The Evidence for Current Cardiovascular Disease … · Cardiovascular Disease Prevention...

The Evidence for Current

Cardiovascular Disease Prevention

Guidelines:

Cholesterol, Cholesterol Therapies,

and Cholesterol Guidelines

Ty J. Gluckman, Ryan J. Tedford, Andrew P. DeFilippis, James

Mudd, Catherine Campbell, & Roger S. Blumenthal

The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease

*Data available from clinical trials or

registries about the usefulness/efficacy in

different subpopulations, such as gender,

age, history of diabetes, history of prior

myocardial infarction, history of heart

failure, and prior aspirin use. A

recommendation with Level of Evidence B

or C does not imply that the

recommendation is weak. Many important

clinical questions addressed in the

guidelines do not lend themselves to

clinical trials. Even though randomized

trials are not available, there may be a

very clear clinical consensus that a

particular test or therapy is useful or

effective.

†In 2003, the ACC/AHA Task Force on

Practice Guidelines developed a list of

suggested phrases to use when writing

recommendations. All guideline

recommendations have been written in full

sentences that express a complete

thought, such that a recommendation,

even if separated and presented apart

from the rest of the document (including

headings above sets of

recommendations), would still convey the

full intent of the recommendation. It is

hoped that this will increase readers’

comprehension of the guidelines and will

allow queries at the individual

recommendation level.

Classification of Recommendations and Levels of Evidence

I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III

I IIa IIb III

Icons Representing the Classification and Evidence Levels for Recommendations

I IIa IIb III

I IIa IIb III

I IIa IIb III

Cholesterol, Cholesterol Therapies,

and Cholesterol Guidelines

Evidence for Current Cardiovascular Disease

Prevention Guidelines

Sources:

P. Barter. Role of Lipoproteins in Inflammation presentation, 2001. Available at

http://www.lipidsonline.org/slides/slide01.cfm?&tk=18&dpg=3&x=293&43416.

Doi H et al. Circulation 2000;102:670-676

Colome C et al. Atherosclerosis 2000;149:295-302

Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994

HDLLDLChylomicrons,VLDL, and

their catabolic remnants

> 30 nm 20–22 nm

Potentially

pro-inflammatory

9–15 nm

Potentially

anti-inflammatory

Lipoprotein Classes

http://www.lipidsonline.org/slides/slide01.cfm?&tk=18&dpg=3&x=293&43416

HDL

LiverOxidative

modificationof LDL

LDL+

VLDL

Cholesterol

excreted

High plasma

LDL

LDL infiltration

into intima

+Macrophages

Foam cells

Fatty streak

Advancedfibrocalcific

lesion

Endothelial

injury

Adherence

of platelets

Release

of PDGFOther

growth

factors

LCAT

APO-A1

APO-A1=Apolipoprotein A1, HDL=High density lipoprotein,

LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein,

PDGF=Platelet-derived growth factor, VLDL=Very low density lipoprotein

Role of Lipoproteins in Atherogenesis

Source: Yusuf S et al. Lancet. 2004;364:937-52.

36

127

10

20

33

0

20

40

60

80

100

Smoking Fruits/

Veg

Exercise Alcohol Psycho-

social

Lipids All 9 risk

factors

PA

R (

%)

1418

90

Diabetes Abdominal

obesity

Hyper-

tension

Lifestyle factors

50

INTERHEART Study

N = 15,152 patients and 14,820 controls in 52 countries

MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors)

Attributable Risk Factorsfor a First Myocardial Infarction

Change in Total Cholesterol Levelsin the United States Over Time

Source: Ford, E. S. et al. Circulation 2009;120:1181-1188

0%

10%

20%

60%

40%

50%

30%

70%

80%

90%

100%

>240 mg/dL (>6.21 mmol/L)

Tota

l C

hole

ste

rol m

g/d

l (m

mol/L)

ag

e-a

dju

ste

d p

erc

en

tage

National Health and Nutrition Examination Survey (NHANES)

200-240 mg/dL (5.17-6.21 mmol/L)

<200 mg/dL (<5.17 mmol/L)

3.7

2.9

2.2

1.7

1.3

1.0

40 70 100 130 160 190

Rela

tive R

isk for

Coro

nary

He

art

Dis

ea

se

(L

og

Sca

le)

LDL-Cholesterol (mg/dL)

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

CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol

CHD Risk According to LDL-C Level

Soluble fiber

Soy protein

Stanol esters

Dietary Adjuncts

Ezetimibe (Zetia)Cholesterol absorption inhibitor

Cholestyramine (generic and Questran)

Colesevelam (Welchol)

Colestipol (Colestid)

Bile acid sequestrants

Atorvastatin (Lipitor)

Fluvastatin (Lescol XL)

Lovastatin (generic and Mevacor)

Pitavastatin (Livalo)

Pravastatin (Pravachol)

Rosuvastatin (Crestor)

Simvastatin (Zocor)

3-Hydroxy-3-Methylglutaryl Coenzyme A

(HMG-CoA) reductase inhibitors [Statins]

