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
Cardiovascular Disease (CVD): No. 1 Cause of Mortality in US Men and Women
Deaths in Thousands, 2002
Cardiovascular Disease (CVD): The Number One Cause of Mortality in Men and Women
Cardiovascular disease (CVD), which includes hypertension, coronary heart disease (CHD), stroke, and congestive heart failure (CHF), has ranked as the number one cause of death in the United States every year since 1900, with 1918—year of the great influenza epidemic--the only exception.
In 2002, CVD claimed roughly as many lives as cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, influenza, and pneumonia combined.
Reference:
American Heart Association. Heart Disease and Stroke Statistics—2005. Dallas: American Heart Association, 2005.
COPD = coronary obstructive pulmonary disease.
American Heart Association. Heart Disease and Stroke Statistics—2005 Update.
*American Heart Association Heart and Stroke Statistical Update. Dallas, Texas: American Heart Association, Available at: and Accessed March 14, 2001.

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
Risk factors for CVD often cluster in predisposed individuals. Patients with dyslipidemias may present various combinations of risk factors and levels of risk.
The National Cholesterol Education Program Third Adult Treatment Panel (NCEP ATP III) recommends that identification of one CVD risk factor should trigger a search for others.
The results of several large-scale studies, including the NHANES, the Framingham Offspring Study, the Scandinavian Simvastatin Survival Study (4S), and the Hoorn Study, indicate that CVD risk increases as the number of abnormalities increases.
Therefore, the presence of even one risk factor considered to be part of the metabolic syndrome should prompt the healthcare provider not only to look for more risk factors but to begin proactive, aggressive treatment to reduce the patient’s risk of developing CVD.
Reference:
[NCEP ATP III. JAMA. 2001;285: need ref FOR nhanes, fos, 4s, Hoorn]
NCEP ATP III. JAMA. 2001;285:

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:
>20%
High
10%-20%
Moderate
The Framingham Point System for Grading CVD Risk
Estimates of CHD risk in the past were based on analyses of numerous factors known to influence cardiovascular mortality (e.g., age, sex, blood pressure, smoking, diabetes).
ATP III risk assessment incorporates the Framingham point system in determining the 10-year CHD mortality risk. The 10-year CHD risk is then used to determine a patient’s overall risk category. A high-risk patient is one for whom the estimated 10-year CHD risk is >20%; a 10% to 20% risk places the patient in a moderate-risk category, while <10% risk places the patient in the low-risk category.
Reference:
NCEP ATP III. Executive summary of the National Cholesterol Education Program Expert Panel. JAMA 2001;285:
<10%
Low
CHD = coronary heart disease.
NCEP ATP III. JAMA 2001;285:2486–2497.
Wilson PWF, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837–1847.

9. Dyslipidemias Are Risk Factors for CVD
Hypertriglyceridemia
Elevated LDL
Small, dense LDL
Atherosclerosis
Low HDL
Diabetes
Hypertension
Insulin resistance
Endothelial Dysfunction
Risk Factor Clustering in Metabolic Syndrome
This slide shows a number of CVD risk factors that have been associated with the development of atherosclerosis and endothelial dysfunction.
Reference:
Deedwania PC. [title TK] Am J Med. 1998;105:1S-3S.
Hyperinsulinemia
Hypercoagulability
Visceral adiposity
HDL = high-density lipoprotein; LDL = low-density lipoprotein.
Deedwania PC. Am J Med. 1998;105:1S-3S.

