Transcript Managing Dyslipidemia - Practicing Clinicians Exchange

Dyslipidemia and Cardiovascular
Risk Reduction:
An Evidence-Based Review
MacRae 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 with
dyslipidemia 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 States
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
 37%
HDL: high-density lipoprotein
1. 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 disease
 Diabetes
 Multiple other risk factors contributing to a
Framingham 10-year risk of CHD >20%
 Other major risk factors
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 lipoprotein
CHD: coronary heart disease
NCEP ATP III. JAMA. 2001;285:2486-2497.
Major Risk Factors
Other 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.
NCEP ATP III Risk Definitions
Optimal
Borderline
High Risk
High Risk
Total
Cholesterol
<200
200-239
≥240
LDL
<100
130-159
160-189
HDL
≥60
40-59
<40
<150
150-199
200-499
Test
Triglycerides
NCEP ATP III. JAMA. 2001;285:2486-2497.
Very High
Risk
≥190
≥500
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 risk
CHD 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
% Patient Success
80
% at goal
70
60
50
40
30
20
10
0
Overall
Low risk
High risk
Risk Groups
Pearson TA, et al. Arch Intern Med. 2000;160:459-467.
CHD
Overall Persistence (%)
Problem: Patients’ Adherence
to Statin Therapy
100
90
80
70
60
50
40
30
20
10
0
9 Months
Huser MA, et al. Adv Ther. 2005;22:163-171.
12 Months
NCEP Guidelines in a Nutshell
 Evaluate risk for CV events
 10-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
CV: cardiovascular
NCEP ATP III. JAMA. 2001;285:2486-2497.
NCEP ATP III 2001
Thresholds for LDL-Lowering Therapy
Low Risk
Moderate Risk
Moderately
High Risk
High Risk
TLC
(mg/dL)
Consider Drug
Therapy (mg/dL)
0-1 risk factor
≥160
≥190
(optional at 160-189)
2 risk factors;
10-year risk <10%
≥130
≥160
2 risk factors;
10-year risk 10%-20%
≥130
≥130
(optional at 100-129)
≥100
≥130
≥100
(optional at <100)
CHD or CHD risk
equivalents;
10-year risk >20%
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





TG: triglyceride
Grundy SM, et al. Circulation. 2004;110:227-239.
NCEP ATP III
Therapeutic Goals for LDL
Risk Category
LDL Goal (mg/dL)
Low risk
0 to 1 risk factor
<160
Moderate risk
2 risk factors; 10-year risk <10%
<130
Moderately high risk
2 risk factors; 10-year risk 10%-20%
High risk
CHD or CHD risk equivalents; 10-year risk >20%
1. NCEP ATP III. JAMA. 2001;285:2486-2497.
2. Grundy SM, et al. Circulation. 2004;110:227-239.
<130
(optional goal <100)
<100
(optional goal <70,
especially for very high-risk
patients)
Non-HDL as a Secondary Target
 In patients with elevated TGs (≥200 mg/dL),
non-HDL is a secondary target of therapy1,2
Risk Category
LDL Goal
(mg/dL)
Non-HDL Goal
(mg/dL)
Low risk
0 to 1 risk factor
<160
<190
Moderate to moderately high risk
2 risk factors;
10-year risk ≤20%
<130
<160
<100
(optional goal <70 for
very high-risk patients)
<130
(optional goal <100 for
very high-risk patients)
High risk
CHD or CHD risk equivalents;
10-year risk >20%
1.
2.
NCEP ATP III. JAMA. 2001;285:2486-2497.
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
NCEP ATP III1
≥3 Components
IDF2
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
≥100
≥100
Components
Fasting plasma
glucose (mg/dL)
IDF: International Diabetes Federation
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.
Prevalence of Metabolic Syndrome:
NHANES III 1988-1994
Percent Affected
50
Men
Women
40
30
20
10
0
20-29
30-39
40-49
50-59
Age (years)
60-69
NHANES III: Third National Health and Nutrition Examination Survey
Ford ES, et al. JAMA. 2002;287:356-359.
70+
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
70
Affected (%)
60
50
40
30
20
10
0
Total C
 200 mg/dL
LDL-C
 100 mg/dL
C: cholesterol
Saaddine JB, et al. Ann Intern Med. 2006;144:465-474.
HDL-C
<40 mg/dL
Triglycerides
 150 mg/dL
American Diabetes Association Lipid
Treatment Goals
Diabetes without overt CVD
Diabetes with overt CVD
LDL <100 mg/dL
30%-40% reduction with
statin for patients >40 years,
regardless of baseline LDL
LDL <70 mg/dL an option
30%-40% reduction with statin
therapy for all patients
 Decrease triglycerides to <150 mg/dL
 Increase HDL to >40 mg/dL in men and >50 mg/dL in women
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 activity
 Get
regular exercise
 Reduce “screen time”; increase daily activity
 Avoidance of tobacco
 Weight control
 Track weight and caloric intake
 Reduce 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 products
 Limit 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.
Effects of Three Healthful Diets*
on LDL Levels
All (n = 161)
LDL ≥130 mg/dL (n = 75)
Baseline mean = 129.2 mg/dL
Baseline mean = 156.7 mg/dL
0
CARB
PROT
UNSAT
CARB
0
-10
-15
-5
mg/dL
mg/dL
-5
-10
-15
-20
-20
-25
-25
*Each diet: 6% saturated fat; <150 mg/d cholesterol; no trans fat.
Appel LJ, et al. JAMA. 2005;294:2455-2464.