Drug(s)Class

Nicotinic acid Niacin

Therapies to Lower Levels of LDL-C

Acetyl

CoA

HMG-

CoAMevalonate Farnesyl

pyrophosphateSqualene Cholesterol

Squalene

synthaseDolichol

Farnesyl-

transferase

Farnesylated

proteins

E,E,E-

Geranylgeranyl

pyrophosphate

Geranylgeranylated

proteins

Ubiquinones

HMG-CoA

Reductase

Inhibition of the Cholesterol Biosynthetic Pathway

HMG-CoA Reductase Inhibitor:Mechanism of Action

LDL-R–mediated hepatic

uptake of LDL and VLDL

remnants

Serum VLDL remnants

Serum LDL-C

Cholesterol

synthesis

LDL receptor

(B–E receptor)

synthesis

Intracellular

Cholesterol

Apo B

Apo E

Apo B

Systemic CirculationHepatocyte

The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which

stimulates upregulation of the LDL receptor and increases uptake of non-HDL

particles from the systemic circulation

LDL

Serum IDL

VLDLR

VLDL

HMG-CoA Reductase Inhibitor:Mechanism of Action

Source: McKenney JM. Selecting Successful Lipid-lowering Treatment presentation, 2002. Available at

http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=4.

http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=4

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

The Rule of 6’s

Each doubling of the statin dose produces an approximate 6%

reduction in the LDL-C level

HMG-CoA Reductase Inhibitor:Dose-Dependent Effect

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 (%)

Source: Law MR et al. BMJ 2003;326:1423-1427

78 (42)69 (37)60 (32)51 (27)Simvastatin

108 (58)99 (53)90 (48)80 (43)Rosuvastatin

62 (33)53 (29)45 (24)37 (20)Pravastatin

83 (45)68 (37)54 (29)39 (21)Lovastatin‡

61 (33)50 (27)39 (21)29 (15)Fluvastatin

102 (55)91 (49)80 (43)69 (37)Atorvastatin

80 mg/d40 mg/d20 mg/d10 mg/dStatin

Data presented as absolute reductions in LDL-C* (mg/dL) and percent reductions in LDL-C (in parentheses)

*Standardized to LDL-C 186 mg/dL (mean concentration in trials) before Rx.† Independent of pre-Rx LDL-C‡Maximum dose of 80 mg/d administered as two 40-mg tablets

Not FDA approved at 80 mg/d

A Meta-analysis of 164 Trials*†

FDA=Food and Drug Administration, LDL-C=Low density lipoprotein

cholesterol, Rx=Treatment

HMG-CoA Reductase Inhibitor:Reduction in LDL-C

Study populations:

Primary prevention

Acute coronary syndromes (Secondary prevention)

Chronic Coronary heart disease (Secondary prevention)

*Trials with clinical outcomes

HMG-CoA Reductase Inhibitor:Chronological Order of Event Driven Trials

1994 4S 2002 PROSPER

1995 WOSCOPS 2002 ALLHAT-LLA

1996 CARE 2002 ASCOT-LLA

1998 AFCAPS/TEXCAPS 2004 PROVE-IT

1998 LIPID 2004 A to Z

2001 MIRACL 2005 TNT

2002 HPS 2005 IDEAL

2008 JUPITER

West of Scotland Coronary Prevention Study

(WOSCOPS)

CHD=Coronary heart disease, MI=Myocardial infarction,

RRR=Relative risk reduction

Source: Shepherd J et al. NEJM 1995;333:1301-1307

Placebo

7.5

Pravastatin

9

6

3

0

5.3

P<0.001

31% RRR

Rate

of

MI

or

CH

D

death

(%

)

HMG-CoA Reductase Inhibitor Evidence:Primary Prevention

6,595 men with moderate hypercholesterolemia randomized to pravastatin

(40 mg) or placebo for 5 years

A statin provides significant benefit in those with average cholesterol levels

Ris

k o

f M

I or

CH

D d

eath

(%

)

CHD=Coronary heart disease, MI=Myocardial infarction,


Source: Ford I et al. NEJM 2007;357:1477-86

West of Scotland Coronary Prevention Study

(WOSCOPS)


Long-term follow-up at 5 and 10 years after conclusion of the study

A statin provides long-term benefit in those with average cholesterol levels

Rate

of

MI, u

nsta

ble

angin

a, or

SC

D (

%)

Placebo

5.5

Lovastatin

6

4

2

0

3.5

Air Force/Texas Coronary Atherosclerosis Prevention

Study (AFCAPS/TEXCAPS)

P<0.001

37% RRR

MI=Myocardial infarction, RRR=Relative risk reduction,

SCD=Sudden cardiac death

Source: Downs JR et al. JAMA 1998;279:1615–1622


6,605 patients with average LDL-C levels randomized to lovastatin

(20-40 mg) or placebo for 5 years

A statin provides benefit in those with average LDL-C levels

Antihypertensive and Lipid-Lowering Treatment to Prevent

Heart Attack Trial—Lipid Lowering Arm (ALLHAT-LLA)

Source: ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007

CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk


RR, 0.99; P=0.88

1 2 3 4 5 6

32% cross-over

among patients

with CHD

Cum

ula

tive r

ate

%

PravastatinUsual care

0

3

6

9

12

15

18

Years

10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin

(40 mg) or usual care for 5 years

The failure to demonstrate benefit with a statin may be the result of a high

rate of cross over

Anglo-Scandinavian Cardiac Outcomes Trial—Lipid

Lowering Arm (ASCOT-LLA)

