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Hypertriglyceridemia and Cardiovascular Disease Management: The Role of Omega3 Fatty Acids

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Title: Hypertriglyceridemia and Cardiovascular Disease Management: The Role of Omega3 Fatty Acids


1
Hypertriglyceridemia and Cardiovascular Disease
Management The Role of Omega-3 Fatty Acids
  • Ronald A. Codario, MD
  • Assistant Clinical Professor of Medicine
  • University of Pennsylvania
  • Philadelphia, Pennsylvania

2
Key Question
  • How often do you recommend omega-3 fatty
  • acids as treatment for your patients with
  • hypertriglyceridemia?
  • Frequently
  • Sometimes
  • Seldom
  • Never
  • Use your keypad to vote now!

3
Faculty Disclosure
  • Dr Codario speakers bureau AstraZeneca, Merck
    Co., Inc., Novartis Pharmaceuticals
    Corporation, Reliant Pharmaceuticals, Inc.,
    sanofi-aventis Group.

4
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

5
Key Question
  • How confident are you in understanding
  • the importance of hypertriglyceridemia in
  • assessing cardiovascular risk?
  • Very confident
  • Somewhat confident
  • Not confident
  • Use your keypad to vote now!

6
Cardiovascular Disease (CVD) No. 1 Cause of
Mortality in US Men and Women
Deaths in Thousands, 2002
COPD coronary obstructive pulmonary
disease. American Heart Association. Heart
Disease and Stroke Statistics2005 Update.
7
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. 20012852486-2497.
8
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 subcategories

gt20
High
Moderate
10-20
lt10
Low
CHD coronary heart disease. NCEP ATP III. JAMA
200128524862497.
9
Dyslipidemias Are Risk Factors for CVD
Hypertriglyceridemia
Elevated LDL
Small, dense LDL
Atherosclerosis
Low HDL
Diabetes
Hypertension
Insulin resistance
Endothelial Dysfunction
Hyperinsulinemia
Hypercoagulability
Visceral adiposity
HDL high-density lipoprotein LDL low-density
lipoprotein. Deedwania PC. Am J Med.
19981051S-3S.
10
Dyslipidemias Are Prominent in Metabolic
Syndrome
Diagnosis is established when 3 of these risk
factors are present.
NCEP ATP III. JAMA. 20012852486-2497.
11
Key Question
  • How do the NCEP ATP III guidelines categorize
  • a TG range of 150-199 mg/dL?
  • Very high
  • Borderline high
  • Normal
  • Low-normal
  • Use your keypad to vote now!

NCEP ATP III. JAMA. 20012852486-2497.
12
ATP III Lipid Classifications
  • TG (mg/dL)
  • lt150 Normal
  • 150-199 Borderline high
  • 200-499 High
  • 500 Very high
  • Total cholesterol (mg/dL)
  • lt200 Desirable
  • 200-239 Borderline high
  • 240 High
  • LDL (mg/dL)
  • lt100 Optimal
  • 130-159 Borderline high
  • 160-189 High
  • HDL (mg/dL)
  • lt40 (M) Low
  • lt50 (F) Low
  • 60 High

NCEP ATP III. JAMA. 20012852486-2497.
13
Key Question
  • Elevated TGs at a level requiring intervention
  • present a particular risk for which of the
  • following groups?
  • Women
  • Male athletes with no significant family history
  • Individuals with a family history of early heart
    disease
  • Women using oral contraceptives
  • Use your keypad to vote now!

14
Elevated Triglycerides Increase CHD Risk
Framingham Heart Study
2.5
Women
2.0
Men
1.5
Relative Risk for CHD
1.0
0.5
0.0
50
100
150
200
250
300
350
400
TGs in VLDL and IDL
For every increase in serum TG level of 89
mg/dL, risk of CHD increases 30 in men and 69
in women2
Meta-analysis of 17 prospective studies
VLDL very low density lipoproteins, IDL
intermediate density lipoprotein.
1. Castelli WP. Can J Cardiol. 19884(suppl
A)5A-10A. 2. Hokanson JE. Curr Cardiol Rep.
20024488-493.
15
Increased Risk From TG Is Independent of HDL
17.2
18
Triglycerides (mg/dL)
16
lt200
14
200-299
12
300
Odds Ratio
10
7.9
8
6.7
6.1
5.7
6
4.3
3.7
3.1
4
2.2
1.3
1.0
1.1
2
0
lt30
30-39
40-49
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.
2005451003-1012.
16
HDL-C and Coronary Artery Disease Risk
3.0
2.5
2.0
Relative Risk
1.5
25
1.0
45
0.5
65
HDL-C (mg/dL)
85
0.0
100
160
220
LDL-C (mg/dL)
Data from Framingham Heart Study (Men)
Kwiterovich PO. Am J Cardiol. 19988213Q-21Q.
17
Lipid Profile Guidelines
  • Patients with multiple risk factors are
    candidates for intensified therapy (LDL lt100
    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
    gt199 mg/dL

