Dyslipidemia and Cardiovascular Risk Reduction: An Evidence-Based Review Robert M. Guthrie, MD Professor of Emergency Medicine Professor of Internal Medicine.

Dyslipidemia and Cardiovascular Risk Reduction:

An Evidence-Based ReviewRobert M. Guthrie, MD

Professor of Emergency Medicine

Professor of Internal Medicine

Professor of Pharmacology

The Ohio State University College of Medicine

Columbus, Ohio

Key Question

What percentage of your patients withdyslipidemia who are receiving statin therapy alone achieve LDL goal?

1. <25%

2. 26%-50%

3. 51%-75%

4. 76%-100%

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Faculty Disclosure

Dr Guthrie: grants/research support: Abbot Laboratories, Boehringer-Ingelheim Corporation, Bristol-Myers Squibb Company, GlaxoSmithKline; speakers bureau: AstraZeneca.

Learning Objectives

Discuss current guidelines for the management of dyslipidemia

Describe the results of recent clinical trials relevant to the management of dyslipidemia

State lipid goals according to patients’ level of cardiovascular risk

Cardiovascular Disease (CVD)

Leading cause of death in the United States37% of all US deaths in 20031

Total US cost in 2006 = $403.1 billion1

Associated with high blood levels of cholesterol and other lipids, and low HDL levels1

Risk assessment, risk reduction1,2

HDL: high-density lipoprotein1. Thom T, et al. Circulation. 2006;113:e85-e151.2. NCEP ATP III. JAMA. 2001;285:2486-2497.

NCEP ATP III Risk Determinants

LDL level CHD or CHD risk equivalents:

Other clinical atherosclerotic diseaseDiabetesMultiple other risk factors contributing to a

Framingham 10-year risk of CHD >20% Other major risk factors

NCEP ATP III. JAMA. 2001;285:2486-2497.

NCEP ATP III: Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)LDL: low-density lipoproteinCHD: coronary heart disease

Major Risk FactorsOther Than LDL and CHD

Cigarette smoking Hypertension

BP ≥140/90 mm Hg or on antihypertensive medication Low HDL level

<40 mg/dL Family history of premature CHD

Male first-degree relative <55 years Female first-degree relative <65 years

Age Men ≥45 years Women ≥55 years

BP: blood pressure

NCEP ATP III. JAMA. 2001;285:2486-2497.

Test OptimalBorderline High Risk

High RiskVery High

Risk

Total Cholesterol

<200 200-239 ≥240

LDL <100 130-159 160-189 ≥190

HDL ≥60 40-59 <40

Triglycerides <150 150-199 200-499 ≥500

NCEP ATP III Risk Definitions

NCEP ATP III. JAMA. 2001;285:2486-2497.

Risk Assessment:Dyslipidemia and CVD

Framingham risk calculator1,2 Based on age, sex, total and HDL

cholesterol, smoking, BP Mobile Lipid Clinic3

Free NCEP ATP III–based tools Palm® and Windows®

Reynolds risk calculator4

For healthy women without diabetes

1. Risk assessment tool for estimating 10-year risk of developing hard CHD (myocardial infarction and coronary death). Available at http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof. Accessed on January 17, 2007.

2. Grundy SM, et al. J Am Coll Cardiol. 1999;34:1348-1359.3. Mobile Lipid Clinic. Available at http://www.mobilelipidclinic.com/DesktopDefault.aspx. Accessed on

January 17, 2007.4. Reynolds Risk Score. Available at http://www.reynoldsriskscore.org/default.aspx. Accessed on

February 23, 2007.

NCEP ATP III Risk Categories

Risk Category Criteria

Low risk 0-1 risk factor

Moderate risk≥2 risk factors;

10-year risk <10%

Moderately high risk≥2 risk factors;

10-year risk 10%-20%

High riskCHD or CHD risk equivalents;

10-year risk >20%

Grundy SM, et al. Circulation. 2004;110:227-239.

Dyslipidemia

Presence of abnormal levels of blood lipids and lipoproteins1

Diagnosed using fasting lipoprotein profile1

Nearly 40% of US adults have LDL levels ≥130 mg/dL (borderline high or higher)2

1. NCEP ATP III. JAMA. 2001;285:2486-2497.2. Thom T, et al. Circulation. 2006;113:e85-e151.

Key Question

Why do so many patients have high lipid levels?