Source: Sever PS et al. Lancet. 2003;361:1149-1158

*Post-treatment LDL-C level

CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol,

RR=Relative risk


0

1

2

3

4

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Atorvastatin 90 mg/dl*

Placebo 126 mg/dl*

P=0.0005

Cum

ula

tive incid

ence o

f

MI and

fata

l C

HD

(%

)

Follow-up (yr)

36% RRR

10,305 patients with HTN randomized to atorvastatin (10 mg) or

placebo for 5 years

A statin provides significant benefit in moderate- to high-risk

individuals by lowering LDL-C levels below current goals

Source: O’Keefe JH Jr et al. JACC 2004;43:2142-6

–1

10

0

2

4

6

8

Statin

PlaceboWOSCOPS

AFCAPS

LDL cholesterol (mg/dL)

55 1951751551351159575

CH

D e

vent ra

te (

%)

WOSCOPS

ASCOT

AFCAPS

ASCOT

P=0.0019

Relationship between LDL-C Levels and Event Rates in

Select Primary Prevention Statin Trials

AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering

Arm, WOSCOPS= West of Scotland Coronary Prevention Study


Nu

mbe

r of

ad

vers

e C

V

even

ts*

pe

r 10

00

pe

rson

yea

rs

Placebo

5.0

Pravastatin

6

4

2

0

3.3

Management of Elevated Cholesterol in the Primary

Prevention Group of Adult Japanese (MEGA) Trial

P=0.01

33% RRR

Source: Nakamura H et al. Lancet 2006;368:1155-63

*Composite of cardiac and sudden death, myocardial infarction, angina, and

cardiac or vascular intervention

7,832 men (age 40-70 years) and postmenopausal women (up to age 70

years) with total cholesterol levels of 220-270 mg/dL randomized to

pravastatin (10-20 mg) or placebo for 5.3 years

A statin provides benefit in those with high cholesterol levels


Justification for the Use of Statins in Prevention: An

Intervention Trial Evaluating Rosuvastatin (JUPITER)17,802 men (>50 years) and women (>60 years) with LDL-C <130 mg/dL

and hs-CRP >2 mg/L randomized to rosuvastatin (20 mg) or placebo for up

to 5 years*

A statin provides benefit in those with elevated hs-CRP levels

0 1 2 3 4

0.0

00.0

40

.08

Follow-up (years)

Rosuvastatin

Placebo

44% RRR

P<0.00001, NNT=25

Cum

ula

tive incid

ence o

f C

V

death

, M

I, C

VA

, hospitaliz

ation

for

unsta

ble

angin

a, and

art

erial re

vascula

rization

Ridker PM et al. NEJM 2008;359:2195-207

*The study was stopped prematurely after 1.9 years


0

5

10

15

Myocardial Ischemia Reduction with Aggressive

Cholesterol Lowering (MIRACL) Trial

17.4%

14.8%

RR=0.84, P=0.048

Co

mb

ine

d c

ard

iova

scu

lar

event ra

te (

%)*

Weeks

*Includes death, MI resuscitated cardiac arrest, recurrent symptomatic

myocardial ischemia requiring emergency rehospitalization.

4 8 12 160

Atorvastatin

Source: Schwartz GG et al. JAMA 2001;285:1711-1718

HMG-CoA Reductase Inhibitor Evidence:Secondary Prevention

Placebo

3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo

for 16 weeks

Acute intensive statin therapy provides significant CV benefit

Pravastatin or Atorvastatin Evaluation and Infection

Therapy (PROVE-IT)—TIMI 22 Study

ACS=Acute coronary syndrome, CV=Cardiovascular,

MI=Myocardial infarction, UA=Unstable angina

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

4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin

(40 mg) for 24 months

Acute intensive statin therapy provides significant CV benefit


Follow-up (months)3 6 9 12 15 18 21 24 27 30

30

25

20

15

10

5

0

P =0.005

Recurr

ent

MI, c

ard

iac d

eath

,

UA

, re

vascula

rization, or

str

oke

16% RRR

Atorvastatin

Pravastatin

Aggrastat to Zocor (A to Z) Trial

Source: de Lemos JA et al. JAMA 2004;292:1307-1316

*Includes CV death, MI, readmission for an ACS, and CVA


Time from randomization (months)

Cum

ula

tive

event ra

te (

%)*

0

5

10

15

20

0 4 8 12 16 20 24

Placebo + Simvastatin 20 mg/day

HR=0.89, P=0.14

Simvastatin 40/80 mg/day

4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin

(20 mg) for 24 months

Acute intensive statin therapy produces a trend towards CV benefit

Scandinavian Simvastatin Survival Study (4S)

Mort

alit

y (

%)

Placebo

11.5

Simvastatin

12

8

4

0

8.2

P<0.001

30% RRR

Source: 4S Group. Lancet 1994;344:1383–1389

MI=Myocardial infarction, RRR=Relative risk reduction

4,444 patients with angina pectoris or previous MI randomized to

simvastatin (20-40 mg) or placebo for 5.4 years

A statin provides significant benefit in those with average LDL-C levels


Cholesterol and Recurrent Events (CARE) Study

Placebo

13.2

Pravastatin

15

10

5

0

10.2

P=0.003

24% RRR

Rate

of

MI

or

CH

D

death

(%

)

