1 Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell, Vera Bittner, Gregg.

1

Cholesterol, Cholesterol Therapies, Cholesterol, Cholesterol Therapies, and Cholesterol Guidelinesand Cholesterol Guidelines

Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell, Vera

Bittner, Gregg Fonarow & Roger S. Blumenthal

2

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

Potentiallyanti-inflammatory

Lipoprotein ClassesLipoprotein Classes

3

The Role of Lipoproteins in AtherogenesisThe Role of Lipoproteins in Atherogenesis

HDL

Liver Oxidativemodification

of LDL

LDL+

VLDL

Cholesterolexcreted

High plasmaLDL

LDL infiltrationinto intima

+Macrophages

Foam cells

Fatty streak

Advancedfibrocalcific

lesion

Endothelialinjury

Adherenceof platelets

Releaseof PDGF

Othergrowthfactors

LCATAPO-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

(-)

4

3.7

2.9

2.2

1.7

1.3

1.0

40 70 100 130 160 190

Re

lativ

e R

isk

for

Co

ron

ary

H

ea

rt D

isea

se (

Lo

g S

cale

)

LDL-Cholesterol (mg/dL)

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

CHD Risk According to LDL-C LevelCHD Risk According to LDL-C Level

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

5

Therapies to Lower LDL-CTherapies to Lower LDL-C

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)

Pravastatin (Pravachol)

Rosuvastatin (Crestor)

Simvastatin (Zocor)

3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors [Statins]

Drug(s)Class

Nicotinic acid Niacin

6

HMG-CoA Reductase Inhibitor: Mechanism of ActionHMG-CoA Reductase Inhibitor: Mechanism of Action

AcetylCoA

HMG-CoA

Mevalonate Farnesylpyrophosphate

Squalene Cholesterol

Squalenesynthase

Dolichol

Farnesyl-transferase

Farnesylatedproteins

E,E,E-Geranylgeranylpyrophosphate

Geranylgeranylatedproteins

Ubiquinones

HMG-CoA Reductase

Inhibition of the Cholesterol Biosynthetic Pathway

7

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 CirculationHepatocyteThe 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

LDLLDL

Serum IDL

VLDLRVLDLR

VLDL

HMG-CoA Reductase Inhibitor: Mechanism of ActionHMG-CoA Reductase Inhibitor: Mechanism of Action

8Illingworth 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 (%)

HMG-CoA Reductase Inhibitor: Dose-Dependent EffectHMG-CoA Reductase Inhibitor: Dose-Dependent Effect

The Rule of 6’s

Each doubling of the statin dose produces an additional 6% (approximate) reduction in the LDL-C level

9Law 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/d Statin

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*†

HMG-CoA Reductase Inhibitor: Reduction in LDL-CHMG-CoA Reductase Inhibitor: Reduction in LDL-C

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

10

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

HMG-CoA Reductase Inhibitor Trials: ChronologyHMG-CoA Reductase Inhibitor Trials: Chronology

Study Population:

Primary preventionAcute coronary syndromesChronic Coronary heart disease

11

HMG-CoA Reductase Inhibitor: Primary PreventionHMG-CoA Reductase Inhibitor: Primary Prevention

West of Scotland Coronary Prevention Study (WOSCOPS)

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

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

Placebo

7.5

Pravastatin

9

6

3

0

5.3

P<0.001

31% RRRR

ate

of M

I or

CH

D

deat

h (%

)

6,595 men with moderate hypercholesterolemia randomized to pravastatin (40 mg) or placebo for 5 years

Statins provide significant benefit in those with average cholesterol levels

12

Rat

e of

MI,

unst

able

an

gina

, or

SC

D (

%)

Placebo

5.5

Lovastatin

6

4

2

0

3.5

HMG-CoA Reductase Inhibitor: Primary PreventionHMG-CoA Reductase Inhibitor: Primary PreventionAir Force/Texas Coronary Atherosclerosis Prevention Study

(AFCAPS/TEXCAPS)

P<0.001

37% RRR

MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death

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

Statins provide benefit in those with average LDL-C levels

13

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Arm (ALLHAT-LLA)

