Transcript Document

Hypertriglyceridemia and
Cardiovascular Disease Management:
The Role of Omega-3 Fatty Acids
William S. Harris, PhD
Research Professor of Medicine
Sanford School of Medicine
University of South Dakota
Director, Nutrition and Metabolic Disease Research Institute
Sanford Research/University of South Dakota
Sioux Falls, South Dakota
Key Question
How often do you recommend omega-3 fatty
acids as treatment for your patients with
hypertriglyceridemia?
1. Frequently
2. Sometimes
3. Seldom
4. Never
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Faculty Disclosure
 Dr Harris: advisor, grants/research support:
Monsanto Company; advisor, grants/research
support, speakers bureau: Reliant Pharmaceuticals,
Inc.; scientific advisor: OmegaMetrix, LLC.
Learning Objectives:
Hypertriglyceridemia
 Discuss the etiology of hypertriglyceridemia
and its potential impact on CVD outcomes
 Develop treatment plans to help patients achieve
LDL-C, HDL-C, and triglyceride targets through
diet, exercise, and drug therapy
 Assess the role of omega-3 acid ethyl esters in
management of hypertriglyceridemia with regard
to efficacy, safety, and concomitant drug use
Key Question
How confident are you in understanding
the importance of hypertriglyceridemia in
assessing cardiovascular risk?
1. Very confident
2. Somewhat confident
3. Not confident
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Cardiovascular Disease (CVD): No. 1
Cause of Mortality in US Men and Women
Deaths in Thousands, 2002
500
Males
Females
400
300
200
100
0
CVD
Cancer
COPD
Diabetes
COPD = coronary obstructive pulmonary disease.
American Heart Association. Heart Disease and Stroke Statistics—2005 Update.
Assessing CVD Risk:
The Cornerstone of Treatment
 Risk factors often cluster in predisposed individuals
 CVD risk increases along with the number
of abnormalities
 Identification of 1 risk factor should prompt the
search for others and signal initiation of proactive,
aggressive risk-reduction strategies
NCEP ATP III. JAMA. 2001;285:2486-2497.
Framingham Point System for
Grading Cardiovascular Risk
 Risk score based on sum of graded risk factors that
defines a 10-year hard CHD (myocardial infarction +
CHD death) risk percentage
 10-year risk
>20%
subcategories:
High
10%-20%
<10%
CHD = coronary heart disease.
NCEP ATP III. JAMA 2001;285:2486–2497.
Moderate
Low
Dyslipidemias Are Risk Factors for CVD
Hypertriglyceridemia
Elevated LDL
Small, dense LDL
Low HDL
Atherosclerosis
Diabetes
Hypertension
Insulin resistance
Hyperinsulinemia
Hypercoagulability
Visceral adiposity
HDL = high-density lipoprotein; LDL = low-density lipoprotein.
Deedwania PC. Am J Med. 1998;105:1S-3S.
Endothelial
Dysfunction
Dyslipidemias Are Prominent
in Metabolic Syndrome*
Risk Factor
Defining Level (Adults)
TG
≥150 mg/dL
HDL-cholesterol
 Men
 Women
<40 mg/dL
<50 mg/dL
Waist circumference
 Men
 Women
>102 cm (>40 in)
>88 cm (>35 in)
Blood pressure
≥130/85 mm Hg
Fasting glucose
≥100 mg/dL
* Diagnosis is established when ≥3 of these risk factors are present.
NCEP ATP III. JAMA. 2001;285:2486-2497.
Key Question
How do the NCEP ATP III guidelines categorize
a TG range of 150-199 mg/dL?
1. Very high
2. Borderline high
3. Normal
4. Low-normal
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NCEP ATP III. JAMA. 2001;285:2486-2497.
?
ATP III Lipid Classifications
 Total cholesterol (mg/dL)
<200
200-239
≥240
Desirable
Borderline high
High
 LDL (mg/dL)
<100
130-159
160-189
Optimal
Borderline high
High
 HDL (mg/dL)
<40 (M)
<50 (F)
≥60
Low
Low
High
NCEP ATP III. JAMA. 2001;285:2486-2497.
TG (mg/dL)
<150
150-199
200-499
≥500
Normal
Borderline high
High
Very high
Key Question
Elevated TGs at a level requiring intervention
present a particular risk for which of the
following groups?
1. Women
2. Male athletes with no significant family history
3. Individuals with a family history of early
heart disease
4. Women using oral contraceptives
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Elevated Triglycerides
Increase CHD Risk
Relative Risk for CHD
Framingham Heart Study
2.5
Women
Men
2.0
1.5
1.0
0.5
0.0
50
100
150
200
250
300
350
400
TGs in VLDL and IDL
Meta-analysis of 17
prospective studies
For every increase in serum TG level of
89 mg/dL, risk of CHD increases 30% in
men and 69% in women2
VLDL = very low density lipoproteins, IDL = intermediate density lipoprotein.
1. Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.
2. Hokanson JE. Curr Cardiol Rep. 2002;4:488-493.
Odds Ratio
Increased Risk From TG Is
Independent of HDL
18
16
14
12
10
8
6
4
2
0
17.2
Triglycerides (mg/dL)
<200
200-299
≥300
5.7 6.1
2.2
<30
7.9
6.7
3.1
4.3
3.7
1.3
30-39
40-49
1.0 1.1
50+
HDL (mg/dL)
TG levels associated with CAD risk are graded and independent.
Lipids analyzed from 653 patients with premature familial CAD and 1029 control subjects.
Hopkins PN et al. J Am Coll Cardiol. 2005;45:1003-1012.
HDL-C and Coronary Artery
Disease Risk
Relative Risk
3.0
2.5
2.0
1.5
25
1.0
45
0.5
65
85
0.0
100
160
LDL-C (mg/dL)
Data from Framingham Heart Study (Men)
Kwiterovich PO. Am J Cardiol. 1998;82:13Q-21Q.
220
HDL-C
(mg/dL)
Lipid Profile Guidelines
 Patients with multiple risk factors are candidates




