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Dyslipidemia and Cardiovascular Risk Reduction:
An Evidence-Based ReviewMacRae F. Linton, MD
Professor of Medicine and Pharmacology
Division of Cardiovascular Medicine
Vanderbilt University Medical Center
Nashville, Tennessee
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%
Use your keypad to vote now!
?
Faculty Disclosure
Dr Linton: grants/research support: AstraZeneca, Merck & Co., Inc., Pfizer Inc; honoraria: AstraZeneca, Merck & Co., Inc., Pfizer Inc, Schering-Plough Corporation.
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
Use your keypad to vote now!
?
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
Evaluate risk for CV events10-year risk >20%, CHD Risk Equivalent
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,
especially for very high-risk patients)
1. NCEP ATP III. JAMA. 2001;285:2486-2497.2. Grundy SM, et al. Circulation. 2004;110:227-239.
Non-HDL as a Secondary Target In patients with elevated TGs (≥200 mg/dL),
non-HDL is a secondary target of therapy1,2
Risk CategoryLDL Goal (mg/dL)
Non-HDL Goal (mg/dL)
Low risk0 to 1 risk factor
<160 <190
Moderate to moderately high risk2 risk factors; 10-year risk ≤20%
<130 <160
High riskCHD or CHD risk equivalents; 10-year risk >20%
<100(optional goal <70 for
very high-risk patients)
<130(optional goal <100 for very high-risk patients)
1. NCEP ATP III. JAMA. 2001;285:2486-2497.2. Grundy SM, et al. Circulation. 2004;110:227-239.
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)
≥102 cm (40˝) in men; ≥88 cm (35˝) in women
Europid ≥94 cm (37˝) (men); ≥80 cm (31.5˝) (women)
South Asians≥90 cm (35.5˝) (men); ≥80 cm (31.5˝)
(women)Japanese
≥90 cm (35.5˝) (men); ≥80 cm (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
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
Use your keypad to vote now!
?
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
MRC/BHF Heart Protection Study:Risk Reduction Versus Baseline LDL
-40
-35
-30
-25
-20
-15
-10
-5
0
≥135 mg/dL 116 to <135 mg/dL
<116 mg/dL <100 mg/dL
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Red
uct
ion
in
Ris
k o
fM
ajo
r V
ascu
lar
Eve
nts
(%
)
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
Agents That Affect Lipid Metabolism1,2
1. NCEP ATP III. JAMA. 2001;285:2486-2497. 2. Knopp RH, et al. Eur Heart J. 2003;24:729-741.
Drug Class LDL-C HDL-C TG
Statins 18%-55% 5%-15% 7%-30%
Bile acid sequestrants 15%-30% 3%-5% Variable
Nicotinic acid 5%-25% 15%-35% 20%-50%
Fibric acids Variable 10%-20% 20%-50%
Ezetimibe 18% 1% 2%
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
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 first line of drug treatment and significantly reduce risk of CVD and stroke3-5
Other agents (eg, fibrates, niacin, ezetimibe)1,2,6
1. Grundy SM, et al. Circulation. 2004;110:227-239.2. Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E.3. NCEP ATP III. JAMA. 2001;285:2486-2497.4. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.5. Shepherd J, et al. Lancet. 2002;360:1623-1630.6. Deedwania P, Volkova N. Expert Rev Cardiovasc Ther. 2005;3:453-463.
Therapeutic Considerations
Statins are effective and safe in the elderly1-3
Monitor for side effects (liver, muscle)1,4
Consider drug & food interactions1,4
Consider liver and kidney function1,4
Other agents (eg, fibrates, niacin)1,5
Differences in tolerability among fibrates1
Fibrates have different drug interactions than statins1
Also consider liver and kidney function1
1. Deedwania P, Volkova N. Expert Rev Cardiovasc Ther. 2005;3:453-463.
2. Helmy T, et al. Med Gen Med. 2005;7:8.
3. Pohlel K, et al. Curr Opin Lipidol. 2006;17:54-57.4. Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E.5. 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
Q & A
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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