RR, 0.99; P=0.88

1 2 3 4 5 6

32% cross-over among patients with CHD

Cum

ulat

ive

rate

%

PravastatinUsual care

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

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

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

There is no significant difference between the two treatment arms, but a high rate of cross-over


14

Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA)

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

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

ulat

ive

inci

denc

e of

M

I and

fata

l CH

D (

%)

Follow-up (yr)

36% RRR

*Post-treatment LDL-C level

CHD=Coronary heart disease, RR=Relative risk


10,305 patients with HTN randomized to atorvastatin (10 mg) or placebo for 5 years

Statins provide significant benefit in moderate- to high-risk individuals by lowering LDL-C levels below current goals

15O’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

rat

e (%

)

WOSCOPS

ASCOT

AFCAPS

ASCOT

P=0.0019

Relationship between LDL-C Levels and Event Rates in 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

16

0

5

10

15

Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial

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

17.4%

14.8%

RR=0.84, P=0.048

Com

bine

d ca

rdio

vasc

ular

ev

ent r

ate

(%)*

Weeks

*Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization.

4 8 12 160

Atorvastatin

Placebo

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

3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks

Acute intensive treatment significantly reduces event rates

17

Follow-up (months)

3 6 9 12 15 18 21 24 27 30

30

25

20

15

10

5

0

P =0.005

Rec

urre

nt M

I, ca

rdia

c de

ath,

U

A, r

evas

cula

rizat

ion,

or

stro

ke

16% RRR

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

Atorvastatin

Pravastatin

ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, UA=Unstable angina

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 treatment significantly reduces event rates

18

Time from randomization (months)

Cum

ulat

ive

even

t ra

te (

%)*

0

5

10

15

20

0 4 8 12 16 20 24

Aggrastat to Zocor (A to Z) Trial

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

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

Placebo + Simvastatin 20 mg/day

Simvastatin 40/80 mg/day

HR=0.89, P=0.14


4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin (20 mg) for 24 months

Acute intensive treatment produces a trend towards reduced cardiovascular events

19


Scandinavian Simvastatin Survival Study (4S)

Mor

talit

y (%

)

Placebo

11.5

Simvastatin

12

8

4

0

8.2

P<0.001

30% RRR

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

Statins provide significant benefit in those with average LDL-C levels

20


Cholesterol and Recurrent Events (CARE) Study

Placebo

13.2

Pravastatin

15

10

5

0

10.2

P=0.003

24% RRRR

ate

of M

I or

CH

D

deat

h (%

)

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


4,159 patients with a history of MI randomized to pravastatin (40 mg) or placebo for 5 years

Statins provide significant benefit in those with average cholesterol levels

21

HMG-CoA Reductase Inhibitor: Secondary PreventionHMG-CoA Reductase Inhibitor: Secondary PreventionLong-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


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

Statins provide significant benefit across a broad range of cholesterol levels

22

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,

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

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

Statins provide significant benefit across a broad range of LDL-C levels

23Shepherd J et al. Lancet 2002;360:1623-1630

0

10

20

0 1 2 3 4

CH

D d

eath

, non

-fat

al

MI,

stro

ke (

%)

Years

Placebo

Pravastatin

15% RRR, P=0.014

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)



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

Statins provide benefit in older men

24

Years

Maj

or C

V E

vent

* (%

)

0 1 2 3 4 5 6

P<0.001

22% RRR

Treating to New Targets (TNT) Trial

Atorvastatin (10 mg)


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


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

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

0.00

0.05

0.10

0.15

10,001 patients with stable CHD randomized to atorvastatin (80 mg) or atorvastatin (10 mg) for 4.9 years

High-dose statins provide benefit in chronic CHD

25

Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial


Cum

ulat

ive

Haz

ard

(%)

Years Since Randomization

0 1 2 3 4 5

4

8

12

HR=0.89, P=0.07

Simvastatin (20 mg)


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 statins provide a strong trend towards benefit after a MI

26LaRosa JC et al. NEJM 2005;352:1425-1435

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

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)

HPSCARE

LIPIDLIPID

CAREHPSE

vent

(%

) 4S

4SStatinPlacebo

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


LDL-C=Low density lipoprotein cholesterol

27Cannon 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

HMG-CoA Reductase Inhibitor: Intensive TherapyHMG-CoA Reductase Inhibitor: Intensive Therapy

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

28

• 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)

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

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.