for intensified therapy (LDL <100 mg/dL)
Diabetes, aortic aneurysm, symptomatic carotid
disease, and peripheral vascular disease are
coronary risk equivalents
Complete lipid profile (TC, LDL, HDL, TG) is the
preferred initial test
More frequent tests for persons with multiple
CHD risk factors
Recommend treatment beyond LDL lowering
for TG >199 mg/dL
NCEP ATP III. Circulation. 2002;106:3143-3421.
Treating Dyslipidemias:
An Overview
 Stratify patient’s risk for CVD
 Treat individual abnormalities aggressively
and proactively
 Target therapy toward:
 Reducing acquired causes through diet and
lifestyle modifications
 Treating associated lipid- and non–lipid-based
CVD risk factors with lifestyle modifications
and pharmacotherapy
NCEP ATP III. JAMA. 2001;285:2486-2497.
Pharmacotherapy Commonly Used to
Reduce CVD Risk and/or Alter Risk Factors
Therapeutic Target
Drug Class/Examples
Preventive CVD risk reduction





Aspirin (low-dose)
Omega-3 fatty acids
Statins
Thiazolidinediones
ACE inhibitors (ramipril)
LDL-C

Statins
HDL-C


Fibrates
Niacin
TG



Fibrates
Omega-3 acid ethyl esters
Niacin
Weight loss/management (long-term)

Orlistat
Insulin resistance


Thiazolidinediones
Metformin
Key Question
Why do patients continue to have dyslipidemia
despite efforts to manage blood lipid levels?
1. Patients don’t adhere to prescribed treatments
2. Managed care formulary restraints
3. Reluctance to use combination therapy
4. Available treatments are not adequate to control
the range of blood lipids
5. All of the above
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Hypertriglyceridemia
and Risk Management
 Causes
 Efficacy of pharmacotherapy
 Treatment strategies
 Role of omega-3 acid ethyl esters
TG-Rich Particles
Chylomicron
VLDL
1. Non-HDL-C =
total cholesterol – HDL
IDL
2. Non-HDL-C is the sum
of all the atherogenic
particles
LDL
HDL
Causes of Elevated TG Levels
 Acquired Causes





Overweight/obesity
Physical inactivity
Smoking
Excess alcohol intake
High carbohydrate intake
(>60% of total energy)
NCEP ATP III. Circulation. 2002;106:3143-3421.
 Secondary Causes







