1

Comprehensive Lipid Management—Beyond LDL-C Lowering

2

Objectives

Review current treatment guidelines for reducing CVD risks

Describe additional risk factors for CVD beyond LDL-C

Discuss the need to more aggressively target HDL-C and triglyceride levels

CVD=cardiovascular disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol

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Comprehensive Lipid Management—Beyond LDL-C Lowering

Current Treatment Guidelines for Reducing CVD Risks

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European Guidelines for Lipid Management in Asymptomatic Patients

Total risk <5%Provide lifestyle advice to reduce TC <5 mmol/L (190 mg/dL) and LDL-C <3 mmol/L (115 mg/dL)

Follow-up at a minimum of 5-year intervals

Total risk ≥5%Measure fasting TC, HDL-C, and triglycerides

Calculate LDL-C

Patient to follow lifestyle advice for at least 3 months

Repeat measurements

TC <5 mmol/L (190 mg/dL)LDL-C <3 mmol/L (115 mg/dL)Reinforce lifestyle advice with annual follow-up

If total risk remains ≥5%, consider drugs to achieve cholesterol targets:– TC <4.5 mmol/L (175 mg/dL)– LDL-C <2.5 mmol/L (100 mg/dL)

TC ≥5 mmol/L (190 mg/dL)LDL-C ≥3 mmol/L (115 mg/dL)Reinforce lifestyle advice and start drug therapy

Patients with TC ≥5 mmol/L

Markers of increased CV risk• HDL-C <1.0 mmol/L (40 mg/dL) (men) or <1.2 mmol/L (46 mg/dL) (women)• Fasting triglycerides >1.7 mmol/L (150 mg/dL)

TC=total cholesterol; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; CV=cardiovascularwith permission from De Backer G et al. Eur Heart J. 2003;24:1601–1610.

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Joint British Societies’ Guidelines for Lipid Management: TC and LDL-C Goals

Measure random (nonfasting) TC and HDL-C as part of a CVD risk assessment

Total CVD risk 20%Total CVD risk <20% and no cardiovascular

complications and no diabetes

Provide lifestyle advice and follow-up

Repeat cardiovascular risk assessment within 5 years

Measure fasting TC, HDL-C, and triglycerides

Calculate LDL-C

• HDL-C: inversely related to cardiovascular risk but no treatment target specified• Triglycerides: >1.7 mmol/L associated with increased CVD risk

TC=total cholesterol; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; CVD=cardiovascular diseasefrom Joint British Societies. Heart. 2005;91(suppl V):v1–v52. Reproduced/amended with permission from the BMJ Publishing Group.

Provide lifestyle advice

Monitor blood lipids and treat to target:– TC <4 mmol/L – LDL-C <2 mmol/L

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If LDL-C goal achieved,

treat other lipid risk factors

Progression of Drug Therapy in Primary Prevention

Initiation ofLDL-C lowering

drug therapy

If LDL-C goal not achieved,

intensify LDL-C lowering

drug therapy

If LDL-C goal not achieved, intensify drug

therapy or refer to a lipid

specialist

Monitor response and

adherence to therapy

6Weeks

6Weeks

Every4–6

Months

LDL-C Goal Is a Primary Focus in NCEP ATP III Guidelines

LDL-C=low-density lipoprotein cholesterol; NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel III from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.

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Major Updates to NCEP ATP III Guidelines

LDL-C <2.6 mmol/L (<100 mg/dL) for HIGH RISK

LDL-C <1.8 mmol/L (<70 mg/dL) for VERY-HIGH RISK (optional goal)

LDL-C <3.4 mmol/L (<130 mg/dL) for MODERATE RISK

LDL-C <3.4 mmol/L (<130 mg/dL) for MODERATELY HIGH RISK (optional goal)

The intensity of LDL-C lowering drug therapy in high-risk and moderately high-risk patients should be sufficient to achieve at least a 30%–40% reduction in LDL-C

AHA/NHLBI Scientific Statement:

In patients with low HDL-C (<1.03 mmol/L [<40 mg/dL] in men, <1.3 mmol/L [<50 mg/dL] in women) and high triglycerides (≥1.7 mmol/L [≥150 mg/dL])

Add fibrate or nicotinic acid after LDL-C–lowering drug therapy

NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel III; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; AHA=American Heart Association; NHLBI=National Heart, Lung, and Blood Institutefrom Grundy SM et al. Circulation. 2004;110:227–239; Grundy SM et al. Circulation. 2005;112:2735–2752.