Srouce: Sacks FM et al. NEJM 1996;335:1001–1009

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

reduction

4,159 patients with a history of MI randomized to pravastatin (40 mg)

or placebo for 5 years

A statin provides significant benefit in those with average cholesterol levels


Long-term Intervention with Pravastatin in Ischemic

Disease (LIPID) Study

CH

D D

eath

(%

)

Placebo

8.3

Pravastatin

9

6

3

0

6.4

P<0.001

24% RRR


reduction

Source: LIPID Study Group. NEJM 1998;339:1349–1357

9,014 patients with a history of MI or hospitalization for unstable angina

randomized to pravastatin (40 mg) or placebo for 6.1 years

A statin provides significant benefit across a broad range of cholesterol levels


Baseline

LDL-C (mg/dL)

Statin

(n = 10,269)

Placebo

(n = 10,267)

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

100–129 668 (18.9%) 871 (24.7%)

130 1083 (21.6%) 1356 (26.9%)

All patients 2033 (19.8%) 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)

CAD=Coronary artery disease, CI=Confidence

interval, DM=Diabetes mellitus

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


Source: Shepherd J et al. Lancet 2002;360:1623-1630

Prospective Study of Pravastatin in the Elderly at Risk

(PROSPER)

CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction,



0

10

20

0 1 2 3 4

CH

D d

eath

, non

-fata

l

MI, s

troke (

%)

Years

Placebo

15% RRR, P=0.014

Pravastatin

5,804 patients aged 70-82 years with a history of, or risk factors for, vascular

disease randomized to pravastatin (40 mg) or placebo for 3.2 years

A statin provides CV benefit in older men

Treating to New Targets (TNT) Trial

CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction,


Source: LaRosa JC et al. NEJM 2005;352:1425-35

*Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke


Years

Ma

jor

CV

Eve

nt*

(%

)

0 1 2 3 4 5 6

P<0.001

22% RRRAtorvastatin (10 mg)

0.00

0.05

0.10

0.15

Atorvastatin (80 mg)

10,001 patients with stable CHD randomized to atorvastatin (80 mg) or

atorvastatin (10 mg) for 4.9 years

High-dose statin therapy provides benefit in chronic CHD

Incremental Decrease in End Points Through Aggressive

Lipid Lowering (IDEAL) Trial

Source: Pedersen et al. JAMA 2005;294:2437-2445

HR=Hazard ratio, MI=Myocardial infarction

*Includes coronary death, hospitalization for nonfatal acute MI, or cardiac

arrest with resuscitation

8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or

simvastatin (20 mg) for 5 years

High-dose statin therapy provides a strong trend towards CV benefit after a MI


Cum

ula

tive H

azard

(%)

Years Since Randomization

0 1 2 3 4 5

4

8

12

HR=0.89, P=0.07

Simvastatin (20 mg)

Atorvastatin (80 mg)

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

CARE=Cholesterol and Recurrent Events Trial, HPS=Heart Protection Study, LDL-C=Low denity lipoprotein cholesterol, LIPID=Long-term Intervention with

Pravastatin in Ischaemic Disease; 4S=Scandinavian Simvastatin Survival Study, TNT=Treating to New Targets

Relationship between LDL-C Levels and Event Rates in

Secondary Prevention Statin Trials of Patients with Stable CHD


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

CARELIPIDLIPID

CAREHPS

Event (%

) 4S

4SStatinPlacebo

Source: Thavendiranathan, P. et al. Arch Intern Med 2006;166:2307-2313

Meta-analysis of randomized controlled trials

comparing risk reductions between primary and secondary prevention patients

Primary Secondary Primary Secondary Primary Secondary

Major CHD

events29.2 20.8 1.66 2.4 60 33

Major CV

events14.4 17.8 0.37 0.8 268 125

Nonfatal

MI31.7 NA 1.65 NA 61 NA

PCI or

CABG33.8 20.3 1.08 2.7 93 37

Relative

Risk Reduction

Absolute

Risk Reduction

Number Needed

To Treat

CABG=Coronary artery bypass graft surgery, CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, PCI=Percutaneous

coronary intervention

HMG-CoA Reductase Inhibitor Evidence:Degree of Benefit in Prevention Types

Source: Cannon CP et al. JAMA 2005;294:2492-2494

RR in MI or

CHD Death (%)

RR in Primary

End Point (%)

LDL-C Reduction

(mg/dL)

Duration

(years)

PopulationTrial

1111235Stable CAD

(N = 8888)IDEAL

2122245Stable CAD

(N =10,001)TNT

1511142ACS

(N = 4497)A to Z

1616332ACS

(N = 4162)

PROVE IT-

TIMI 22

Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259

ACS=Acute coronary syndrome, CAD=Coronary artery disease,

CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol,

MI=Myocardial infarction, RR=Relative reduction

HMG-CoA Reductase Inhibitor Evidence:Effect of Intensive Therapy

Magnitude of event reduction among trials of intensive statin therapy

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

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

• Dose-dependent phenomenon that is usually reversible

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

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

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

74,102 subjects in 35 randomized clinical trials with statins

*The rate of myalgias leading to discontinuation of atorvastatin in the TNT

trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively.