PROT
UNSAT
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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Reduction of
Major Vascular Events (%)
MRC/BHF Heart Protection Study
Coronary
Mortality
Nonfatal
MI
Major
Coronary
Events
0
-5
-10
-15
-20
-25
-30
-35
-40
MI: myocardial infarction
MRC/BHF: Medical Research Council/British Heart Foundation
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Stroke
MRC/BHF Heart Protection Study:
Risk Reduction Versus Baseline LDL
Reduction in Risk of
Major Vascular Events (%)
≥135 mg/dL
116 to <135
mg/dL
<116 mg/dL
0
-5
-10
-15
-20
-25
-30
-35
-40
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
<100 mg/dL
Reduction of
Major Vascular Events (%)
ASCOT-LLA Trial
Nonfatal MI
+
Fatal CHD
Total CV
Events
Total
Coronary
Events
Stroke
0
-5
-10
-15
-20
-25
-30
-35
-40
ASCOT-LLA: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
Sever PS, et al. Lancet. 2003;361:1149-1158.
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
ASTEROID: A Study to Evaluate the Effect of Rosuvastatin on Intravascular UltrasoundDerived Coronary Atheroma Burden
Nissen SE, et al. JAMA. 2006;295:1556-1565.
Reduction in Incidence ( %)
Cholesterol Treatment Trialists’ (CTT)
Meta-Analysis
All-Cause
Mortality
Major
Vascular
Events
0
-5
-10
-15
-20
-25
Baigent C, et al. Lancet. 2005;366:1267-1278.
Coronary
Mortality
Stroke
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
MERCURY II: Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY
Ballantyne CM, et al. Am Heart J. 2006;151:975.e1-975.e9.
Agents That Affect Lipid Metabolism1,2
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%
Variable
 10%-20%
 20%-50%
 18%
 1%
 2%
Fibric acids
Ezetimibe
1. NCEP ATP III. JAMA. 2001;285:2486-2497.
2. Knopp RH, et al. Eur Heart J. 2003;24:729-741.
NCEP ATP III
Drug Therapy Progression
6 wk
Begin drug
therapy to
decrease LDL
6 wk
If goal not met,
intensify drug
therapy
NCEP ATP III. JAMA. 2001;285:2486-2497.
If goal not met,
intensify drug
therapy or
refer to lipid
specialist
4-6 mo
Continue
to monitor
response and
adherence
Improving Patients’ Adherence
 Simplify medication regimens
fewer pills per day1
 Avoid medication switching2
 Help patients remember to take medications
 Time pills with events like meals, bedtime3
 Recommend pill boxes, personal alarms
 Teach patients about risks and benefits
 Offer educational tools, brochures, Web sites
 Use follow-up lipid tests to monitor progress4
 Prescribe
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 adherence
 Ask patients how they understand their condition
and the need to treat it
 Listen and probe for perceived barriers
 Customize your suggestions to their needs
 Enlist 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 qd
 Nefazodone 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/dL
 LDL: 156 mg/dL
 HDL: 59 mg/dL
 Triglycerides: 148 mg/dL
ATP III: Framingham Point
Scores to Estimate 10-Year Risk
Age
Points
20-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-79
-7
-3
0
3
6
8
10
12
14
16
Total
Age
Cholesterol 20-39
<160
160-199
200-239
240-279
280
0
4
8
11
13
SBP
If
If
mm Hg Untreated Treated
<120
120-129
130-139
140-159
160
0
1
2
3
4
0
3
4
5
6
HDL
mg/dL
Points
60
50-59
40-49
<40
-1
0
1
2
Nonsmoker
Smoker
Age
40-49
Age
50-59
Age
60-69
Age
70-79
0
9
0
7
0
4
0
2
0
1
Age
Total C
HDL-C
Systolic BP (SBP)
Smoking status
Point total
Age
40-49
Age
50-59
Age
60-69
Age
70-79
0
3
6
8
10
0
2
4
5
7
0
1
2
3
4
0
1
1
2
2
NCEP ATP III. JAMA. 2001;285:2486-2497.
Age
20-39
16
2
0
4
0
22
Point
Total
<9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
10-Year
Risk, %
<1
1
1
1
1
2
2
3
4
5
6
8
11
14
17
22
27
30
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 changes
 First
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.
2.
3.
4.
5.
6.
Grundy SM, et al. Circulation. 2004;110:227-239.
Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E.
NCEP ATP III. JAMA. 2001;285:2486-2497.
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
Shepherd J, et al. Lancet. 2002;360:1623-1630.
Deedwania P, Volkova N. Expert Rev Cardiovasc Ther. 2005;3:453-463.
Therapeutic Considerations
 Statins are effective and safe in the elderly1-3
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
 Monitor
1.
2.
Deedwania P, Volkova N. Expert Rev Cardiovasc
Ther. 2005;3:453-463.
Helmy T, et al. Med Gen Med. 2005;7:8.
3.
4.
5.
Pohlel K, et al. Curr Opin Lipidol. 2006;17:54-57.
Stone NJ, et al. Am J Cardiol. 2005;96:53E-59E.
Rubins HB, et al. N Engl J Med. 1999;341:410-418.
Therapeutic Considerations
 Drug interactions
channel blockers1
 Antidepressants2
 Others (eg, warfarin)3
 Comorbid conditions
 Regular monitoring of hepatic, renal function
 Decreased renal function
 Calcium
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 patient
 Risk determines lipid goals
 Comorbid 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 important
2. Very important
3. Somewhat important
4. Not very important
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