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ADA Recommendations for Adults With Diabetes

Parameter Target

Glycemic control

HbA1C <7.0%a

Preprandial capillary plasma glucose 5.0–7.2 mmol/L (90–130 mg/dL)

Peak postprandial capillary plasma glucoseb <10.0 mmol/L (<180 mg/dL)

Blood pressure <130/80 mm Hg

Lipidsc

LDL-C <2.6 mmol/L (<100 mg/dL)

Triglycerides <1.7 mmol/L (<150 mg/dL)

HDL-C >1.0 mmol/L (>40 mg/dL)d

aReferenced to a nondiabetic range of 4.0%–6.0% using a DCCT-based assay; bPostprandial glucose measurements should be made 1–2 hours after the beginning of a meal, generally peak levels in patients with diabetes; cCurrent NCEP ATP III guidelines suggest that in patients with triglycerides ≥2.3 mmol/L (≥200 mg/dL), the “non–HDL-C” (total cholesterol minus HDL-C) be used. The goal is ≤3.4 mmol/L (≤130 mg/dL); dFor women, it has been suggested that the HDL-C goal be increased by 0.26 mmol/L (10 mg/dL)

ADA=American Diabetes Association; HbA1C=glycosylated hemoglobin; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; DCCT=Diabetes Control and Complications Trial; NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel IIICopyright © 2007 American Diabetes Association from Diabetes Care®, Vol. 30, 2007; S4–S41. Reprinted with permission from the American Diabetes Association.

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Guidelines for Management of Low HDL-C/High Triglycerides

European guidelines Emphasis on lifestyle changes

(eg, reduce body weight, increase physical activity)

Drug therapy may be needed for hypertension, dyslipidemia, diabetes

IDF Consensus Reduce triglycerides/increase HDL-C and

reduce LDL-C

Definition of metabolic syndrome is central obesity plus 2 of 4 factors including HDL-C <1.0 mmol/L (<40 mg/dL) (men)/ <1.3 mmol/L (<50 mg/dL) (women), and triglycerides ≥1.7 mmol/L (≥150 mg/dL)

AHA/NHLBI Statement Modify risk factors (eg, obesity, physical

inactivity, atherogenic diet, smoking)

Drug therapy may be needed for elevations in LDL-C, blood pressure, and glucose

Consider adding fibrates or nicotinic acid for low HDL-C/high non–HDL-C after LDL-C–lowering therapy

ADA Standards of Care Raise HDL-C to >1.2 mmol/L (>46 mg/dL)

(men) or >1.3 mmol/L (>50 mg/dL) (women); lower triglycerides to <1.7 mmol/L (<150 mg/dL)

HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; AHA=American Heart Association; NHLBI=National Heart, Lung, and Blood Institute; IDF=International Diabetes Federation; ADA: American Diabetes Associationwith permission from De Backer G et al. Eur Heart J. 2003;24:1601–1610; Grundy SM et al. Circulation. 2005;112:2735–2752; International Diabetes Federation. Available at: www.idf.org/webdata/docs/metac_syndrome_def.pdf; American Diabetes Association. Diabetes Care. 2006;29(suppl 1):S4–S42.

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Summary: European, British, and US Guidelines for Lipid Management

LDL-C remains primary treatment target Goals for patients at high risk

– European: <2.5 mmol/L (<100 mg/dL)

– British: <2.0 mmol/L (<77 mg/dL)

– US: <2.6 mmol/L (<100 mg/dL)<1.8 mmol/L (<70 mg/dL) for very high-risk optional goal

HDL-C not currently a treatment target Low levels considered marker of increased risk

– European: <1.0 mmol/L (40 mg/dL) (men) and <1.2 mmol/L (46 mg/dL) (women)

– British: Not specified

– US: <1.03 mmol/L (40 mg/dL) (men) and <1.3 mmol/L (50 mg/dL) (women)

LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol with permission from De Backer G et al. Eur Heart J. 2003;24:1601–1610; Joint British Societies. Heart. 2005;91(suppl V):v1–v52; Grundy SM et al. Circulation. 2005;112:2735–2752; Grundy SM et al. Circulation. 2004;110:227–239; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497.