1. Lack of screening and treatment by clinicians

2. Lack of effective medications

3. Lack of therapy adherence by patients

4. 1 and 3

5. All of the above

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Problem: Low Success Rates in Achieving Lipid Goals

0

10

20

30

40

50

60

70

80

Overall Low risk High risk CHD

% at goal

Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

% P

atie

nt

Su

cces

s

Risk Groups

Problem: Patients’ Adherence to Statin Therapy

0

10

20

30

40

50

60

70

80

90

100

9 Months 12 Months

Huser MA, et al. Adv Ther. 2005;22:163-171.

Ove

rall

Per

sist

ence

(%

)

NCEP Guidelines in a Nutshell

Identify individuals at high risk of CV events: 10-year risk >20%10-year risk 10%-20%

Start therapeutic lifestyle changes and/or medication Adjust intensity of therapy to individual risk level Monitor progress to goal lipid control

Adherence is always a factor

NCEP ATP III. JAMA. 2001;285:2486-2497.

CV: cardiovascular

NCEP ATP III 2001Thresholds for LDL-Lowering Therapy

TLC(mg/dL)

Consider Drug Therapy (mg/dL)

Low Risk 0-1 risk factor ≥160≥190

(optional at 160-189)

Moderate Risk2 risk factors;

10-year risk <10% ≥130 ≥160

Moderately High Risk

2 risk factors; 10-year risk 10%-20%

≥130≥130

(optional at 100-129)

High RiskCHD or CHD risk

equivalents;10-year risk >20%

≥100≥130≥100

(optional at <100)

TLC: therapeutic lifestyle changes

1. NCEP ATP III. JAMA. 2001;285:2486-2497.2. Grundy SM, et al. Circulation. 2004;110:227-239.

NCEP ATP III Thresholds:Update 2004

Very high-risk patients LDL ≥100 mg/dL consider drug therapy LDL goal <70 mg/dL a therapeutic option

Moderately high-risk patients LDL goal <100 mg/dL a therapeutic option

High-risk and moderately high-risk patients 30%-40% reduction in LDL recommended

High-risk patients with high TG or low HDL levels Consider fibrate or nicotinic acid

High-risk or moderately high-risk patients with lifestyle-related risk factors Therapeutic lifestyle change regardless of LDL

Grundy SM, et al. Circulation. 2004;110:227-239.

TG: triglyceride

NCEP ATP IIITherapeutic Goals for LDL

Risk Category LDL Goal (mg/dL)

Low risk0 to 1 risk factor

<160

Moderate risk2 risk factors; 10-year risk <10%

<130

Moderately high risk2 risk factors; 10-year risk 10%-20%

<130(optional goal <100)

High riskCHD or CHD risk equivalents; 10-year risk >20%

<100(optional goal <70 for very

high-risk patients)

1. NCEP ATP III. JAMA. 2001;285:2486-2497.2. Grundy SM, et al. Circulation. 2004;110:227-239.

Review of Key Clinical Trials Conducted in 2005

Persons with diabetes and CHD should be treated aggressively with statins, even if they are not otherwise at high risk

The first line of therapy should continue to be statins rather than fibrates (which are still useful in combination therapy)

Risk Category LDL Goal (mg/dL)

High risk

CHD or CHD risk equivalents;

10-year risk >20%

<77

Cheng AY, Leiter LA. Curr Opin Cardiol. 2006;21:400-404.

Importance of Individualized Dyslipidemia Management

Dyslipidemia is a complex disease caused by the interplay of genetic, dietary, and physiologic factors

Dyslipidemia often occurs concurrently with other medical conditions

Treatment strategy is evolving based on new data

Metabolic Syndrome Definitions:NCEP ATP III and IDF

Components NCEP ATP III1

≥3 ComponentsIDF2

WC + ≥2 Components

Waist Circumference (WC; inches)

≥40 (men); ≥34.5 (women) Europid ≥37 (men); ≥31.5 (women)

South Asians≥35.50 (men); ≥31.5 (women)

Japanese≥35.50 (men); ≥31.5 (women)

Triglycerides (mg/dL) ≥150 ≥150

HDL (mg/dL) <40 (men); <50 (women) <40 (men); <50 (women)

BP (mm Hg) Systolic ≥130 or diastolic ≥85 Systolic ≥130 or diastolic ≥85

Fasting Plasma Glucose (mg/dL)

≥100 ≥100

1. Grundy SM, et al. Circulation. 2005;112:2735-2752.2. International Diabetes Federation. Rationale for new IDF worldwide definition of metabolic syndrome. Available at http://www.idf.org/webdata/docs/Metabolic_syndrome_rationale.pdf. Accessed on February 3, 2007.