HMG-CoA Reductase Inhibitor:Adverse Effects

Hepatocyte

Skeletal myocyte

Concomitant Use of Meds

Fibrate

Nicotinic acid (Rarely)

Cyclosporine

Antifungal azoles**

Macrolide antibiotics†

HIV protease inhibitors

Nefazadone

Verapamil, Amiodarone

Other Conditions

Advanced age (especially >80 years)

Women > Men especially at older age

Small body frame, frailty

Multisystem disease‡

Multiple medications

Perioperative period

Alcohol abuse

Grapefruit juice (>1 quart/day)

Risk Factors for the Development of Myopathy*

Source: Pasternak RC et al. Circulation 2002;106:1024-1028

**Itraconazole, Ketoconazole†Erythromycin, Clarithromycin

HMG-CoA Reductase Inhibitor:Adverse Effects

‡Chronic renal insufficiency, especially from diabetes

mellitus

*General term to describe diseases of muscles

Gall Bladder

LDL Receptors

VLDL and LDL removal

Cholesterol 7- hydroxylase

Conversion of cholesterol to BA

BA Secretion

Liver

BA Excretion

Terminal Ileum

Bile Acid

Enterohepatic Circulation

Reabsorption of

bile acids

LDL-C

BA=Bile acid, LDL-C=Low density lipoprotein cholesterol,

VLDL=Very low density lipoprotein cholesterol

Bile Acid Sequestrant:Mechanism of Action

Source: Insull W et al. Mayo Clin Proc 2001;76:971-82

*P<0.001 vs placebo†P=0.04 vs placebo

% C

han

ge f

rom

baselin

e

at w

eek 2

4

TGHDL-CLDL-C

*

†

Placebo

Colesevelam 3.8 grams/day

Bile Acid Sequestrant Evidence:Efficacy at Reducing LDL-C

5

-1

0

10

3

-15

-20

-15

-10

-5

0

5

10

15

Lipid Research Clinics-Coronary Primary Prevention

Trial (LRC-CPPT)

Placebo

8.6

Cholestyramine

9

6

3

0

7.0

P<0.05

19% RRR

Rate

of

MI

or

CH

D

death

(%

)

Source: The LRC-CPPT Investigators. JAMA 1984;251:351-64


reduction

3,806 men with primary hypercholesterolemia randomized to cholestyramine

(24 grams) or placebo for 7.4 years

A bile acid sequestrant provides benefit in those with high cholesterol levels

Bile Acid Sequestrant Evidence:Primary Prevention

Dietary cholesterol

Production in liver Absorption from intestine

Bloodstream

LDL-C VLDL

Cholesterolsynthesis

Biliary cholesterol

Chylomicrons

Fecal sterols and neutral sterols

Ezetimibe:Mechanism of Action

LDL-C

Mean %

change f

rom

baselin

e t

o w

eek 1

2

–20

–15

–10

–5

0

+5

–16.9*

+0.4

Triglycerides

–5.7

HDL-C

–1.6

+1.3

Placebo

Ezetimibe 10 mg

892 patients with primary hypercholesterolemia randomized

to ezetimibe (10 mg) or placebo for 12 weeks

*p<0.01 compared to placebo

Source: Dujovne CA et al. Am J Cardiol 2002;90:1092-7

Ezetimibe Evidence:Efficacy at Reducing LDL-C

+5.7

Therapy Dose (g/day) Effect

Dietary soluble fiber 5-10 (psyllium) LDL-C 10-15%

Soy protein 20-30 LDL-C 5-7%

Stanol esters 1.5-2 LDL-C 15-20%

Sources:

Kwiterovich Jr PO. Pediatrics 1995;96:1005-9

Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214

Miettinen TA et al. Ann Med 2004;36:126-34

Dietary Adjuncts Evidence:Efficacy at Reducing LDL-C

4.0

3.0

2.0

1.0

25 45 65HDL-C (mg/dL)

CH

D r

isk r

atio

2.0

1.0

0

4.0

Framingham Study

Source: Kannel WB. Am J Cardiol 1983;52:9B–12B

CHD=Coronary heart disease, HDL-C=High-density lipoprotein cholesterol

CHD Risk According to HDL-C Level

Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in

reduced LDL-C levels and increased HDL-C levels

Liver Circulation

HDL

Serum VLDL

results in reduced

lipolysis to LDL

Serum LDL

VLDL

VLDL

secretion

Apo B

Hepatocyte Systemic Circulation

Mobilization of FFA

TG

synthesis

VLDL

LDL

FFA=Free fatty acids, HDL=High density lipoprotein, LDL=Low density

lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein

Nicotinic Acid:Mechanism of Action

Source: McKenney JM. Selecting Successful Lipid-lowering Treatments presentation,

2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14

http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14

Me

an

ch

an

ge

fro

m B

ase

line

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

500

HDL-C

LDL-C

TG

–9%

–14%

–22% –21%–17%

30%30%26%

22%15%

10%

–28%

–35%

–44%–39%

–11%

–5%

1000 1500 2000 2500Dose (mg) 3000

Nicotinic Acid Evidence:Effect on Lipid Parameters

-50

-40

-30

-20

-10

0

10

20

30

P=0.0012

100

90

80

70

60

50

40

0 2 4 6 8 10 12 14 16

Years of follow-up

Surv

ival (%

)

Source: Canner PL et al. JACC 1986;8:1245–1255

Nicotinic acid

stopped

Coronary Drug Project (CDP)

Nicotinic Acid

MI=Myocardial infarction

Nicotinic Acid Evidence:Secondary Prevention

Placebo

Source: Brown BG et al. NEJM 2001;345:1583-92

HDL-Atherosclerosis Treatment Study (HATS)