Hepatocyte

Skeletal myocyte

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

29

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)

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

Risk Factors for the Development of Myopathy*

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

*General term to describe diseases of muscles**Itraconazole, Ketoconazole†Erythromycin, Clarithromycin‡Chronic renal insufficiency, especially from diabetes mellitus

30

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

Bile Acid Sequestrant: Mechanism of ActionBile Acid Sequestrant: Mechanism of Action

LDL-CBA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein cholesterol

31

Bile Acid Sequestrant: Efficacy at Reducing LDL-CBile Acid Sequestrant: Efficacy at Reducing LDL-C

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

*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

hang

e fr

om b

asel

ine

at w

eek

24TGHDL-CLDL-C

*

†

Placebo

Colesevelam 3.8 grams/day

32

Bile Acid Sequestrant: Primary PreventionBile Acid Sequestrant: Primary Prevention

Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT)

Placebo

8.6

Cholestyramine

9

6

3

0

7.0

P<0.05

19% RRR

Rat

e of

MI o

r C

HD

de

ath

(%)

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


3,806 men with primary hypercholesterolemia randomized to cholestyramine (24 grams) or placebo for 7.4 years

Bile acid sequestrants provide benefit in those with high cholesterol levels

33

Dietary cholesterol

Production in liver Absorption from intestine

Bloodstream

LDL-C VLDL

Cholesterolsynthesis

Biliary cholesterol

Chylomicrons

Fecal sterols and neutral sterols

Ezetimibe: Mechanism of ActionEzetimibe: Mechanism of Action

34

LDL-C

Mea

n %

cha

nge

from

base

line

to w

eek

12

–20

–15

–10

–5

0

+5

–18

+1

Triglycerides*

–8

0

HDL-C

–2

+1.0

Placebo

Ezetimibe 10 mg

Ezetimibe: Efficacy at Reducing LDL-CEzetimibe: Efficacy at Reducing LDL-C

Pooled Phase III Study Results

*Median % change

Knopp RH. Int J Clin Pract 2003;57:363-8

35

Therapy Dose (g/day) Effect

Dietary soluble fiber 2-8 LDL-C 5-10%

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

Stanol esters 1.5-4 LDL-C 10-15%

Dietary Adjuncts: Efficacy at Reducing LDL-CDietary Adjuncts: Efficacy at Reducing LDL-C

Jones PJ. Curr Atheroscler Rep 1999;1:230-235Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214Rambjor GS et al. Lipids 1996;31:S45-S49Ripsin CM et al. JAMA 1992;267:3317-3325

36Jenkins DJ et al. JAMA 2003;290:502-10

Diet Evidence: Effect on Lipid Parameters and CRPDiet Evidence: Effect on Lipid Parameters and CRP

0

10

20

30

-50

-40

-30

-20

-10

0 2 4 0 2 4 0 2 4

LDL-C

Cha

nge

from

Bas

elin

e (%

) LDL-C:HDL-C CRP

Weeks Weeks Weeks

Low fat diet

Statin

Dietary portfolio*

46 dyslipidemic patients randomized to a low fat diet, a low fat diet and lovastatin (20 mg), or a dietary portfolio* for 4 weeks

A diversified diet improves lipid parameters and CRP levels

*Enriched in plant sterols, soy protein, viscous fiber, and almonds

37

Liver Circulation

HDL

Serum VLDL results in reduced lipolysis to LDL

Serum LDL

VLDL

Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL-C levels and increased HDL-C levels

VLDL secretion

Apo B

Hepatocyte Systemic Circulation

Mobilization of FFA

TG synthesis

VLDL

LDL

Nicotinic Acid: Mechanism of ActionNicotinic Acid: Mechanism of Action

FFA=Free fatty acids, HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein

38

-50

-40

-30

-20

-10

0

10

20

30

Ch

ang

e fr

om

Ba

selin

e

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%

Nicotinic Acid: Efficacy at Raising HDL-CNicotinic Acid: Efficacy at Raising HDL-C