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Comprehensive Lipid Management—Beyond LDL-C Lowering

Non–LDL-C Risk Factors for CVD

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Nonlipid Risk Factors for CHD

Risk Factor Values Associated With CHD

Age >45 years (male) or >55 years (female)

Family history First-degree relative with premature CHD

Cigarette smoking Current smoker

Hypertension BP >140/90 mmHg or use of antihypertensive

ObesityBMI >25 kg/m2 + waist >102 cm (men) or >88 cm (women)

CHD=coronary heart disease; BP=blood pressure; BMI=body mass indexfrom Mahley RW et al. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division; 2006:933–966.

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HDL-C: Inverse Correlation With CHD Risk

110

3021

0

20

40

60

80

100

120

<0.9 mmol/L 0.9–1.4 mmol/L >1.4 mmol/L

HDL-C

Inc

ide

nc

e,

pe

r 1

00

0

in 6

Ye

ars

Prospective Cardiovascular Münster (PROCAM) Study

186 events, 4407 men aged 40–65 years

HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart diseasefrom Assmann G et al. In: Lipid Metabolism Disorders and Coronary Heart Disease: Primary Prevention, Diagnosis and Therapy Guidelines for General Practice. 2nd ed. Munich: MMV Medizin Verlag; 1993:19–67. Permission pending.

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Low HDL-C Levels Substantially Increase CHD Risk at all LDL-C Levels

1.2

1.9

2.9

0.60.9

1.5

0.30.4 0.7

0.1 0.2 0.3

The independent effect of raising HDL-C and lowering triglycerides on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Systolic blood pressure=135 mmHg

LDL-C

CH

D R

ela

tiv

e R

isk

2.6 mmol/L 4.1 mmol/L

2.2 mmol/L0

0.5

1.0

1.5

2.0

3.0

2.5

1.7 mmol/L

1.2 mmol/L

0.6 mmol/L

5.7 mmol/L

HDL-C

Framingham Heart Study

HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterolReprinted from Am J Cardiol, Vol. 59, Kannel WB, Status of risk factors and their consideration in antihypertensive therapy, 80A–90A, Copyright 1987, with permission from Elsevier.

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Relationship of HDL-C + Triglyceride Profile to CHD Risk

Framingham Study – Subgroup Analysis

0

50

100

150

350

CH

D/1

000/

10 Y

ears

0

50

100

200

Men Women

150

<1.03 1.03–1.27 >1.27 <1.29 1.29–1.53 >1.53

HDL-C, mmol/L HDL-C, mmol/L

Triglycerides<1.02 mmol/L1.02–1.57 mmol/L>1.57 mmol/L

Triglycerides<0.90 mmol/L0.90–1.34 mmol/L>1.34 mmol/L

200

250

300

CH

D/1

000/

10 Y

ears

HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart diseaseReprinted from Am J Cardiol, Vol. 70, Castelli WP, Epidemiology of triglycerides: a view from Framingham, 3H–9H, Copyright 1992, with permission from Elsevier.

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“Lipid Triad” Increases Coronary Risk vs Elevated LDL-C Only

Scandinavian Simvastatin Survival Study (4S) Placebo Arm —Subgroup Analysis

n=284 n=284

20.9

8.5

35.9

12.2

0

5

10

15

20

25

30

35

40

Major Coronary Events Coronary Mortality

Eve

nt

Rat

e, %

n=237 n=237

Elevated LDL-C onlyElevated LDL-C + lowest HDL-C quartile/highest triglyceride quartile (lipid triad)

LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterolfrom Ballantyne CM et al. Circulation. 2001;104:3046–3051.