**

**Includes cardiovascular death, MI, stroke, or need for coronary

revascularization

Nicotinic Acid Evidence:Secondary Prevention

160 men with CAD, low HDL-C, and normal LDL-C randomized to simvastatin

(10-20 mg) + niacin (1000 mg bid), simvastatin (10-20 mg) + niacin (1000 mg

bid) + antioxidants, antioxidants, or placebo for 3 years

A statin plus niacin provides benefit to men with CAD and low HDL-C levels

Source: Sarwar N et al. Circulation 2007;115:450-8

CHD=Coronary heart disease

CHD Risk According to Triglyceride Levels

Meta-analysis of 29 prospective studies evaluating the risk of

CHD relative to triglyceride level (top third vs. bottom third)

An elevated triglyceride level is associated with increased CHD risk

Liver

TG

IDL

VLDL

LPL

CE

CE FCFC

MacrophageMature HDL

Nascent

HDL

LDL-R

Intestine

CE=Cholesterol ester, FC=Free cholesterol, HDL=High density lipoprotein,

IDL=Intermediate density lipoprotein, LDL-R=Low density lipoprotein

receptor, LPL=Lipoprotein lipase, TG=Triglyceride,

Fibrate+

+

Fibrate:Mechanism of Action

Source: Knopp RH et al. Am J Med 1987;83:50-9

-20*

+11*

-38*

+15*

-45*

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50Type IIa hyperlipidemia Type IIb hyperlipidemia

Me

an %

change f

rom

baselin

e

HDL=High density lipoprotein cholesterol,

LDL=Low density lipoprotein cholesterol, TG=Triglyceride

180 patients with type IIa or IIb hyperlipidemia randomized to fenofibrate

(100 mg three times daily) or placebo for 24 weeks

LDL TG

HDL

TG

HDL

Fibrate Evidence:Effect on Lipid Parameters

-6*

LDL

*p<0.01

Sources:

Frick MH et al. NEJM 1987;317:1237-1245

Manninen V et al. Circulation 1992;85:37-45

BIP Study Group. Circulation 2000;102:21-27

Rubins HB et al. NEJM 1999;341:410-418

*Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL

**Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C <35 mg/dL

***Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05)

0

5

10

15

20

25

30

% C

HD

De

ath

/No

nfa

tal M

I Rx

Placebo

2.7 4.1*** 2.7

8

13.615

13

22

17

22***

66%

34%

9%

42%

22%

PRIMARY PREVENTION SECONDARY PREVENTIONHHS HHS* BIP BIP** VA-HIT

Fibrate Evidence:Primary and Secondary Prevention

Fenofibrate Intervention and Event Lowering in Diabetes

(FIELD)

CH

D D

eath

or

Nonfa

tal M

I (%

)

Placebo

5.9

Fenofibrate

9

6

3

0

5.2

P=0.16

11% RRR

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

for 5 years

A fibrate does not provide significant additional benefit* in diabetics

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

*Unadjusted for concomitant statin use

CHD=Coronary heart disease, MI=Myocardial infarction

Fibrate Evidence:Primary Prevention

Fibrate Evidence:Primary and Secondary Prevention

Action to Control Cardiovascular Risk in Diabetes

(ACCORD) Lipid Trial5,518 diabetic patients on statin therapy randomized to fenofibrate

(160 mg) or placebo for 4.7 years

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

in diabetics

CV

death

, nonfa

tal

str

oke o

r nonfa

tal

MI (%

/yea

r)

Placebo

2.4

Fenofibrate

3

2

1

0

2.2

P=0.32

8% RRR

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

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

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

cholesterol, TC=Total cholesterol, TG=Triglycerides

Good- 9%+ 1%- 18%- 13%Ezetimibe

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

Good- 30%+ 11-13%- 4-21%- 19%Fibrates

Reasonable

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

PoorNeutral or + 3%- 10-18%- 7-10%Bile acid

sequestrants

Patient

tolerabilityTGHDL-CLDL-CTCTherapy

Effect of Pharmacotherapyon Lipid Parameters

*Daily dose of 40mg of each drug, excluding rosuvastatin

% R

ed

uctio

n

Triglyceride

*P<0.05

-10

-20

-30

-40

-50

0

-46*

-21*

Total Cholesterol

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

27 patients with hypertriglyceridemia and low HDL-C treated with -3 fatty

acid (4 grams/day) for 7 months

-3 Fatty Acids Evidence:Effect on Lipid Parameters

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

Japan Eicosapentaenoic acid Lipid Intervention Study

(JELIS)

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

Years

-3 Fatty Acids Evidence:Primary and Secondary Prevention

18,645 patients with hypercholesterolemia randomized to EPA (1800 mg)

with a statin or a statin alone for 5 years

-3 fatty acids provide CV benefit, particularly in secondary prevention

-3 Fatty Acids Evidence:Secondary Prevention

**p<0.05

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

N-3 Fatty Acids

Placebo

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

Diet and Reinfarction Trial (DART)

All

cause m

ort

alit

y (

%)

2,033 men with a history of a MI randomized to a diet of reduced fat with an

increased ratio of polyunsaturated to saturated fat, increased fatty fish

intake*, or increased fiber intake for 2 years

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

*Corresponds to 2.5 grams of EPA (PUFA)