1000 1500 2000 2500Dose (mg) 3000

39

P=0.0012

100908070605040

0 2 4 6 8 10 12 14 16

Years of follow-up

Sur

viva

l (%

)

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

Nicotinic acid stopped

Nicotinic Acid: Secondary PreventionNicotinic Acid: Secondary Prevention

Coronary Drug Project (CDP)

Nicotinic AcidPlacebo

8,341 men with previous myocardial infarction randomized to nicotinic acid (3 grams) or placebo for 15 years

Nicotinic acid provides long-term benefit following a MI

MI=Myocardial infarction

40Brown BG et al. NEJM 2001;345:1583-92

Nicotinic Acid: Secondary PreventionNicotinic Acid: Secondary Prevention

HDL-Atherosclerosis Treatment Study (HATS)

*

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

Simvastatin + niacin benefits men with CAD and low HDL-C*Includes cardiovascular death, MI, stroke, or need for coronary revascularization

41

0.0

0.5

1.0

1.5

2.0

2.5

3.0

50 100 150 200 250 300 350 400

MenWomen

RR

Triglyceride Level (mg/dL)

Castelli WP. Can J Cardiol 1988;4:5A-10A

CHD Risk According to Triglyceride LevelsCHD Risk According to Triglyceride Levels

Framingham Study

CHD=Coronary heart disease, RR=Relative Risk

42

Fibrate: Mechanism of ActionFibrate: Mechanism of Action

Liver

TG

IDL

VLDL

LPL

CECE 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+

+

43

Fibrate: Efficacy at Reducing TriglycerideFibrate: Efficacy at Reducing Triglyceride

Goldberg AC et al. Clin Ther 1989;11:69–83

1520

-46

45

23

-55-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

TG = 350–499 mg/dL TG = 500–1500 mg/dL

Mea

n %

cha

nge

from

bas

elin

e

TG=Triglyceride level

147 patients with type IV/V hyperlipoproteinemia randomized to fenofibrate (100 mg three times daily) or placebo for 8 weeks

LDLTG

HDLTG

HDLLDL

44

Frick MH et al. NEJM 1987;317:1237-1245Manninen V et al. Circulation 1992;85:37-45BIP Study Group. Circulation 2000;102:21-27Rubins 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%

CH

D D

eat

h/N

onfa

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 PREVENTION

HHS HHS* BIP BIP** VA-HIT

Fibrate: Primary and Secondary PreventionFibrate: Primary and Secondary Prevention

45

Fibrate: Secondary PreventionFibrate: Secondary Prevention

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)

CH

D D

eath

or

Non

fata

l MI (

%)

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 yrs

Fenofibrate fails to provide significant additional benefit*

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

*Unadjusted for concomitant statin use

CHD=Coronary heart disease, MI=Myocardial infarction

46

HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglycerides *Daily dose of 40mg of each drug, excluding rosuvastatin

Good 9%1%18% 13%Ezetimibe

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

Good30%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 tolerability

TGHDL-CLDL-CTCTherapy

Cholesterol Management PharmacotherapyCholesterol Management Pharmacotherapy

47

% R

edu

ctio

n

Triglyceride

*P<0.05

-10 -20 -30 -40 -50

0

-46*

-21*

Total Cholesterol

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

-3 Fatty Acids: Efficacy at Reducing Triglyceride-3 Fatty Acids: Efficacy at Reducing Triglyceride

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

48Yokoyama M et al. Lancet. 2007;369:1090-8

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

JELIS Trial18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with

a statin or a statin alone for 5 years

EPA provides additional cardiovascular benefit to those on statin therapy, particularly in secondary prevention

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

49

*Post myocardial infarction

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

7.0%

8.0%

DART* (n=3,482) GISSI* (n=11,324)