IDF: International Diabetes Federation

Prevalence of Metabolic Syndrome: NHANES III 1988-1994

0

10

20

30

40

50

MenWomen

Per

cen

t A

ffec

ted

20-29 30-39 40-49 50-59 60-69 70+Age (years)

Ford ES, et al. JAMA. 2002;287:356-359.NHANES III: Third National Health and Nutrition Examination Survey

Metabolic Syndrome Prevalence by Race and Ethnicity

0

5

10

15

20

25

30

35

40

Men Women

White

African American

Mexican American

Other

% A

ffec

ted

Ford ES, et al. JAMA. 2002;287:356-359.

Pattern of Dyslipidemia in Type 2 Diabetes

Triglycerides HDL Qualitative changes in LDL

Higher proportion of smaller and denser LDL particles susceptible to oxidation and atherogenicity

Mean LDL levels not different in high-risk patients with or without diabetes, but important risk factor

Haffner SM. Diabetes Care. 2004;27(suppl 1):S68-S71.

Prevalence of Dyslipidemia in Patients With Type 2 Diabetes

0

10

20

30

40

50

60

70

Aff

ecte

d (

%)

Total C≥200 mg/dL

LDL-C≥100 mg/dL

HDL-C40 mg/dL

Triglycerides≥150 mg/dL

C: cholesterol

Saaddine JB, et al. Ann Intern Med. 2006;144:465-474.

American Diabetes Association Lipid Treatment Goals

Decrease triglycerides to <150 mg/dL Increase HDL to >40 mg/dL in men and >50 mg/dL in women

Diabetes without overt CVD Diabetes with overt CVD

LDL <100 mg/dL30%-40% reduction with

statin for patients >40 years, regardless of baseline LDL

LDL <70 mg/dL an option30%-40% reduction with statin

therapy for all patients

American Diabetes Association. Diabetes Care. 2006;29(suppl 1):S4-S42.

Therapeutic Lifestyle Changes

Adherence to 5 healthful lifestyles reduced coronary events by ≈62% in 16 years

Lifestyle changes reduced coronary events by 57% in men taking medications for HTN or dyslipidemia

Men who adopted 2 lifestyle changes had 27% lower risk than those who did not

HTN: hypertension

Chiuve SE, et al. Circulation. 2006;114:160-167.

LIFESTYLE CHANGES Eliminate tobacco exposure Body mass index <25 kg/m2

30 min/d physical activity Limit alcohol use to 1-2

drinks/d Top 40% of healthy diet

score

Lifestyle Modifications

Physical activityGet regular exerciseReduce “screen time”; increase daily activity

Avoidance of tobacco Weight control

Track weight and caloric intakeReduce food portion size

Healthful diet

Lichtenstein AH, et al. Circulation. 2006;114:82-96.

Dietary Modifications Improve Lipid Profiles

Limit intake of saturated fat, trans fat, and cholesterol1

Choose lean meats, fish, and vegetable alternatives

Choose fat-free and low-fat dairy productsLimit intake of partially hydrogenated fats

Dietary changes can significantly decrease LDL2

1. Lichtenstein AH, et al. Circulation. 2006;114:82-96.2. Appel LJ, et al. JAMA. 2005;294:2455-2464.

-25

-20

-15

-10

-5

0

Effects of Three Healthful Diets*on LDL Levels

All (n = 161)Baseline mean = 129.2 mg/dL

LDL ≥130 mg/dL (n = 75) Baseline mean = 156.7 mg/dL

CARB PROT UNSAT CARB PROT UNSAT

*Each diet: 6% saturated fat; <150 mg/d cholesterol; no trans fat.

Appel LJ, et al. JAMA. 2005;294:2455-2464.

mg

/dL

mg

/dL

-25

-20

-15

-10

-5

0

Key Question

What is your next step if lifestyle changes don’t decrease lipid levels to goal?

