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 Heart Disease Prevention ProgramProgram

Division of CardiologyDivision of Cardiology

University of California, IrvineUniversity of California, Irvine

Learning ObjectivesLearning Objectives

Discuss the epidemiological evidence for a role of Discuss the epidemiological evidence for a role of cholesterol and lipoproteins in coronary heart diseasecholesterol and lipoproteins 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

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

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

Source: NHANES IV 2003-2004 data, US population projected to 2007. N = 212 million

Low HDL-C (26%, 54.7 M)Men: HDL < 40 mg/dl

Women: HDL < 50 mg/dl

High TG (13%, 27.5 M)TG ≥ 200 mg/dl

High LDL-C (28%, 59.7 M)≥2RF and FRS >20, CVD, DM or CKD: LDL ≥ 100 mg/dL

≥2RF and FRS ≤20: LDL ≥ 130 mg/dl<2RF: LDL ≥ 160 mg/dL

3% (6.8 M)

4% (7.6 M)

3% (6.2 M)

6% (13.7 M)

13% (26.6 M)

3% (6.9 M)

16% (33.0 M)

Overall U.S. Adult Population

No Lipid Disorder52%, 111.1 M

Ghandehari and Wong et al., Am Heart J 2008

Low HDL-C (27%, 2.1 M)Men: HDL < 40 mg/dl

Women: HDL < 50 mg/dl

High TG (27%, 2.2 M)TG ≥ 200 mg/dl

High LDL-C (60%, 4.7 M)LDL ≥ 100 mg/dL

10% (0.76 M)

5% (0.38 M)

10% (0.81 M)

5% (0.41 M)

7% (0.56 M)

3% (0.23 M)

35%(2.8 M)

Overall Coronary Heart Disease Subpopulation

No Lipid Disorder26%, 2.1 M

Source: NHANES IV 2003-2004 data, US population projected to 2007. N = 8 million

Treatment Rates among U.S. Adults with Treatment Rates among U.S. Adults with Dyslipidemia in 2003-2004 Dyslipidemia in 2003-2004

(Ghandehari and Wong et al., Am Heart J 2008)(Ghandehari and Wong et al., Am Heart J 2008)

Overall 35%, Men 36%, Women 34%Overall 35%, Men 36%, Women 34%

Non-Hispanic Whites 36%, Blacks 26%, Non-Hispanic Whites 36%, Blacks 26%, Hispanic 28%Hispanic 28%

No Disease 24%, CHD 63%, Stroke 36%, No Disease 24%, CHD 63%, Stroke 36%, Diabetes 48%Diabetes 48%

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

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: 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

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

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

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

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

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

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

METEOR Trial: Study DesignMETEOR Trial: Study Design

Primary Endpoint: Annualized rate of change in maximum CIMTPrimary Endpoint: Annualized rate of change in maximum CIMT Secondary Endpoint: Annualized rate of change in maximum CIMT derived Secondary Endpoint: Annualized rate of change in maximum CIMT derived

from the near and far walls of the right and left common carotid artery; the from the near and far walls of the right and left common carotid artery; the right and left carotid bulb; the right and left internal carotid artery; and right and left carotid bulb; the right and left internal carotid artery; and annualized rate of change in mean CIMT for the near and far walls of the annualized rate of change in mean CIMT for the near and far walls of the right and left common carotid artery.right and left common carotid artery.

Primary Endpoint: Annualized rate of change in maximum CIMTPrimary Endpoint: Annualized rate of change in maximum CIMT Secondary Endpoint: Annualized rate of change in maximum CIMT derived Secondary Endpoint: Annualized rate of change in maximum CIMT derived

from the near and far walls of the right and left common carotid artery; the from the near and far walls of the right and left common carotid artery; the right and left carotid bulb; the right and left internal carotid artery; and right and left carotid bulb; the right and left internal carotid artery; and annualized rate of change in mean CIMT for the near and far walls of the annualized rate of change in mean CIMT for the near and far walls of the right and left common carotid artery.right and left common carotid artery.

Rosuvastatin (Rosuvastatin (40mg)40mg)n=702n=702

Rosuvastatin (Rosuvastatin (40mg)40mg)n=702n=702

PlaceboPlacebon=282n=282

PlaceboPlacebon=282n=282

984 asymptomatic patients with moderately elevated cholesterol and low risk of CVD984 asymptomatic patients with moderately elevated cholesterol and low risk of CVDaccording to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk according to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk

factor and LDL 120-190mg/dL or factor and LDL 120-190mg/dL or >> 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk < 10%); HDL-C disease risk < 10%); HDL-C <<60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the 60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the

extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) 5:2 Randomized. Double-blinded. Placebo-controlled.5:2 Randomized. Double-blinded. Placebo-controlled.