NCEP ATP III. Circulation. 20021063143-3421.
18
Treating Dyslipidemias An Overview
  • Stratify patients risk for CVD
  • Treat individual abnormalities aggressively and
    proactively
  • Target therapy toward
  • Reducing acquired causes through diet and
    lifestyle modifications
  • Treating associated lipid- and nonlipid-based
    CVD risk factors with lifestyle modifications
    and pharmacotherapy

NCEP ATP III. JAMA. 20012852486-2497.
19
Pharmacotherapy Commonly Used to Reduce CVD Risk
and/or Alter Risk Factors

20
Key Question
  • Why do patients continue to have dyslipidemia
  • despite efforts to manage blood lipid levels?
  • Patients dont adhere to prescribed treatments
  • Managed care formulary restraints
  • Reluctance to use combination therapy
  • Available treatments are not adequate to control
    the range of blood lipids
  • All of the above
  • Use your keypad to vote now!

21
Hypertriglyceridemia and Risk Management
  • Causes
  • Efficacy of pharmacotherapy
  • Treatment strategies
  • Role of omega-3 acid ethyl esters

22
TG-Rich Particles
Chylomicron
  • Non-HDL-C
  • total cholesterol HDL
  • 2. Non-HDL-C is the sum of all the atherogenic
    particles

VLDL
IDL
LDL
HDL
23
Causes of Elevated TG Levels
  • Acquired Causes
  • Overweight/obesity
  • Physical inactivity
  • Smoking
  • Excess alcohol intake
  • High carbohydrate intake (gt60 of total energy)
  • Secondary Causes
  • Diabetes mellitus
  • Chronic renal failure
  • Nephrotic syndrome
  • Cushings disease
  • Lipodystrophy
  • Pregnancy
  • Medication use (eg, corticosteroids,
    beta-blockers, retinoids, thiazide diuretics,
    antiretroviral therapy)

NCEP ATP III. Circulation. 20021063143-3421.
24
Key Question
  • Results of studies have shown that
  • statins can reduce TG levels on average by
  • what percentage?
  • 30
  • 55
  • gt60
  • Use your keypad to vote now!
  • NCEP ATP III. Circulation. 20021063143-3421.

25
Efficacy of Pharmacotherapy
Administer with caution due to risk of myopathy
and rhabdomyolysis.
  • NCEP ATP III. Circulation. 20021063143-3421 2.
    Wierzbicki AS et al. Curr Med Res Opin.
    200319155-168.

26
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.htmOTC
www.cfsan.fda.gov/dms/supplmnt.html.
27
Fibrates Can Lower TG Levels and Increase HDL
  • How do fibrates work? Activate transcriptional
    factors critical for lipid metabolism
    (peroxisome proliferator-activated receptor alpha
    PPAR-a)
  • Benefit Reduce cardiovascular event rates in
    high-risk patients1 with
  • Low LDL (lt125 mg/dL) or
  • Combined dyslipidemia (LDL gt125 TG gt200) 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.
2003261513-1517 2. Grundy SM et al.
Circulation. 2004110227-239.
28
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.
198681245-1255 2. Bays HE et al. Am J Cardiol.
200391667-672 3. Brown BG et al. N Engl J
Med. 20013451583-1592 4. Grundy SM et al.
Circulation. 2004110227-239.
29
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. 1999343191-197
Covington MB. Am Fam Physician. 200470133-140.
Ren B et al. J Biol Chem. 199727226827-26832
Madsen L et al. Lipids. 199934951-963
Willumsen N et al. J Lipid Res.
19933413-22Harris WS et al. Am J Clin Nutr.
199766254-260 Lu G et al. J Nutr Biochem.
199910151-158.
30
Omega-3 Acid Ethyl Ester Dosing
  • 1 g omega-3 acid ethyl ester capsule
    contains 465 mg EPA 375 mg DHA
  • Dose for hypertriglyceridemia (gt499 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.
31
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. 200470133-140.
32
Key Question
  • The NCEP ATP III guidelines recommend drug
  • intervention to reduce TG levels at which level
  • of risk?
  • Very high 500 mg/dL
  • High 200-499 mg/dL
  • Borderline high 150-199 mg/dL
  • Normal lt150 mg/dL
  • Use your keypad to vote now!