1. Use a bile acid sequestrant

2. Use a fibrate

3. Use a statin

4. Use niacin (nicotinic acid)

5. Use ezetimibe

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MRC/BHF Heart Protection Study

-40

-35

-30

-25

-20

-15

-10

-5

0

Coronary Mortality

Nonfatal MI

Major Coronary

Events Stroke

Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.

Red

uct

ion

of

Maj

or

Vas

cula

r E

ven

ts (

%)

MI: myocardial infarctionMRC/BHF: Medical Research Council/British Heart Foundation

ASCOT-LLA Trial

-40

-35

-30

-25

-20

-15

-10

-5

0

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

Nonfatal MI+

Fatal CHDTotal CV Events

Total Coronary

Events Stroke

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

Red

uct

ion

of

Maj

or

Vas

cula

r E

ven

ts (

%)

ASTEROID Trial

Intravascular ultrasound (IVUS) was used to assess coronary atherosclerosis

Rosuvastatin (40 mg/d) for 24 months decreased LDL by 53% and increased HDL by 15%

Significant regression of atherosclerosis was seen

Nissen SE, et al. JAMA. 2006;295:1556-1565.

ASTEROID: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden

Cholesterol Treatment Trialists’ (CTT) Meta-Analysis

-25

-20

-15

-10

-5

0

Baigent C, et al. Lancet. 2005;366:1267-1278.

All-Cause Mortality

Major Vascular Events

Coronary Mortality Stroke

Red

uct

ion

in

In

cid

ence

( %

)

MERCURY II Trial

More high-risk patients reached their LDL target of <100 mg/dL with rosuvastatin (10 or 20 mg/d) than with atorvastatin (10 or 20 mg/d) or simvastatin (20 or 40 mg/d)

Likewise, more patients at very high risk reached their LDL goal of <70 mg/dL with rosuvastatin than with atorvastatin or simvastatin

Ballantyne CM, et al. Am Heart J. 2006;151:975.e1-975.e9.

MERCURY II: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY

Other Lipid-Lowering Drugs

Fibrates can decrease triglycerides and increase HDL levels1-3

Niacin (nicotinic acid) can also decrease triglycerides and increase HDL levels1-3

Ezetimibe can further decrease LDL levels by selectively inhibiting intestinal absorption of cholesterol1,3

Bile acid sequestrants may decrease LDL1-3

Combination therapy may be effective1,3

1. Treat Guidel Med Lett. 2005;3:15-22.2. NCEP ATP III. JAMA. 2001;285:2486-2497.3. Grundy SM, et al. Circulation. 2004;110:227-239.

NCEP ATP IIIDrug Therapy Progression

NCEP ATP III. JAMA. 2001;285:2486-2497.

6 wk 4-6 mo

If goal not met, intensify drug

therapy

6 wk

If goal not met, intensify drug

therapy or refer to lipid

specialist

Begin drug therapy to

decrease LDL

Continue to monitor

response and adherence

Improving Patients’ Adherence

Simplify medication regimensPrescribe fewer pills per day1

Avoid medication switching2

Help patients remember to take medicationsTime pills with events like meals, bedtime3

Recommend pill boxes, personal alarms Teach patients about risks and benefits

Offer educational tools, brochures, Web sitesUse follow-up lipid tests to monitor progress4

1. Iskedjian M, et al. Clin Ther. 2002;24:302-316. 2. Thiebaud P, et al. Am J Manag Care. 2005;11:670-674.3. Branin JJ. Home Health Care Serv Q. 2001;20:1-16.4. Benner JS, et al. Pharmacoeconomics. 2004;22(suppl 3):13-23.

Improving Patients’ Adherence

Medication adherence drops as costs rise1

Ask if patients have prescription drug coverage Identify generic or preferred drugs Urge patients to raise cost problems over time

Depression can reduce adherence2

Look for and ask about signs of depression Treat and/or refer depressed patients

for counseling

1. Shrank WH, et al. Arch Intern Med. 2006;166:332-337.2. Stilley CS, et al. Ann Behav Med. 2004;27:117-124.

Share Decision Making

A patient-clinician partnership based on mutual respect and trust improves medication adherenceAsk patients how they understand their condition

and the need to treat itListen and probe for perceived barriersCustomize your suggestions to their needsEnlist family members as advocates

Piette JD, et al. Arch Intern Med. 2005;165:1749-1755.