Diabetes mellitus
Chronic renal failure
Nephrotic syndrome
Cushing’s disease
Lipodystrophy
Pregnancy
Medication use (eg,
corticosteroids, beta-blockers,
retinoids, thiazide diuretics,
antiretroviral therapy)
Key Question
Results of studies have shown that
statins can reduce TG levels on average by
what percentage?
1. ≤30%
2. ≤55%
3. >60%
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NCEP ATP III. Circulation. 2002;106:3143-3421.
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Efficacy of Pharmacotherapy
Drug
Reduction in TG Level
Statins1
Up to 30%
Fibrates1
20%-50%
Niacin1
20%-50%
Fish oil (omega-3 acid ethyl
esters)1
30%-40%
Fibrate + statin2*
~40%
Niacin + statin1
~40%
*Administer with caution due to risk of myopathy and rhabdomyolysis.
1. NCEP ATP III. Circulation. 2002;106:3143-3421; 2. Wierzbicki AS et al. Curr Med Res Opin.
2003;19:155-168.
What Are the Different Types of Treatment
That Can Lower Serum TG?
 Prescription drugs
 Require
a prescription
 Over-the-counter (OTC) drugs
 FDA considers them safe and effective for use
without a prescription to treat a medical problem
 Dietary supplement
 Product taken by mouth that contains a "dietary
ingredient" intended to supplement the diet; does
not require a prescription
www.fda.gov/cder/drugsatfda/glossary.htm#OTC; www.cfsan.fda.gov/~dms/supplmnt.html.
Fibrates Can Lower TG Levels
and Increase HDL
 How do fibrates work? Activate transcriptional
factors critical for lipid metabolism (peroxisome proliferatoractivated receptor alpha [PPAR-α])
 Benefit: Reduce cardiovascular event rates in high-risk
patients1 with:
 Low LDL (<125 mg/dL) or
 Combined dyslipidemia (LDL >125 + TG >200) or
 Typical diabetic or metabolic syndrome dyslipidemias
 Fenofibrate Combinations:
 With statins in patients with high TG or low HDL once
LDL is at goal.2
 With ezetimibe in patients intolerant of statins
1. Robins et al. Diabetes Care. 2003;26:1513-1517; 2. Grundy SM et al. Circulation. 2004;110:227-239.
Niacin for Lipid Management
 Raises HDL-C levels and reduces CHD risk,
used alone or in combination with statins1-3
 Recommended by NCEP ATP III in combination
with statins for patients with high TG or low HDL4
 Side effects include flushing, dizziness, palpitations,
tachycardia, gout, hyperglycemia, and nausea
1. Canner PL et al. J Am Coll Cardiol. 1986;8:1245-1255; 2. Bays HE et al. Am J Cardiol.
2003;91:667-672; 3. Brown BG et al. N Engl J Med. 2001;345:1583-1592;
4. Grundy SM et al. Circulation. 2004;110:227-239.
Omega-3 Acid Ethyl Esters:
How Do They Lower TG?
 How do they work?