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Novel Risk Factors That May Also Contribute to Atherosclerosis

In recent years, a number of new risk factors or markers have been proposed as significant predictors of atherosclerosis and its complications Risk factors or markers can be grouped as

– Inflammatory markers

– Hemostasis/thrombosis markers

– Platelet-related markers

– Lipid-related factors

– Other factors

Four emerging risk factors that have been identified are

– CRP

– Lp (a)

– Fibrinogen

– Homocysteine

CRP=C-reactive protein; Lp (a)=lipoprotein (a)from Hackam DG et al. JAMA. 2003;290:932–940.

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LDL-C Particle Size and CVD Risk

Study Result

Stanford Coronary Risk Intervention Project (SCRIP)

Small, dense LDL-C levels at baseline were the best predictor for progression of coronary stenosis

Pravastatin Limitation of Atherosclerosis in the Coronary arteries trial (PLAC-I)

Small LDL-C was associated with a 5-fold greater risk of angiographic progression

Familial Atherosclerosis Treatment Study (FATS)

Increased LDL-C buoyancy with therapy was the most powerful predictor of coronary stenosis regression

Diabetes Atherosclerosis Intervention Study (DAIS)

Increased LDL-C size and decreased apo B–containing lipoproteins with treatment were associated with decreased coronary stenosis progression

LDL-C=low-density lipoprotein cholesterol; CVD=cardiovascular disease; apo B=apolipoprotein Bfrom Morgan JM et al. Prev Cardiol. 2004;7:182–188.

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Comprehensive Lipid Management—Beyond LDL-C Lowering

Moving Toward More Aggressive Management of Atherosclerosis Risk

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Monocyte

Induction of adhesionmolecules and chemotaxis

AdhesionVCAM-1ICAM-1P-selectinE-selectin

MigrationMCP-1CCR-2oxLDL

Oxidation

CytokinesMMPsEndothelin-1

Endothelialcells

Smooth muscle cells

Inti

ma

Internal elastic lamina

Lu

men

CD36SR-A

Differentiation(GM-CSF)

MacrophageFoam cell

T lymphocyte

CD40

IFN-gamma

Multiple Factors Contribute to Atheroma Formation

LDL-C, β-VLDL, Lp (a)

LDL-C=low-density lipoprotein cholesterol; ß-VLDL=beta-very low-density lipoprotein; Lp (a)=lipoprotein (a); VCAM-1=vascular cell adhesion molecule-1; ICAM-1=intercellular adhesion molecule-1; MCP-1=monocyte chemoattractant protein-1; CCR-2=specific receptor present on the surface of monocytes; oxLDL=oxidized low-density lipoprotein; MMP=matrix metalloproteinases; GM-CSF=granulocyte-macrophage colony-stimulating factor; SR-A=macrophage scavenger receptor class Afrom Fan J et al. J Atheroscler Thromb. 2003;10:63–71. Reprinted with permission from Japan Atherosclerosis Society.

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HDL-C=high-density lipoprotein cholesterol; ß-VLDL=beta-very low-density lipoprotein; Lp (a)=lipoprotein (a); VCAM-1=vascular cell adhesion molecule-1; ICAM-1=intercellular adhesion molecule-1; MCP-1=monocyte chemoattractant protein-1; CCR-2=specific receptor present on the surface of monocytes; oxLDL=oxidized low-density lipoprotein; MMP=matrix metalloproteinases; GM-CSF=granulocyte-macrophage colony-stimulating factor; SR-A=macrophage receptor class A; SR-BI=Scavenger receptor class B type IAdapted from Fan J et al. J Atheroscler Thromb. 2003;10:63–71. Reprinted with permission from Japan Atherosclerosis Society; Rader DJ. J Clin Invest. 2006;116:3090–3100.