11,324 patients with a history of a MI randomized to -3 polyunsaturated

fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years

-3 fatty acids provide significant CV benefit after a MI

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


Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto

miocardico (GISSI-Prevenzione)

CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal

Perc

ent of

patients

P=0.048P=0.053

P=0.023

P=0.008

stroke stroke

02468

10121416

Death,

NF MI,

NF stroke

(2 way)

CV

death,

NF MI,

and NF

Death,

NF MI,

NF stroke

(4 way)

CV

death,

NF MI,

and NF

N-3 PUFA

Placebo

3,827 patients 3-14 days following a MI randomized to -3 fatty acids (460

mg EPA + 380 mg DHA) or placebo for 1 year

-3 fatty acids provide no benefit following a MI in those with high

utilization of risk reducing therapies

OMEGA Trial

Source: Senges J et al. Presented at the Annual Scientific Sessions of the

American College of Cardiology, March 2009, Orlando, FL

Placebo

8.8

Fatty acids

12

8

4

0

10.4

P=0.10Rate

of

rein

farc

tion,

str

oke,

or

death

* (%

)


*This is a secondary endpoint


0 10 20

2 RFs

0-1 RFs

CAD or Risk

Equivalent**

A risk assessment tool* is needed for individuals with >2 RFs

Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol

in Adults. JAMA 2001;285:2486-97

CAD=Coronary artery disease, CHD=Coronary heart disease,

DM=Diabetes mellitus, RF=Risk factor

**Includes DM, non-coronary atherosclerotic vascular disease, and

>20% 10-year CHD risk by the FRS*Such as the Framingham Risk Score (FRS)

10-year CHD Risk

Risk Assessment forLDL-C Lowering

Years Points

20-34 -9

35-39 -4

40-44 0

45-49 3

50-54 6

55-59 8

60-64 10

65-69 11

70-74 12

75-79 13

Step 1: Age Points

TC (mg/dl)

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

<160 0 0 0 0 0

160-199 4 3 2 1 0

200-239 7 5 3 1 0

240-279 9 6 4 2 1

>280 11 8 5 3 1

Step 2: Total Cholesterol Points

HDL-C (mg/dl) Points

>60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-C Points

SBP (mmHg)

If untreated

If treated

<120 0 0

120-129 0 1

130-139 1 2

140-159 1 2

>160 2 3

Step 4: SBP Points

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

Nonsmoker 0 0 0 0 0

Smoker 8 5 3 1 1

Step 5: Smoking Status Points

Age

Total Cholesterol

HDL-C

Systolic Blood Pressure

Smoking Status

Point Total

Step 6: Sum of Points

Point Total

10-year Risk

Point Total

10-year Risk

Point Total

10-year Risk

<0 <1% 6 2% 13 12%

0 1% 7 3% 14 16%

1 1% 8 4% 15 20%

2 1% 9 5% 16 25%

3 1% 10 6% >17 >30%

4 1% 11 8%

5 2% 12 10%

Step 7: 10-year CHD Risk

Risk Stratification:Framingham Risk Score for Men

Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at

http://www.framinghamheartstudy.org/risk/hrdcoronary.html.

http://www.framinghamheartstudy.org/risk/hrdcoronary.html

Step 1: Age Points

TC (mg/dl)

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

<160 0 0 0 0 0

160-199 4 3 2 1 1

200-239 8 6 4 2 1

240-279 11 8 5 3 2

>280 13 10 7 4 2

Step 2: Total Cholesterol Points

HDL-C (mg/dl) Points

>60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-C Points

SBP (mmHg)

If untreated

If treated

<120 0 0

120-129 1 3

130-139 2 4

140-159 3 5

>160 4 6

Step 4: SBP Points

Age 20-39

Age 40-49

Age 50-59

Age 60-69

Age 70-79

Nonsmoker 0 0 0 0 0

Smoker 9 7 4 2 1

Step 5: Smoking Status Points

Age

Total Cholesterol

HDL-C

Systolic Blood Pressure

Smoking Status

Point Total

Step 6: Sum of Points

Point Total

10-year Risk

Point Total

10-year Risk

Point Total

10-year Risk

<9 <1% 15 3% 22 17%

9 1% 16 4% 23 22%

10 1% 17 5% 24 27%

11 1% 18 6% >25 >30%

12 1% 19 8%

13 2% 20 11%

14 2% 21 14%

Step 7: 10-year CHD Risk

Risk Stratification:Framingham Risk Score for Women

Years Points

20-34 -7

35-39 -3

40-44 0

45-49 3

50-54 6

55-59 8

60-64 10

65-69 12

70-74 14

75-79 16

Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at

http://www.framinghamheartstudy.org/risk/hrdcoronary.html.

http://www.framinghamheartstudy.org/risk/hrdcoronary.html

Risk Category LDL-C Goal Initiate TLC

Consider

Drug Therapy

High risk:

CHD or CHD risk equivalents

(10-year risk >20%)

<100 mg/dL

(optional goal:

<70)

100 mg/dL >100 mg/dL

(<100 mg/dL: consider drug

options)

Moderately high risk:

2+ risk factors*

(10-year risk 10% to 20%)

<130 mg/dL

(optional goal:

<100)

130 mg/dL >130 mg/dL

(100-129 mg/dL: consider

drug options)

Moderate risk:

2+ risk factors*

(10 year risk <10%)