Case Study

Case Study

76-year-old white nonsmoking woman History of hypertension, depression Current medications:

Diltiazem 240 mg qdNefazodone 150 mg bid

Examination: Height 5′6″; weight 146 lb; BMI 23.6 kg/m2; BP 139/82 mm Hg; pulse 72 bpm

BMI: body mass index

Laboratory Results

Creatinine: 1.4 mg/dL Lipid panel

Total cholesterol: 245 mg/dLLDL: 156 mg/dLHDL: 59 mg/dLTriglycerides: 148 mg/dL

ATP III: Framingham Point Scores to Estimate 10-Year Risk

Age Points

20-3435-3940-4445-4950-5455-5960-6465-6970-7475-79

-7-30368

10121416

SBP mm Hg

If Untreate

d

<120120-129130-139140-159

160

01234

If Treated

03456

HDL mg/dL Points

6050-5940-49

<40

-1012

Total Cholestero

l

<160160-199200-239240-279

280

048

1113

0368

10

02457

01234

01122

Age 20-39

Age40-49

Age50-59

Age60-69

Age70-79

NCEP ATP III. JAMA. 2001;285:2486-2497.

Point Total

10-Year Risk, %

<99

101112131415161718192021222324

25

<111112234568

1114172227

30

Age 20-39

NonsmokerSmoker

09

Age50-59

04

Age60-69

02

Age70-79

01

Age40-49

07

Age 16

Total C 2

HDL-C 0

Systolic BP (SBP) 4

Smoking status 0

Point total 22

Decision Point

What is this patient’s risk category?

1. High

2. Moderately high

3. Moderate

4. Either moderate or moderately high

5. Lower

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Therapeutic Considerations

Therapeutic lifestyle changesFirst line of treatment Include dietary modification, exercise,

and weight control Lipid-lowering medications1,2

Statins are safe and effective,3-5 and significantly reduce risk of CVD and stroke6-8

Other agents (eg, fibrates, niacin)9

1. Grundy SM, et al. Circulation. 2004;110:227-239.2. Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E.3. Deedwania P, Volkova N. Expert Rev Cardiovasc Ther. 2005;3:453-463.4. Helmy T, et al. MedGenMed. 2005;7:8.5. Pohlel K, et al. Curr Opin Lipidol. 2006;17:54-57.

6. NCEP ATP III. JAMA. 2001;285:2486-2497.7. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.8. Shepherd J, et al. Lancet. 2002;360:1623-1630.9. Rubins HB, et al. N Engl J Med. 1999;341:410-418.

Therapeutic Considerations

Drug interactionsCalcium channel blockers1

Antidepressants2

Others (eg, warfarin)3

Comorbid conditions Regular monitoring of hepatic, renal function

Decreased renal function

1. Herman RJ. CMAJ. 1999;161:1281-1286. 2. Karnik NS, Maldonado JR. Psychosomatics. 2005;46:565-568. 3. Treat Guidel Med Lett. 2005;3:15-22.

Special Populations

Women1

CHD delayed 10 to 15 years versus men Premature CHD risk associated with multiple

risk factors and metabolic syndrome Treatment approach should be similar for

women and men African Americans1

Highest overall CHD mortality rate Asian Indians2,3

Increased risk of metabolic syndrome and CHD versus whites

1. NCEP ATP III. JAMA. 2001;285:2486-2497.2. Misra A, Vikram NK. Curr Sci. 2002;83:1483-1494.3. Enas EA, et al. Indian Heart J. 1996;48:343-353.

Conclusions

Improving patients’ adherence will improve clinical outcomes

Optimal results require both lifestyle and medical interventions

Lipid-lowering therapy must be tailored to the individual patientRisk determines lipid goalsComorbid conditions influence treatment

PCE Takeaways

PCE Takeaways

1. Use risk calculation tools

2. Identify appropriate goals based on risk… and treat to goal!

3. Appreciate the unique profile of diabetic patients with dyslipidemia

4. Address common barriers to adherence and modify treatment regimen accordingly

Key Question

How important are the IVUS data when conveying information linking medical treatment to atherosclerosis regression to patients?1. Extremely important2. Very important3. Somewhat important4. Not very important

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