NCEP ATP III. Circulation. 20021063143-3421.
33
GISSI-Prevenzione Trial (n 11,324
post-MI) Early Effect on All-Cause Mortality
1.00
Omega-3 Acid Ethyl Esters (850 mg/d)
0.99
0.98
Probability
0.97
0.59 (95 CI, 0.36-0.97) P .037
Control
0.96
0.95
330
210
150
60
0
90
180
270
30
120
240
300
360
Days
Marchioli R et al. Circulation.
20021051897-1903.
34
NCEP ATP III Definitions of Patient Risk
Categories Based on Fasting TG Level
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 2002VII-3-VII-5, Appendix III-A.
35
American Heart Association Recommendations
Kris-Etherton et al. Circulation.
20021062747-2757.
36
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 297611-619.
37
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)
NS
350-401
128-164
P lt.025
P lt.025
P lt.0005
P lt.005
after 48 weeks (NS after 24 weeks)
Durrington PN et al. Heart. 200185544-548.
38
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. 200730S4-S41. Grundy SM et
al. Circulation. 2004110227-239.
39
Focused Treatment for Hypertriglyceridemia
NCEP ATP III. Circulation. 20021063143-3421.
40
Focused Treatment for Hypertriglyceridemia
(contd)
NCEP ATP III. Circulation. 20021063143-3421.
41
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. 200470133-140.
42
Case Studies
43
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.
44
Case Study 1 (contd)
  • Framingham score
  • 4 if nonsmoker
  • 8 if smoker
  • Does hypertriglyceridemia present a particular
    risk to this patient?
  • Is pharmacotherapy warranted?

45
Decision Point
  • How would you modify treatment to focus
  • management of the patients persistent
  • dyslipidemia?
  • Add gemfibrozil
  • Add fenofibrate
  • Add niacin
  • Add omega-3 acid ethyl esters
  • Advise diet modification and exercise only
  • Use your keypad to vote now!

46
Pros and Cons of Therapies to Lower TG Level
47
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.
48
Case Study 2 (contd)
  • Total cholesterol 177 mg/dL
  • HDL 27 mg/dL
  • LDL 120 mg/dL
  • TG 151 mg/dL

49
Decision Point
  • Which of the following would you advise to
  • manage his dyslipidemia and improve his
  • cardiovascular risk profile?
  • Gemfibrozil
  • Fenofibrate
  • Omega-3 acid ethyl esters
  • Fenofibrate/ezetimibe
  • Fenofibrate/omega-3 acid ethyl esters
  • Ezetimibe/low dose statin
  • Use your keypad to vote now!

50
Q A
51
PCE Takeaways
52
PCE Takeaways
  • Dyslipidemias
  • Risk factors for CHD
  • Prominent in metabolic syndrome
  • Hypertriglyceridemia is an independent risk
    factor for CHD
  • Target therapy
  • Reduce acquired causes diet, exercise, smoking
    cessation, alcohol moderation, weight loss,
    prescription medications
  • Pharmacotherapy aimed at specific targets LDL,
    HDL, TG

53
PCE Takeaways
  • 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)
  • If LDL is also elevated, omega-3 acid ethyl
    esters and other agents can be combined with
    statins


54
PCE Takeaways
  • 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

55
Key Question
  • How likely are you to initiate therapy using
  • omega-3 fatty acids for your patients
  • with hypertriglyceridemia?
  • Very likely
  • Likely
  • Somewhat likely
  • Not likely
  • Use your keypad to vote now!
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