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

Key Question

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

1. Frequently

2. Sometimes

3. Seldom

4. Never

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Faculty Disclosure

Dr Codario: speakers bureau: AstraZeneca, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Reliant Pharmaceuticals, Inc., sanofi-aventis Group.

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 inassessing cardiovascular risk?

1. Very confident

2. Somewhat confident

3. Not confident

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COPD = coronary obstructive pulmonary disease.American Heart Association. Heart Disease and Stroke Statistics—2005 Update.

Cardiovascular Disease (CVD): No. 1 Cause of Mortality in US Men and Women

0

100

200

300

400

500

CVD Cancer COPD Diabetes

Males

Females

Deaths in Thousands, 2002

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 subcategories:

<10%

10%-20%

>20%

Low

Moderate

High

CHD = coronary heart disease.NCEP ATP III. JAMA 2001;285:2486–2497.

Dyslipidemias Are Risk Factors for CVD

HDL = high-density lipoprotein; LDL = low-density lipoprotein.Deedwania PC. Am J Med. 1998;105:1S-3S.

Elevated LDL

Small, dense LDL

Low HDL

Diabetes

Hypertension

Insulin resistance

Hyperinsulinemia

Hypercoagulability

Atherosclerosis

EndothelialDysfunction

Visceral adiposity

Hypertriglyceridemia

Dyslipidemias Are Prominent in Metabolic Syndrome*

NCEP ATP III. JAMA. 2001;285:2486-2497.

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.

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.

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ATP III Lipid Classifications

Total cholesterol (mg/dL)<200 Desirable200-239 Borderline high≥240 High

LDL (mg/dL)<100 Optimal130-159 Borderline high160-189 High

HDL (mg/dL)<40 (M) Low<50 (F) Low≥60 High

TG (mg/dL)<150 Normal150-199 Borderline

high200-499 High≥500 Very high

NCEP ATP III. JAMA. 2001;285:2486-2497.

Key Question

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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1. Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A. 2. Hokanson JE. Curr Cardiol Rep. 2002;4:488-493.

Elevated Triglycerides Increase CHD Risk

For every increase in serum TG level of 89 mg/dL, risk of CHD increases 30% in men and 69% in women2

Rel

ativ

e R

isk

for

CH

D

TGs in VLDL and IDL

MenWomen

Framingham Heart Study

Meta-analysis of 17 prospective studies

0.0

0.5

1.0

1.5

2.0

2.5

50 100 150 200 250 300 350 400

VLDL = very low density lipoproteins, IDL = intermediate density lipoprotein.

Increased Risk From TG Is Independent of HDL

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.

TG levels associated with CAD risk are graded and independent.

0

2

4

6

8

10

12

14

16

18

<30 30-39 40-49 50+

<200

200-299

≥300

HDL (mg/dL)

Od

ds

Rat

io

5.7 6.1

17.2

2.23.1

4.3

1.3

3.7

6.7

1.0 1.1

7.9

Triglycerides (mg/dL)

HDL-C and Coronary Artery Disease Risk

Kwiterovich PO. Am J Cardiol. 1998;82:13Q-21Q.

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Rel

ativ

e R

isk

100 160 220

LDL-C (mg/dL)

8565

4525

HDL-C(mg/dL)

Data from Framingham Heart Study (Men)

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 treatments2. Managed care formulary restraints3. Reluctance to use combination therapy4. Available treatments are not adequate to control

the range of blood lipids5. 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

IDL

LDL

1. Non-HDL-C = total cholesterol – HDL

2. Non-HDL-C is the sum of all the atherogenic particles

HDL

Causes of Elevated TG Levels

Acquired Causes Overweight/obesity Physical inactivity Smoking Excess alcohol intake High carbohydrate intake

(>60% of total energy)

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)

NCEP ATP III. Circulation. 2002;106:3143-3421.

Key Question

Results of studies have shown that statins can reduce TG levels on average bywhat 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

1. NCEP ATP III. Circulation. 2002;106:3143-3421; 2. Wierzbicki AS et al. Curr Med Res Opin. 2003;19:155-168.

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.

What Are the Different Types of Treatment That Can Lower Serum TG?

Prescription drugsRequire 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 proliferator-activated 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 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 <150 mg/dL

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NCEP ATP III. Circulation. 2002;106:3143-3421.

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GISSI-Prevenzione Trial (n = 11,324 post-MI)

Early Effect on All-Cause Mortality

Marchioli R et al. Circulation. 2002;105:1897-1903.

1.00

0.99

0.98

0.97

0.96

0.95

Pro

bab

ilit

y

330210150600 90 180 270

Days

30 120 240 300 360

0.59 (95% CI, 0.36-0.97)

P = .037

Omega-3 Acid Ethyl Esters (850 mg/d)

Control

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; 2002:VII-3-VII-5, Appendix III-A.

Patient Risk CategoryFasting TG Level

(mg/dL)

Very high ≥500

High 200-499

Borderline high 150-199

Normal <150

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 recommendationsAs 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

Durrington PN et al. Heart. 2001;85:544-548.

*after 48 weeks (NS after 24 weeks)

-4.4%-1.4%

5.6%0.1% 1.7%1.3%

12.8%

-8.0%-10.2%

-15.7%

-39.0%

-29.0%

-40%

-30%

-20%

-10%

0%

10%

20%

TG VLDL Non-HDL TC LDL HDL

Simvastatin + Placebo, n = 25

Simvastatin + Omega-3, n = 21P <.0005

P <.005

P <.025P <.025*

NS350-401 128-164

Simvastatin 10-40 mg/d (average 32 mg/d)

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

NCEP ATP III. Circulation. 2002;106:3143-3421.

Serum TG(mg/dL)

Primary Goal

Secondary Goal Intervention

<150 Lower LDL None None

150-199 Lower LDL None Lifestyle changes Evaluate for metabolic

syndrome

200-499 Lower LDL Lower non–HDL-C Modify lifestyle Evaluate for metabolic

syndrome Consider drug therapy

Focused Treatment for Hypertriglyceridemia (cont’d)

NCEP ATP III. Circulation. 2002;106:3143-3421.

Serum TG(mg/dL)

Primary Goal

Secondary Goal

Intervention

>500 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 <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 score4% if nonsmoker8% if smoker

Does hypertriglyceridemia present a particular risk to this patient?

Is pharmacotherapy warranted?

Decision Point

How would you modify treatment to focusmanagement of the patient’s 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

+ + —

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 hiscardiovascular risk profile?

1. Gemfibrozil2. Fenofibrate3. Omega-3 acid ethyl esters4. Fenofibrate/ezetimibe5. Fenofibrate/omega-3 acid ethyl esters6. Ezetimibe/low dose statin

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Q & A

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

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

6. CHD is the number one killer of women

7. 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

8. 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 patientswith hypertriglyceridemia?

1. Very likely

2. Likely

3. Somewhat likely

4. Not likely

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