Inhibit synthesis of VLDL and TG in the liver
 Increase rate of hepatic fatty acid oxidation
 Benefit
 Reduce serum TG; lower risk of cardiac sudden death and
all-cause mortality; mildly lower BP; reduce inflammatory
and thrombotic risk
 How used?
 1-4 g/d by mouth, alone or combined with statin; no drug
interactions or clinically important adverse effects
Berge RK et al. Biochem J. 1999;343:191-197; Covington MB. Am Fam Physician. 2004;70:133-140.
Ren B et al. J Biol Chem. 1997;272:26827-26832; Madsen L et al. Lipids. 1999;34:951-963; Willumsen
N et al. J Lipid Res. 1993;34:13-22;Harris WS et al. Am J Clin Nutr. 1997;66:254-260; Lu G et al.
J Nutr Biochem. 1999;10:151-158.
Omega-3 Acid Ethyl Ester Dosing
 1 g omega-3 acid ethyl ester capsule contains:
465 mg EPA + 375 mg DHA
 Dose for hypertriglyceridemia (>499 mg/dL)
 4 g: 4 capsules once a day or 2 capsules twice
a day with or without meals
DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid.
Available at: www.omacorrx.com/HCP-OMACOR/OMACOR_Dosing.html.
Accessed February 13, 2007.
Clinical Benefits of
Omega-3 Fatty Acids
Evidence supports use:
 Hypertriglyceridemia (2-4 g/d)
 Secondary CVD prevention (fish oil capsules)
 Rheumatoid arthritis (mild effect)
 Hypertension (mild effect)
Covington MB. Am Fam Physician. 2004;70:133-140.
Key Question
The NCEP ATP III guidelines recommend drug
intervention to reduce TG levels at which level
of risk?
1. Very high
≥500 mg/dL
2. High
200-499 mg/dL
3. Borderline high
150-199 mg/dL
4. Normal
<150 mg/dL
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NCEP ATP III. Circulation. 2002;106:3143-3421.
?
GISSI-Prevenzione Trial (n = 11,324 post-MI)
Early Effect on All-Cause Mortality
1.00
Omega-3 Acid
Ethyl Esters
(850 mg/d)
Probability
0.99
0.98
0.97
0.59
(95% CI, 0.36-0.97)
P = .037
Control
0.96
0.95
0
30
60
90
120
150
180
Days
Marchioli R et al. Circulation. 2002;105:1897-1903.
210
240
270
300
330
360
NCEP ATP III Definitions of Patient Risk
Categories Based on Fasting TG Level
Patient Risk Category
Fasting TG Level
(mg/dL)
Very high
≥500
High
200-499
Borderline high
150-199
Normal
<150
National Institutes of Health. Third Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III). NIH Publication No. 02-5215. Bethesda, Md: National Institutes of Health;
2002:VII-3-VII-5, Appendix III-A.
American Heart Association
Recommendations
Patient Population
Recommendation
No documented
coronary disease
Eat a variety of fish (preferably oily) at
least twice weekly (salmon; mackerel; trout; herring;
sardines; fresh, not canned, tuna; swordfish,
anchovies; carp). Include foods rich in alpha-linolenic
acid (flaxseed, canola, soybean, walnuts)
Documented
coronary disease
Consume approximately 1 g EPA
plus DHA daily, preferably from oily fish. EPA/DHA
supplements may be used in consultation with a
health care provider
Hypertriglyceridemia
Consume 2-4 g of EPA plus
DHA daily in capsules by prescription
Kris-Etherton et al. Circulation. 2002;106:2747-2757.
American Heart Association Evidence-Based
Guidelines for Prevention of CVD in Women:
2007 Update
 As many as 20% of all coronary events in women
occur in the absence of traditional risk factors
 Clinical recommendations
 As an adjunct to diet, omega-3 fatty acids
in capsule form (approximately 850-1000 mg
EPA and DHA) may be considered in women
with CHD
 Higher doses (2-4 g) may be used for treatment
of women with high TG levels
Ridker PM et al. JAMA. 2007; 297:611-619.
Omega-3 Acid Ethyl Esters Improve the Lipid
Profile in Patients With High TG on Simvastatin
Simvastatin 10-40 mg/d (average 32 mg/d)
TG
VLDL
Non-HDL
TC
LDL
HDL
20%
NS
350-401
128-164
10%
1.3%
0.1%
0%
-4.4%
-10%
-10.2%
-15.7%
P <.025
-8.0%
P <.025*
Simvastatin + Placebo, n = 25
-29.0%
P <.0005
-40%
5.6%
-1.4%
-20%
-30%
1.7%
12.8%
-39.0%
P <.005
*after 48 weeks (NS after 24 weeks)
Durrington PN et al. Heart. 2001;85:544-548.
Simvastatin + Omega-3, n = 21
NCEP ATP III Recommendations and ADA
Standards of Care for Treating Dyslipidemias
 Consider adding a fenofibrate, omega-3 acid ethyl
esters, or niacin in patients with elevated TG
or low HDL after patient has achieved the LDL
goal with statin therapy
 Combination therapy using statins and other
lipid-lowering agents may be necessary
ADA. Diabetes Care. 2007;30:S4-S41. Grundy SM et al. Circulation. 2004;110:227-239.
Focused Treatment for
Hypertriglyceridemia
Serum TG
(mg/dL)
Primary
Goal
<150
Lower LDL
None
 None
150-199
Lower LDL
None
 Lifestyle changes
Secondary Goal
Intervention
 Evaluate for metabolic
syndrome
200-499
Lower LDL
Lower non–HDL-C
 Modify lifestyle
 Evaluate for metabolic
syndrome
 Consider drug therapy
NCEP ATP III. Circulation. 2002;106:3143-3421.
Focused Treatment for
Hypertriglyceridemia (cont’d)
Serum TG
(mg/dL)
Primary
Goal
Secondary
Goal
>500
Lower
serum TG
level to
prevent
pancreatitis
Prevent CHD
NCEP ATP III. Circulation. 2002;106:3143-3421.
Intervention
 Modify lifestyle
 Omega-3 acid ethyl esters,
fibrates, niacin
 Re-evaluate LDL-lowering
efforts when TG <500 mg/dL
 In extreme cases, no alcohol,
very low-fat diet
Summary: Omega-3 Fatty Acids
and Hypertriglyceridemia
 Omega-3 fatty acids from fish protect against
heart disease
 A dose of 4 g/d (acid ethyl esters) effectively
lowers TG
 Can be safely combined with statins
 Have no known drug-drug interactions
 May prolong bleeding time in some patients
 Are not contaminated with mercury
 Endorsed by the American Heart Association
Covington MB. Am Fam Physician. 2004;70:133-140.
Case Studies
Case Study 1
 Woman aged 63 years with a history of hypertension