Mean age = 57 years. 40% Female.Mean age = 57 years. 40% Female.

984 asymptomatic patients with moderately elevated cholesterol and low risk of CVD984 asymptomatic patients with moderately elevated cholesterol and low risk of CVDaccording to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk according to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk

factor and LDL 120-190mg/dL or factor and LDL 120-190mg/dL or >> 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk < 10%); HDL-C disease risk < 10%); HDL-C <<60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the 60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the

extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) extracranial carotid arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm) 5:2 Randomized. Double-blinded. Placebo-controlled.5:2 Randomized. Double-blinded. Placebo-controlled.

Mean age = 57 years. 40% Female.Mean age = 57 years. 40% Female.

RR

6, 12, 18 and 24 mos. follow-up6, 12, 18 and 24 mos. follow-up

ACC 2007ACC 2007

-0.0014

0.0131

-0.005

0.000

0.005

0.010

0.015

-0.0014

0.0131

-0.005

0.000

0.005

0.010

0.015• After two years, After two years,

treatment with treatment with rosuvastatin was rosuvastatin was associated with a associated with a statistically statistically significant reduction significant reduction in the rate of in the rate of progression of CIMT progression of CIMT thickening in overall thickening in overall carotid segments, carotid segments, while the placebo while the placebo group displayed group displayed progression progression (p<0.001).(p<0.001).

Cha

nge

in C

IMT

for

12

Car

otid

Art

ery

site

s C

hang

e in

CIM

T f

or 1

2 C

arot

id A

rter

y si

tes

(mm

/yea

r)(m

m/y

ear)

METEOR Trial: Primary EndpointMETEOR Trial: Primary EndpointMETEOR Trial: Primary EndpointMETEOR Trial: Primary Endpoint

n = 702n = 702

n = 282n = 282

p < 0.001 p < 0.001

ACC 2007ACC 2007

Change in maximum CIMT with rosuvastatin vs. placeboChange in maximum CIMT with rosuvastatin vs. placebo

RosuvastatinRosuvastatin

PlaceboPlacebo

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

ASTEROID Trial, ACC 2008ASTEROID Trial, ACC 2008

AA SStudy tudy tto o EEvaluate the Effect of valuate the Effect of RRosuvastatin osuvastatin oon n IIntravascular ntravascular UUltrasound-ltrasound-DDerived Coronary erived Coronary

Atheroma BurdenAtheroma Burden

AA SStudy tudy tto o EEvaluate the Effect of valuate the Effect of RRosuvastatin osuvastatin oon n IIntravascular ntravascular UUltrasound-ltrasound-DDerived Coronary erived Coronary

Atheroma BurdenAtheroma Burden

Prior studies have shown evidence of a decrease Prior studies have shown evidence of a decrease in atherosclerosis progression with statin therapy.in atherosclerosis progression with statin therapy.

No statin monotherapy has demonstrated a No statin monotherapy has demonstrated a cessation or regression of atherosclerosis.cessation or regression of atherosclerosis.

ASTEROID Trial: Study DesignASTEROID Trial: Study Design

Primary Endpoint: Rosuvastatin regression of coronary Primary Endpoint: Rosuvastatin regression of coronary atherosclerosis by intravascular ultrasound (IVUS)atherosclerosis by intravascular ultrasound (IVUS)

Secondary Endpoint: Rosuvastatin regression of coronary Secondary Endpoint: Rosuvastatin regression of coronary atherosclerosis by quantitative coronary angiography atherosclerosis by quantitative coronary angiography (QCA).(QCA).

Rosuvastatin Rosuvastatin 40 mg/day40 mg/day

n=292n=292

507 patients 507 patients >> 18 years with angiographic evidence of CAD, excluding patients 18 years with angiographic evidence of CAD, excluding patients using lipid-lowering medication for more than 3 mos within the previous 12 using lipid-lowering medication for more than 3 mos within the previous 12

mos, uncontrolled triglyceride levels, and poorly controlled diabetes. mos, uncontrolled triglyceride levels, and poorly controlled diabetes. Prospective. Multicenter. International. Open Label. Treatment for 24 mos. Prospective. Multicenter. International. Open Label. Treatment for 24 mos.

292 patients with 613 matched stenoses at baseline and study end.292 patients with 613 matched stenoses at baseline and study end.

Presented at ACC 08Presented at ACC 08

24 month treatment24 month treatment

Copyleft Clinical Trial Results. You Must Redistribute Slides

0.0

10.0

20.0

30.0

40.0

50.0

60.0

Baseline Study End

• The mean percent The mean percent diameter stenosis diameter stenosis decreased from decreased from 37.3±8.4% to 37.3±8.4% to 36±10.1% after 24 36±10.1% after 24 months of months of rosuvastatin therapy.rosuvastatin therapy.