N-3 Fatty Acids

Placebo

-3 Fatty Acids: Secondary Prevention-3 Fatty Acids: Secondary Prevention

Burr ML et al. Lancet 1989;2:757-761GISSI Investigators. Lancet 1999;354:447-455

Diet and Reinfarction Trial (DART)Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto

miocardico (GISSI)

All

cau

se m

ort

alit

y (%

)

-3 fatty acids reduce mortality post MI

50

4.0

3.0

2.0

1.0

25 45 65HDL-C (mg/dL)

CH

D r

isk

ratio

2.0

1.0

0

4.0

CHD Risk According to HDL-C LevelsCHD Risk According to HDL-C Levels

Framingham Study

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

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

51

0 10 20

2 RFs

0-1 RFs

CAD or Risk Equivalent**

Risk Profile Assessment for LDL-C Lowering Risk Profile Assessment for LDL-C Lowering

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

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

52

Years Points

20-34 -935-39 -440-44 045-49 350-54 655-59 860-64 1065-69 1170-74 1275-79 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 0160-199 4 3 2 1 0200-239 7 5 3 1 0240-279 9 6 4 2 1

>280 11 8 5 3 1

Framingham Risk Score: MenFramingham Risk Score: Men

Step 2: Total Cholesterol Points

HDL-C (mg/dl) Points

>60 -150-59 040-49 1<40 2

Step 3: HDL-C Points

SBP (mmHg)

If untreated

If treated

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

>160 2 3

Step 4: SBP PointsAge

20-39Age

40-49Age

50-59Age

60-69Age

70-79

Nonsmoker 0 0 0 0 0

Smoker 8 5 3 1 1

Step 5: Smoking Status Points

AgeTotal Cholesterol

HDL-CSystolic 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

53

Years Points

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

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 0160-199 4 3 2 1 1200-239 8 6 4 2 1240-279 11 8 5 3 2

>280 13 10 7 4 2

Framingham Risk Score: WomenFramingham Risk Score: Women

Step 2: Total Cholesterol Points

HDL-C (mg/dl) Points

>60 -150-59 040-49 1<40 2

Step 3: HDL-C Points

SBP (mmHg)

If untreated

If treated

<120 0 0120-129 1 3130-139 2 4140-159 3 5

>160 4 6

Step 4: SBP PointsAge

20-39Age

40-49Age

50-59Age

60-69Age

70-79

Nonsmoker 0 0 0 0 0

Smoker 9 7 4 2 1

Step 5: Smoking Status Points

AgeTotal Cholesterol

HDL-CSystolic 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

54

Risk Category LDL-C Goal Initiate TLCConsider

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)

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

ATP III LDL-C Goals and Cut-points for Drug TherapyATP III LDL-C Goals and Cut-points for Drug Therapy

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

55

Level (mg/dl) Classification

<200 Desirable

200-239 Borderline High

>240 High


<40 Desirable


>50 High


<150 Normal


200-499 High

>500 Very High

ATP III Classification of Other Lipoprotein LevelsATP III Classification of Other Lipoprotein Levels

Total Cholesterol HDL-Cholesterol

Triglyceride


56

Cholesterol Management Guidelines (Continued)Cholesterol Management Guidelines (Continued)

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


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

57


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

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


HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, NCEP=National Cholesterol Education Program, TG=Triglyceride

58

Secondary Prevention

Cholesterol Management GuidelinesCholesterol Management Guidelines

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

Restriction of saturated fat (<7% of total calories), trans-fatty acids, and cholesterol (<200 mg/day) in all patients

Promotion of daily physical activity and weight management in all patients

Increase in -3 fatty acid consumption in all patients


59



Initiation or intensification of LDL-C lowering drug therapy in those with a baseline or on-treatment LDL-C level >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



60



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

61



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



62



Therapeutic options to reduce non-HDL-cholesterol include:

Intensification of LDL-C lowering drug therapy

Niacin (after initiation of LDL-C lowering drug therapy)

Fibrate therapy (after initiation of LDL-C lowering drug therapy)




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

1 Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines Andrew P. DeFilippis, Ty J. Gluckman, James Mudd, Catherine Campbell, Vera Bittner, Gregg.

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