and hypercholesterolemia
Current medications: ramipril 10 mg/d;
simvastatin 40 mg/d
BMI 33; waist 36 inches; BP 128/82 mm Hg
FBS, TSH: normal
Blood lipids
 Total cholesterol: 165 mg/dL
 HDL: 35 mg/dL
 LDL: 100 mg/dL
 TG: 392 mg/dL
FBS = fasting blood sugar; TSH = thyroid-stimulating hormone.
Case Study 1 (cont’d)
 Framingham score
 4%
if nonsmoker
 8% if smoker
 Does hypertriglyceridemia present
a particular risk to this patient?
 Is pharmacotherapy warranted?
Decision Point
How would you modify treatment to focus
management of the patient’s persistent
dyslipidemia?
1. Add gemfibrozil
2. Add fenofibrate
3. Add niacin
4. Add omega-3 acid ethyl esters
5. Advise diet modification and exercise only
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Pros and Cons of Therapies to Lower
TG Level
↑ Risk of Muscle Toxicity
if Used With Statin
↓ TG
↑ HDL
Gemfibrozil
+
+
++++
Fenofibrate
+
+
+
Niacin
+
+++
+
Omega-3 acid
ethyl esters
+
+
—
Agent
Case Study 2
 Man aged 40 years; father had MI at age 40
 BMI 25 kg/m2; waist 34 in; BP 126/82 mm Hg
 EBCT: calcium score 125
 Thallium stress test: small, reversible abnormality
of inferior wall
 FBS and TSH: normal
 Patient had severe flushing and gout
with niacin-ER, backache with simvastatin
EBCT = electron beam computed tomography.
Case Study 2 (cont’d)
 Total cholesterol: 177 mg/dL
 HDL: 27 mg/dL
 LDL: 120 mg/dL
 TG: 151 mg/dL
Decision Point
Which of the following would you advise to
manage his dyslipidemia and improve his
cardiovascular risk profile?
1. Gemfibrozil
2. Fenofibrate
3. Omega-3 acid ethyl esters
4. Fenofibrate/ezetimibe
5. Fenofibrate/omega-3 acid ethyl esters
6. Ezetimibe/low dose statin
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PCE Takeaways
PCE Takeaways
1. Dyslipidemias
 Risk factors for CHD
 Prominent in metabolic syndrome
2. Hypertriglyceridemia is an independent risk
factor for CHD
3. Target therapy
 Reduce acquired causes: diet, exercise, smoking
cessation, alcohol moderation, weight loss,
prescription medications
 Pharmacotherapy aimed at specific targets:
LDL, HDL, TG
PCE Takeaways (cont’d)
4. After lifestyle interventions, a variety of drugs
can be used to treat hypertriglyceridemia
 Niacin
 Fibrates
 Omega-3 acid ethyl esters
 Statins (especially rosuvastatin, atorvastatin,
simvastatin)
5. If LDL is also elevated, omega-3 acid ethyl esters
and other agents can be combined with statins
PCE Takeaways (continued)
 CHD is the number one killer of women
 CHD risks are increased in women with diabetes
or metabolic syndrome
 While LDL lowering is the primary target to
reduce CHD morbidity and mortality, it does
not remove all risk
 The majority of women are still not aware of the
substantial risks associated with dyslipidemia
Key Question
How likely are you to initiate therapy using
omega-3 fatty acids for your patients
with hypertriglyceridemia?
1. Very likely
2. Likely
3. Somewhat likely
4. Not likely
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