• There was a There was a progression of progression of atherosclerosis in 6% atherosclerosis in 6% of patients by of patients by >>0.2mm. 0.2mm. M

ean

diam

eter

ste

nosi

s (

%)

Mea

n di

amet

er s

teno

sis

(%

)ASTEROID Trial: Mean Diameter StenosisASTEROID Trial: Mean Diameter Stenosis

n = 292n = 292 n =292n =292

p < 0.001p < 0.001

Presented at ACC 08Presented at ACC 08Copyleft Clinical Trial Results. You Must Redistribute Slides

37.3 ± 8.4%37.3 ± 8.4% 36.0 ± 10.1%36.0 ± 10.1%

ASTEROID Trial: LDL-C and HDL-C levelsASTEROID Trial: LDL-C and HDL-C levels

Presented at ACC 08Presented at ACC 08Copyleft Clinical Trial Results. You Must Redistribute Slides

• LDL-C levels were reduced to a mean of 61.1±20.3 LDL-C levels were reduced to a mean of 61.1±20.3 mg/dL (53.3% reduction) after rosuvastatin therapy.mg/dL (53.3% reduction) after rosuvastatin therapy.

HDL-C levels increased from 42.8 mg/dL to HDL-C levels increased from 42.8 mg/dL to 48.3±12.4 mg/dL (13.8% increase) after rosuvastatin 48.3±12.4 mg/dL (13.8% increase) after rosuvastatin therapy.therapy.

CONCLUSION: Treatment of rosuvastatin for 24 CONCLUSION: Treatment of rosuvastatin for 24 months was associated with atherosclerosis months was associated with atherosclerosis regression evidenced by an increase in the minimum regression evidenced by an increase in the minimum lumen diameter and a decrease in percent diameter lumen diameter and a decrease in percent diameter stenosis in patients with coronary artery disease. stenosis in patients with coronary artery disease.

• LDL-C levels were reduced to a mean of 61.1±20.3 LDL-C levels were reduced to a mean of 61.1±20.3 mg/dL (53.3% reduction) after rosuvastatin therapy.mg/dL (53.3% reduction) after rosuvastatin therapy.

HDL-C levels increased from 42.8 mg/dL to HDL-C levels increased from 42.8 mg/dL to 48.3±12.4 mg/dL (13.8% increase) after rosuvastatin 48.3±12.4 mg/dL (13.8% increase) after rosuvastatin therapy.therapy.

CONCLUSION: Treatment of rosuvastatin for 24 CONCLUSION: Treatment of rosuvastatin for 24 months was associated with atherosclerosis months was associated with atherosclerosis regression evidenced by an increase in the minimum regression evidenced by an increase in the minimum lumen diameter and a decrease in percent diameter lumen diameter and a decrease in percent diameter stenosis in patients with coronary artery disease. stenosis in patients with coronary artery disease.

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




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.

Shai I et al. N Engl J Med 2008; 359:229-241.

Weight lossWeight loss

GroupGroup Low-fat Low-fat (kg)(kg)

MediterraneaMediterranean (kg)n (kg)

Low-carb Low-carb (kg)(kg)

All patientsAll patients -2.9-2.9 -4.4-4.4 -4.7-4.7All completersAll completers -3.3-3.3 -4.6-4.6 -5.5-5.5MenMen -3.4-3.4 -4.0-4.0 -4.9-4.9WomenWomen -0.1-0.1 -6.2-6.2 -2.4-2.4

Weight Loss with a Low-Carbohydrate, Mediterranean or Low-Fat Diet: Dietary Intervention Randomized Controlled Trial (DIRECT)

322 moderately obese subjects, mean age 52, mean BMI 31, 86% male, randomized to one of three diets for 2 years. Adherence 95% at 1 year, 85% at 2 years.

Shai I et al. N Engl J Med 2008; 359:229-241.

Lipid changesLipid changes

ParameterParameter Low-fat Low-fat (mg/dL)(mg/dL)

Low-carb Low-carb (mg/dL)(mg/dL)

Mediterranean Mediterranean (mg/dL)(mg/dL)

HDLHDL +6.4+6.4 +8.4+8.4 +6.3+6.3LDLLDL -0.05-0.05 -3.0-3.0 -5.6-5.6TriglyceridesTriglycerides -2.8-2.8 -23.7-23.7 -21.8-21.8TC/HDL ratioTC/HDL ratio -0.6-0.6 -1.1-1.1 -0.9-0.9

Conclusions: Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets. Favorable effects on lipids from the low carbohydrate diet and on glycemic control from the Mediterranean diet suggest diets may be tailored to individual needs/preferences.

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

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:

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%

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...