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Fall 2007Symposia Series

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• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007

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Hypertriglyceridemia and Cardiovascular Disease
Management The Role of Omega-3 Fatty Acids

• Ronald A. Codario, MD
• Clinical Instructor in Medicine
• Thomas Jefferson University Hospital
• University of Pennsylvania Health System
• Philadelphia, Pennsylvania

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How often do you recommend omega-3 fattyacids as
treatment for your patients withhypertriglyceride
mia?

• Frequently
• Sometimes
• Seldom
• Never

4
Faculty Disclosure

• Dr Codario speakers bureau Merck Co., Inc.,
  Novartis Pharmaceuticals Corporation, Reliant
  Pharmaceuticals, Inc., sanofi-aventis, Takeda.

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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

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How confident are you in understanding the
importance of hypertriglyceridemia inassessing
cardiovascular risk?

• Very confident
• Somewhat confident
• Not confident

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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.
8
Assessing CVD RiskThe 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.
9
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.
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Dyslipidemias Are Risk Factors for CVD
Hypertriglyceridemia
Elevated LDL
Small, dense LDL
Atherosclerosis
Low HDL
Diabetes
Hypertension
Insulin resistance
EndothelialDysfunction
Hyperinsulinemia
Hypercoagulability
Visceral adiposity
HDL high-density lipoprotein LDL low-density
lipoprotein. Deedwania PC. Am J Med.
19981051S-3S.
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Dyslipidemias Are Prominent in Metabolic
Syndrome
Risk Factor Defining Level (Adults)
TG 150 mg/dL
HDL-cholesterol Men Women lt40 mg/dL lt50 mg/dL
Waist circumference Men Women gt102 cm (gt40 in) gt88 cm (gt35 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. 20012852486-2497.
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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

NCEP ATP III. JAMA. 20012852486-2497.
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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.
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Elevated TGs at a level requiring
interventionpresent 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
Framingham Heart Study
2.5
Men
Women
2.0
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.
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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.
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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.
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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.
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Treating DyslipidemiasAn 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.
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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
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Why do patients continue to have dyslipidemia
despite efforts to manage blood lipid levels?

1. Patients dont 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

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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
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Causes of Elevated TG Levels

• Acquired Causes
• Overweight/obesity
• Physical inactivity
• 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)
• Hypothyroidism

NCEP ATP III. Circulation. 20021063143-3421.
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Results of studies have shown that statins can
reduce TG levels on average bywhat percentage?

1. 30
2. 55
3. gt60

• NCEP ATP III. Circulation. 20021063143-3421.

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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. 20021063143-3421 2.
   Wierzbicki AS et al. Curr Med Res Opin.
   200319155-168.

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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.
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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.
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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.
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Omega-3 Acid Ethyl EstersHow 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.
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Omega-3 Acid Ethyl Ester Dosing

• 1 g omega-3 acid ethyl ester capsule
  contains465 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.
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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.
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The NCEP ATP III guidelines recommend
drugintervention 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 (lt150 mg/dL)

NCEP ATP III. Circulation. 20021063143-3421.
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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.
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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 lt150
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.
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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.
20021062747-2757.
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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.
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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.
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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.
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Focused Treatment for Hypertriglyceridemia
Serum TG (mg/dL) Primary Goal Secondary Goal Intervention
lt150 Lower LDL None None
150-199 Lower LDL None Lifestyle changes Evaluate for metabolic syndrome
200-499 Lower LDL Lower nonHDL-C Modify lifestyle Evaluate for metabolic syndrome Consider drug therapy
NCEP ATP III. Circulation. 20021063143-3421.
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Focused Treatment for Hypertriglyceridemia
(contd)
Serum TG (mg/dL) Primary Goal Secondary Goal Intervention
gt500 Lower serum TG level to prevent pancreatitis Prevent CHD Modify lifestyle Omega-3 acid ethyl esters, fibrates, niacin Re-evaluate LDL-lowering efforts when TG lt500 mg/dL In extreme cases, no alcohol, very low-fat diet
NCEP ATP III. Circulation. 20021063143-3421.
42
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.
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Case Studies
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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.
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Case Study 1 (contd)

• Framingham score
• 4 if nonsmoker
• 8 if smoker
• Does hypertriglyceridemia present a particular
  risk to this patient?
• Is pharmacotherapy warranted?

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How would you modify treatment to
focusmanagement of the patients
persistentdyslipidemia?

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
Agent ? TG ? HDL ? Risk of Muscle Toxicity if Used With Statin
Gemfibrozil
Fenofibrate
Niacin
Omega-3 acid ethyl esters
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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.
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Case Study 2 (contd)

• Total cholesterol 177 mg/dL
• HDL 27 mg/dL
• LDL 120 mg/dL
• TG 151 mg/dL

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Which of the following would you advise to
manage his dyslipidemia and improve
hiscardiovascular 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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Q A
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PCE Takeaways
53
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

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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

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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

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How likely are you to initiate therapy using
omega-3 fatty acids for your patientswith
hypertriglyceridemia?

1. Very likely
2. Likely
3. Somewhat likely
4. Not likely

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A Reminder and Thank You

• Please be sure to complete your CME/CE evaluation
  form and follow-up questionnaire and bring them
  to the registration desk
• Your CME/CE certificate will be e-mailed to you
  within 4 to 6 weeks
• Thanks for coming!

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Fall 2007Symposia Series

• St

• South San Francisco Conference Center
• San Francisco, California
• November 3, 2007