drug Tx

A Model of Steps in A Model of Steps in Therapeutic Lifestyle Changes (TLC)Therapeutic Lifestyle Changes (TLC)

MonitorAdherenceto TLC

Visit N

Factors Influencing NoncomplianceFactors Influencing Noncompliance

Number of daily doses and medicationsNumber of daily doses and medications

Occurrence and severity of side effectsOccurrence and severity of side effects

Incompatibility with patients’ daily routineIncompatibility with patients’ daily routine

Inadequate physician-patient communicationInadequate physician-patient communication

CostCost

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

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


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


Drug TherapyDrug Therapy

HMG CoA Reductase Inhibitors (Statins)HMG CoA Reductase Inhibitors (Statins)

Reduce LDL-C 18–55% & TG 7–30%Reduce LDL-C 18–55% & TG 7–30%

Raise HDL-C 5–15%Raise HDL-C 5–15%

Major side effectsMajor side effects

MyopathyMyopathy

Increased liver enzymesIncreased liver enzymes

ContraindicationsContraindications

Absolute: liver diseaseAbsolute: liver disease

Relative: use with certain drugsRelative: use with certain drugs

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

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.

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

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:

CombinationCombination TherapyTherapy WithWith Intestinal- Intestinal- Acting Agents and Statins: RationaleActing Agents and Statins: Rationale

Statins inhibit compensatory increase in Statins inhibit compensatory increase in cholesterol synthesis induced by blockade cholesterol synthesis induced by blockade of cholesterol absorptionof cholesterol absorption

May increase ability to reach LDL-C goalsMay increase ability to reach LDL-C goals

May allow use of a lower statin doseMay allow use of a lower statin dose

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

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%

ENHANCEENHANCEBackgroundBackground

Patients with FH have a greatly increased risk of Patients with FH have a greatly increased risk of developing premature coronary artery disease and developing premature coronary artery disease and an increased rate of progression of intima-media an increased rate of progression of intima-media thickness (IMT)thickness (IMT)

Primary Outcome:Primary Outcome: change in the carotid IMT, an change in the carotid IMT, an average of the right and left common carotid average of the right and left common carotid arteries, carotid bulbs, and internal carotid arteriesarteries, carotid bulbs, and internal carotid arteries

Secondary Outcomes:Secondary Outcomes: regression in mean regression in mean carotid IMT, new plaque formation, and various carotid IMT, new plaque formation, and various individual measurements of the carotid arteryindividual measurements of the carotid artery

Kastelien J. N Engl J Med. 2008; 358: 1431- 43.

ENHANCEStudy Design

Simvastatin 80 mg

RANDOMIZATION

0 24Months

3 6 9 12 15 18 21

Pre-randomization Phase

FH:LDL-c ≥ 210 mg/dL

Screening and Fibrate

Washout

Placebo Lead-In/ Drug Washout

Weeks

-6-10 to -7

Ezetimibe 10 mg-Simvastatin 80 mg

IMT assessment N = 720


Ezetimibe 10 mg-Simvastatin 80 mgEzetimibe 10 mg-Simvastatin 80 mg

Simvastatin 80 mgSimvastatin 80 mg

ENHANCELDL Changes

SimvastatinEze-Simva

Months

-40

0 6 12 18 24

-50

-60

-70

0

-10

-20

-30

10

Perc

enta

ge c

hang

e fr

om b

asel

ine

P<0.01

-16.5 % incremental reduction in LDL

141 141 ++ 53 53319 319 ++ 65 65Eze-SimvaEze-Simva

193 193 ++ 60 60318 318 ++ 66 66Simva Simva

24 Months 24 Months (mg/dL)(mg/dL)

Baseline Baseline (mg/dL)(mg/dL)


ENHANCEENHANCEPrimary Outcome : Primary Outcome : MeanMean cIMT cIMT

Mean intima-media Mean intima-media thickness of carotid artery thickness of carotid artery (mm)(mm)

Simvastatin Simvastatin monotherapymonotherapy

(n=342)(n=342)

Simvastatin Simvastatin plus ezetimibeplus ezetimibe

(n=338) (n=338)

P valueP value

Mean cIMT, baselineMean cIMT, baseline 0.700.70±0.13±0.13 0.690.69±0.13±0.13 0.640.64

Mean cIMT, 24 moMean cIMT, 24 mo 0.700.70±0.14±0.14 0.710.71±0.15±0.15 0.290.29

Change from baseline (mm)Change from baseline (mm) 0.00580.0058±0.003±0.00377

0.01110.0111±0.0038±0.0038 0.290.29


ENHANCEENHANCEMean cIMT during 24 months of therapyMean cIMT during 24 months of therapy

Mea

n cI

MT

(mm

)

6 12 18 240.60

0.70

0.75

0.80

0.65

Months

P=0.88

SimvastatinEze-Simva

Longitudinal, repeated measures analysis


ENHANCEENHANCEConclusionConclusion

Despite the observed improvements in lipid parameters, Despite the observed improvements in lipid parameters, there were no significant differences in the change in there were no significant differences in the change in carotid IMT between ezetimibe/simvastatin and simvastatin carotid IMT between ezetimibe/simvastatin and simvastatin alone. alone.

Reason(s) for this discrepancy currently remains unknown, Reason(s) for this discrepancy currently remains unknown, however:however:

1. Measurement technique may not be accurate enough to 1. Measurement technique may not be accurate enough to reflect changes in atherosclerotic burdenreflect changes in atherosclerotic burden

2. Ezetimibe lacks vascular benefit despite the observed 2. Ezetimibe lacks vascular benefit despite the observed LDL-c and hsCRP reductionLDL-c and hsCRP reduction

3. The population studied may have been at too low a risk to 3. The population studied may have been at too low a risk to detect changes, limiting the ability to detect a differential detect changes, limiting the ability to detect a differential responseresponse


New Concepts in the Evaluation and Treatment of Dyslipidemia

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