Antiatherogenic Actions of HDL-C

LDL-C, β-VLDL, Lp (a)

Monocyte

CD36SR-A

Induction of adhesionmolecules and chemotaxis

AdhesionVCAM-1ICAM-1P-selectinE-selectin

MigrationMCP-1CCR-2oxLDL

OxidationDifferentiation

(GM-CSF)

MacrophageFoam cell

CytokinesMMPsEndothelin-1

Endothelial cells

T lymphocyte

Inti

ma

Lu

menHDL-C

inhibits oxidation of LDL-C

Internal elastic lamina

Smooth muscle cells

CD40

IFN-gamma

HDL-C inhibits expression of

endothelial cell adhesion molecules

and MCP-1

HDL-C promotes efflux of cholesterol from foam cells via the ABCA1 pathway,

ABCG1 pathway, and SR-BI receptor

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The HDL-C/Triglyceride Axis: An Important Therapy Target

Epidemiologic and clinical trials have shown that low HDL-C and elevated triglycerides are independent risk factors for CHD

High triglycerides and low HDL-C often occur together, commonly in metabolic syndrome

Elevated triglycerides combined with low HDL-C is often referred to as “atherogenic dyslipidemia” or the “lipid triad”

– It is often associated with smaller, dense LDL-C particles

NCEP ATP III guidelines place more emphasis on lowering LDL-C than on raising HDL-C

HDL-C=high-density lipoprotein cholesterol; CHD=coronary heart disease; NCEP ATP III=Third Report of the National Cholesterol Education Program Adult Treatment Panel III; LDL-C=low-density lipoprotein cholesterolGotto AM. Am Heart J. 2002;144(suppl 6):S33–S42; Szapary PO et al. Am Heart J. 2004;148:211–221.

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Unmet Need: Optimize HDL-C Levels

If CV risk is high, LDL-C management alone may not be sufficient

Low levels of HDL-C are common, undertreated, and recognized as a risk factor for premature CHD

HDL-C is not identified as a treatment target in treatment guidelines, but CV risk increases with

– HDL-C <1.0 to 1.03 mmol/L in men

– HDL-C <1.2 to 1.3 mmol/L in women

Each 0.026 mmol/L increase in HDL-C reduces CHD risk by 2% to 3%

HDL-C=high-density lipoprotein cholesterol; CV=cardiovascular; LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart diseasefrom Bruckert E et al. Curr Med Res Opin. 2005;21:1927–1934; Mahley RW et al. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division; 2006:933–966; De Backer G et al. Eur Heart J. 2003;24:1601–1610; Joint British Societies. Heart. 2005;91:v1–v52; Gordon DJ et al. Circulation. 1989;79:8–15; Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486–2497; American Diabetes Association. Diabetes Care. 2006;29(suppl 1);S4–S42.; Grundy SM et al. Circulation. 2005;112:2735–2752.

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Direction for the Future of Lipid Management

Continue emphasis on LDL-C reduction

Recognize that substantial risk of CHD remains for patients on statins alone

Define and treat to optimal HDL-C levels

Explore new treatment options to increase HDL-C and decrease triglycerides with enhanced tolerability

LDL-C=low-density lipoprotein cholesterol; CHD=coronary heart disease; HDL-C=high-density lipoprotein cholesterolfrom Chapman J. Eur Heart J Suppl. 2005;7(suppl F):F56–F62; Cannon CP. JAMA. 2005;294:2492–2494; Gaw A. Cardiovasc Drugs Ther. 2003;17:53–62.

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Direction for the Future of Atherosclerosis Management

Continue to optimize lipoprotein management

Optimize atherosclerosis management with new methods of risk reduction

– Vascular function

– Plaque morphology and composition

– Biomarker identification and treatment

from Chapman J. Eur Heart J Suppl. 2005;7(suppl F):F56–F62; Duffy D et al. Circulation. 2006;113:1140–1150; Chapman MJ. Curr Med Res Opin. 2005;21(suppl 6):S17–S22.

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Summary

Current treatment guidelines for reducing CVD risks focus on LDL-C lowering

Additional risk factors for CVD beyond LDL-C include low HDL-C, high triglycerides, and a variety of inflammatory, thrombosis, and platelet-related markers

The future of CVD risk management includes a more comprehensive strategy that aggressively targets HDL-C and triglyceride levels

CVD=cardiovascular disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol

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Bibliography

28

Bibliography (continued)

29

Comprehensive Lipid Management—Beyond LDL-C Lowering

Before prescribing, please consult the manufacturers’ prescribing information.

Merck does not recommend the use of any product in any different manner than as described

in the prescribing information.

Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

2-09 CVT-2007-W-1246225-SS

01-10-CVT-2009-IT-2653-SS Dep.Aifa 12/02/09

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