<130 mg/dL 130 mg/dL >160 mg/dL

Lower risk:

0-1 risk factor*

<160 mg/dL 160 mg/dL >190 mg/dL

(160-189 mg/dL: LDL-

lowering drug optional)

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

ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-

density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes

*Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90 mmHg or on antihypertensive medication,

HDL-C <40 mg/dl (>60 mg/dl is a negative risk factor), family history of premature CHD, age >45 years in men or >55 years in

women

ATP III LDL-C Goals andCut-points for Drug Therapy

Level (mg/dl) Classification

<200 Desirable

200-239 Borderline High

>240 High


>40 Minimum goal*

40-50 Desired goal*

>50 High


<150 Normal

150-199 Borderline High

200-499 High

>500 Very High

Total Cholesterol HDL-Cholesterol

Triglyceride

Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood

Cholesterol in Adults. JAMA 2001;285:2486-97

ATP III Classification of Other Lipoprotein Levels

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

Goals Recommendations

As set forth by the

NCEP

Obtain a fasting lipid profile in all patients. For those with

an MI, a fasting lipid profile should be obtained within 24

hours of admission.

Start therapeutic lifestyle changes in all patients, including:

• Reduced intake of saturated fat (<7% of total calories)

and cholesterol (<200 mg/day)

• Addition of plant stanols/sterols (2 g/day) and viscous

fiber (10-25 g/day) to enhance LDL-C lowering

• Weight reduction

• Increased physical activity

Source: Expert Panel on Detection, Evaluation, and Treatment of High

Blood Cholesterol in Adults. JAMA 2001;285:2486-97

LDL-C=Low density lipoprotein cholesterol, NCEP=National Cholesterol

Education Program

Cholesterol Management Guidelines

Goals Recommendations

As set forth by the NCEP

HMG-CoA reductase inhibitors (statins) are used first-line to achieve the LDL-C goal

If the LDL-C level is above goal, statin therapy should be intensified + the addition of a second LDL-C lowering agent

If the TG level is >150 mg/dl or the HDL-C level is <40 mg/dl, weight loss, physical activity, and smoking cessation should be emphasized

If the TG level is 200-499 mg/dl after initiation of LDL-C lowering therapy, nicotinic acid or a fibrate should be considered (non-HDL goal is 30 pts higher than LDL goal)

If the TG level is >500 mg/dl, nicotinic acid or a fibrate should be considered before starting LDL-C lowering therapy

Source: Expert Panel on Detection, Evaluation, and Treatment of

High Blood Cholesterol in Adults. JAMA 2001;285:2486-97

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

lipoprotein cholesterol, TG=Triglyceride

Cholesterol Management Guidelines (Continued)

Secondary Prevention

Reduce intake of saturated fat (<7% of total

calories), trans-fatty acids, and cholesterol (<200

mg/day), add plant stanols/sterols (2 grams/day)

and viscous fiber (>10 grams/day), and promote

daily physical activity and weight management

Increase -3 fatty acid consumption in the form of

fish or in capsule form (1 gram/day). Higher doses

are usually required for the treatment of elevated

triglycerides

Source: Smith SC Jr. et al. JACC 2006;47:2130-9


I IIa IIb III

I IIa IIb III


A fasting lipid profile should be obtained in all

patients within 24 hrs of hospitalization for a

NSTE-ACS

In the absence of contraindication, a HMG-CoA

reductase inhibitor should be initiated in all NSTE-

ACS patients, regardless of baseline LDL-C level

and dietary modification


LDL-C=Low density lipoprotein cholesterol, NSTE-ACS=Non ST-Segment

Elevation Acute Coronary Syndrome

Source: Anderson JL et al. JACC 2007;50:652-726

I IIa IIb III

I IIa IIb III

Intensification of LDL-C lowering drug therapy

(Class I, Level B) or addition of a fibrate or niacin

(Class I, Level B in men; Class I, Level C in

women) in those with a TG level of 200-499

mg/dl

Initiation of a fibrate or niacin before LDL-C

lowering drug therapy in those with a TG level

>500 mg/dl

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



Secondary PreventionI IIa IIb III

I IIa IIb III

I IIa IIb III


Initiation or intensification of LDL-C lowering drug

therapy to achieve a LDL-C goal <100 mg/dl

Intensification of LDL-C lowering drug therapy to

achieve a LDL-C <70 mg/dl

Initiation of LDL-C lowering drug therapy in those

with a baseline LDL-C level of 70-100 mg/dl to

achieve a LDL-C level <70 mg/dl

LDL-C=Low density lipoprotein cholesterol



I IIa IIb III

I IIa IIb III

I IIa IIb III


Intensification of LDL-C lowering drug

therapy (Class I, Level B) or addition of a

fibrate or niacin (Class IIa, Level B) to

reduce non-HDL-C

Initiation of a fibrate or niacin before LDL-C

lowering drug therapy in those with a TG

level >500 mg/dl to achieve a non-HDL-

cholesterol <130 mg/dl

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

lipoprotein cholesterol, TG=Triglyceride



I IIa IIb III

I IIa IIb III

I IIa IIb III


Reduction of non-HDL-cholesterol to <130 mg/dl in

those with a TG level of 200-499 mg/dl

Reduction of non-HDL-cholesterol to <100 mg/dl in

those with a TG level of 200-499 mg/dl

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



I IIa IIb III

I IIa IIb III

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