10. 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
>102 cm (>40 in)
>88 cm (>35 in)
Blood pressure
≥130/85 mm Hg
Fasting glucose
≥100 mg/dL
Dyslipidemias figure prominently in NCEP ATP III diagnostic factors for metabolic syndrome
In its 2001 evidence-based treatment guidelines, the NCEP ATP III defined metabolic syndrome in terms of the presence of concomitant abnormalities, including abdominal obesity, increased triglycerides, decreased HDL-cholesterol, hypertension, and impaired fasting glucose level. At least 3 of the components are required for diagnosis of metabolic syndrome using the NCEP ATP III definition.
**The fasting glucose level was originally proposed by NCEP ATP III at 110 mg/dL and has been subsequently lowered to 100 mg/dL in accordance with 2003 American Diabetes Association criteria for impaired fasting glucose.
It should be noted that explicit demonstration of insulin resistance is not required for diagnosis using the ATP III criteria. However, most persons who meet ATP III criteria will be insulin resistant.
Reference:
NCEP ATP III. JAMA 2001;285:
* Diagnosis is established when ≥3 of these risk factors are present.
NCEP ATP III. JAMA. 2001;285:

11. ? Key Question How do the NCEP ATP III guidelines categorize
a TG range of mg/dL?
Very high
Borderline high
Normal
Low-normal
Use your keypad to vote now!
NCEP ATP III. JAMA. 2001;285:

12. ATP III Lipid Classifications
Total cholesterol (mg/dL)
< Desirable
Borderline high
≥240 High
LDL (mg/dL)
< Optimal
Borderline high
High
HDL (mg/dL)
<40 (M) Low
<50 (F) Low
≥60 High
TG (mg/dL)
< Normal
Borderline high
High
≥500 Very high
NCEP ATP III. JAMA. 2001;285:

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
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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
Elevated Triglycerides Increases CHD Risk
An analysis of the Framingham Heart Study data shows a significant relationship of triglycerides to CHD risk in women but not in men. The figure shows the relative risk by triglyceride levels in men and women in the Framingham study population. The follow-up period was 30 years.1
Meta-analysis of 17 prospective studies
Menopause brings a shift in lipid composition. In women, LDL-C increases by about 30 mg/dL and triglyceride increases by about 45 mg/dL from ages to years. A meta-analysis of 17 prospective studies included 11,089 women and 65,863 men found that elevated triglyceride was associated with a greater increase in CHD risk in women than men (69% vs. 30%, respectively). After adjustment for HDL-C levels, the risk remained elevated (RR=1.37 [95% CI: ] for each 1 mmol [88.6 mg/dL] increase in triglyceride level). Thus, elevated TG concentrations are a significant risk factor in women, especially those with low HDL-C levels.2
References:
Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.
Hokanson JE. Curr Cardiol Rep. 2002;4:
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. 1988;4(suppl A):5A-10A Hokanson JE. Curr Cardiol Rep. 2002;4:

15. Increased Risk From TG Is Independent of HDL18
17.2
Triglycerides (mg/dL) 16
<200 14 12
≥300
Odds Ratio 10
7.9 8
6.7
5.7
6.1 6
4.3
3.7 4
3.1
2.2 2
1.3
1.0
1.1
<30
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. 2005;45:

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)
0.0 85
100
160
220
LDL-C (mg/dL)
Data from Framingham Heart Study (Men)
Kwiterovich PO. Am J Cardiol. 1998;82:13Q-21Q.

17. 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 recommendations for testing of cholesterol and lipid profiles.
The NCEP ATP III recommends conducting a fasting lipoprotein profile that includes LDL, HDL, total cholesterol, and triglycerides, at least once every 5 yrs in adults > age 20 (If the testing conditions are non-fasting, only the HDL and total cholesterol values will be usable).
More frequent measurements are required for persons with multiple CHD risk factors and those with 0-1 risk factor whose LDL is slightly below goal levels (as discussed in subsequent slides).
For persons with 2+ risk factors, the lipoprotein profile should be used as a guide to clinical management.
Reference:
NCEP ATP III. Circulation 2002;106:
NCEP ATP III. Circulation. 2002;106:

18. 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
Treatment of dyslipidemias should be guided by an assessment of the patient’s risk for CVD.
Treatment strategies for dyslipidemias will be discussed in this presentation. In general, however, individual abnormalities should be treated using an aggressive, proactive strategy.
Dyslipidemias may be promoted by genetic/epigenetic factors and by acquired causes, such as overweight and obesity, physical inactivity, and carbohydrate-rich diets. Therapeutic interventions should therefore be aimed at 1) reducing underlying acquired causes through diet and lifestyle modifications, and 2) treating associated lipid- and non-lipid-based CVD risk factors (e.g., hypertension, atherogenic dyslipidemia, prothrombotic state).
Reference:
NCEP ATP III. JAMA 2001;285:
NCEP ATP III. JAMA. 2001;285:

19. 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
HDL-C
Fibrates
Niacin TG
Omega-3 acid ethyl esters
Weight loss/management (long-term)
Orlistat
Insulin resistance
Metformin
This slide highlights drugs or drug classes commonly prescribed to treat abnormalities that predispose to cardiovascular risk.
Patients may present different combinations of CVD risk factors. It is not uncommon for patients with metabolic syndrome or a cluster of CVD risk factors to require multiple medications to reduce their risk for CVD.

20. ? Key Question Why do patients continue to have dyslipidemia
despite efforts to manage blood lipid levels?
Patients don’t 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
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21. Hypertriglyceridemia and Risk Management
Causes
Efficacy of pharmacotherapy
Treatment strategies
Role of omega-3 acid ethyl esters
The following slides highlight the specific causes of hypertriglyceridemia and outline NCEP ATP III treatment recommendations.

22. TG-Rich Particles Chylomicron VLDL IDL LDL HDL 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 (>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:

24. ? Key Question Results of studies have shown that
statins can reduce TG levels on average by
what percentage?
≤30%
≤55%
>60%
Use your keypad to vote now!
NCEP ATP III. Circulation. 2002;106:

25. Efficacy of Pharmacotherapy
Drug
Reduction in TG Level
Statins1
Up to 30%
Fibrates1
20%-50%
Niacin1
Fish oil (omega-3 acid ethyl esters)1
30%-40%
Fibrate + statin2*
~40%
Niacin + statin1
This slide shows the relative efficacy of various commonly used lipid-lowering pharmacotherapies for reducing elevated TG levels.
References:
1NCEP ATP III. Circulation 2002;106: ; 2Wierzbicki AS, et al. Curr Med Res Opin 2003;19:
*Administer with caution due to risk of myopathy and rhabdomyolysis.
NCEP ATP III. Circulation. 2002;106: ; 2. Wierzbicki AS et al. Curr Med Res Opin. 2003;19:

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

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-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
Fibrates can improve low HDL-C and elevated TG.
Fibrates exert their actions via the activation of peroxisome proliferator-activated receptors alpha (PPAR-alpha), transcriptional factors critical for lipid metabolism. Activated by prostaglandins and fatty acids, PPARs initiate transcription of an array of genes involved in energy homeostasis and are involved in regulating various types of tumors, inflammation, and cardiovascular diseases.
A series of recent clinical trials has examined the impact of fibrate therapy on the reduction of CHD rates in high-risk patients. These trials, which include the Veterans Affairs HDL-C Intervention Trial (VA-HIT), the Bezafibrate Infarction Prevention Study (BIP), and the Diabetes Atherosclerosis Intervention Study (DAIS), demonstrated that fibrate therapy reduced CHD rates in high-risk patients with either: 1) low LDL (125 mg/dL); 2) combined dyslipidemia (LDL > 125 mg/dL + triglycerides > 200 mg/dL); or 3) typical diabetic or metabolic syndrome dyslipidemias.
Although the evidence base to support fibrate therapy is not as extensive as that for statin therapies, the NCEP ATP III notes that fibrates may be useful in combination with statins in treating patients with elevated triglycerides or a low HDL-C level.1
Reference:
1Grundy SM, et al. Circulation 2004;110:
1. Robins et al. Diabetes Care. 2003;26: ; 2. Grundy SM et al. Circulation. 2004;110:

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
Niacin (Nicotinic acid) also raises HDL-C levels and has been shown efficacious for reducing CHD risk, when used alone1 or in combination with statins.2-3
On the basis of clinical trial results, the US Food and Drug Administration (FDA) has approved one statin-nicotinic acid combination for lipid management.
As with the fibrates, niacin is recommended by NCEP ATP III in combination with statins to treat patients with elevated TG or a low HDL-C level.4
When considering the use of nicotinic acid, the PCP should be aware that many patients report unpleasant side effects, including flushing, dizziness, palpitations, tachycardia, shortness of breath, and nausea.
References:
1Canner PL, et al.. J Am Coll Cardiol 1986;8:
2Bays HE, et al.. Am J Cardiol 2003;91:
3Brown BG, et al.. N Engl J Med 2001;345:
4Grundy SM, et al.. Circulation 2004;110:
1. Canner PL et al. J Am Coll Cardiol. 1986;8: ; 2. Bays HE et al. Am J Cardiol ;91: ; 3. Brown BG et al. N Engl J Med. 2001;345: ;
4. Grundy SM et al. Circulation. 2004;110:

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. 1999;343: ; Covington MB. Am Fam Physician. 2004;70: Ren B et al. J Biol Chem. 1997;272: ; Madsen L et al. Lipids. 1999;34: ; Willumsen N et al. J Lipid Res. 1993;34:13-22;Harris WS et al. Am J Clin Nutr. 1997;66: ; Lu G et al. J Nutr Biochem. 1999;10:

30. Omega-3 Acid Ethyl Ester Dosing
1 g omega-3 acid ethyl ester capsule contains: 465 mg EPA 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: 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. Omega-3 Fatty Acids. American Family Physician. 2004; 70:
Covington MB. Am Fam Physician. 2004;70:

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 mg/dL
Borderline high mg/dL
Normal <150 mg/dL
Use your keypad to vote now!
NCEP ATP III. Circulation. 2002;106:

33. Omega-3 Acid Ethyl Esters (850 mg/d)
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, ) P = .037
Control
0.96
In the GISSI-Prevenzione Trial—Early Effect on All-cause Mortality,
significant benefit was seen very early, at 90 days.
Reference:
Marchioli R et al. Circulation. 2002;105:
0.95 30 60 90
120
150
180
210
240
270
300
330
360
Days
Marchioli R et al. Circulation. 2002;105:

34. Fasting TG Level (mg/dL)
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
Borderline high
Normal
<150
NCEP ATP III Definitions for Patient Types Based on Fasting Triglyceride Levels
According to the latest NCEP guidelines, TG 500 mg/dL are considered very high; drug treatment is indicated at for TG beg at 200 mg/dL. At lower levels, lifestyle interventions may be appropriate.
Reference:
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 Bethesda, Md: National Institutes of Health; 2002:VII-3-VII-5, Appendix III-A.
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 Bethesda, Md: National Institutes of Health; 2002:VII-3-VII-5, Appendix III-A.

35. 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:

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 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:

37. Simvastatin 10-40 mg/d (average 32 mg/d)
Omega-3 Acid Ethyl Esters Improve the Lipid Profile in Patients With High TG on Simvastatin
Simvastatin mg/d (average 32 mg/d) NS
P <.025*
P <.025
OMACOR® Improves the Lipid Profile in Patients With High/Very High TG on Simvastatin
Subjects and methods—59 patients with CHD, receiving simvastatin 10 to 40 mg daily with serum triglycerides >2.3 mmol/L, were randomized to receive OMACOR® 2 g twice a day or placebo for 24 weeks in a double-blind trial. Forty-six patients accepted the offer of active treatment for a further 24 weeks in an open phase of the trial.
OMACOR® BL Placebo BL TG
LDL
HDL 41 41
VLDL 39 35
Results—There was a sustained significant decrease in serum triglycerides by 20% to 30% (P<0.005) and in very low density lipoprotein (VLDL) cholesterol by 30% to 40% (P<0.005) in patients receiving active OMACOR® at 3, 6, and 12 months, respectively, compared either with baseline or placebo.
OMACOR® did not have any deleterious effect on low density or high density lipoprotein cholesterol or on biochemical and hematologic safety tests. There was no adverse effect on glycemic control in patients with diabetes, who showed a decrease in serum triglyceride, which was at least as great as in nondiabetic patients. One patient receiving placebo died of acute myocardial infarction. Three patients withdrew from the trial (two on placebo and one on active treatment). OMACOR® was generally well tolerated.
Conclusion—OMACOR® was found to be a safe and effective means of lowering serum triglycerides over 1 year in patients with CHD and combined hyperlipidemia, whose triglycerides remained elevated despite simvastatin treatment.
Reference:
Durrington PN. Heart. 2001;85:
P <.0005
P <.005
*after 48 weeks (NS after 24 weeks)
Durrington PN et al. Heart. 2001;85:

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
The NCEP ATP III 2004 Update provides the following overall recommendations for treating patients with CVD risk factors:1
Strongly consider statin use in persons with diabetes, except those with severe hypertriglyceridemia.
Consider adding a fibrate, omega-3 fatty acids (from fish oil), or nicotinic acid in persons with elevated TG or low HDL-C after statin therapy has achieved the LDL goal.
Continue to treat patients at low risk in the same way as before.
Reference:
1Grundy SM, et al. Circulation 2004;110:
ADA. Diabetes Care. 2007;30:S4-S41. Grundy SM et al. Circulation. 2004;110:

39. Focused Treatment for Hypertriglyceridemia
Serum TG
(mg/dL)
Primary Goal
Secondary Goal
Intervention
<150
Lower LDL
None
Lifestyle changes
Evaluate for metabolic syndrome
Lower non–HDL-C
Modify lifestyle
Consider drug therapy
NCEP ATP III Recommendations for Treating Hypertriglyceridemia (Serum TG Levels < 500 mg/dL)
The NCEP ATP III makes the following recommendations regarding treatment of hypertriglyceridemia for serum TG levels below 500 mg/dL:
Initiate lifestyle changes as first-line therapy. Lifestyle changes (smoking cessation, physical activity, weight loss/control) favorably modify multiple risk factors, including TG.
Target LDL cholesterol as described in this presentation. Elevated TG levels rarely occur in isolation, and the NCEP ATP III recommends risk stratification based on LDL. According to the NCEP ATP III, LDL cholesterol is the primary target of any therapeutic regimen designed to manage dyslipidemias.
Secondary goal for TG levels between 200 and 500 mg/dL is to lower non-HDL-C.
Reference:
NCEP ATP III. Circulation 2002;106:
NCEP ATP III. Circulation. 2002;106:

40. Focused Treatment for Hypertriglyceridemia (cont’d)
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
NCEP ATP III Recommendations for Treating Hypertriglyceridemia (Serum TG Levels > 500 mg/dL)
The NCEP ATP III makes the following specific recommendations regarding treatment of hypertriglyceridemia at serum TG levels above 500 mg/dL:
Initiate lifestyle changes as first-line therapy. Lifestyle changes (smoking cessation, physical activity, weight loss/control) favorably modify multiple risk factors, including TG.
Lowering serum TG level becomes the primary treatment goal at these elevated TG levels, with a secondary goal of preventing CHD.
Interventions include lifestyle modifications, pharmacotherapy, and fish oil. If TG levels drop below 500 mg/dL, LDL-lowering efforts may be re-evaluated, as LDL reduction becomes the primary goal of therapy at these levels.
Reference:
NCEP ATP III. Circulation 2002;106:
NCEP ATP III. Circulation. 2002;106:

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. 2004;70:

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 (cont’d) Framingham score 4% if nonsmoker 8% if smoker
Does hypertriglyceridemia present a particular risk to this patient?
Is pharmacotherapy warranted?
The patient remains at high risk despite treatment to control blood lipids: “ [with] TG 392 mg/dL the patient remains at high or very high risk of a CV event.”
Why does triglyceridemia present a particular risk to this patient?
“For every increase of 89 mg/dL in serum TG level, risk of CHD increases 30% in men and 69% in women,” as noted in slide 10.
Hokanson JE. Curr. Cardiol. Rep. 2002;4:

45. ? Decision Point How would you modify treatment to focus
management of the patient’s 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
Agent
↓ TG
↑ HDL
↑ Risk of Muscle Toxicity if Used With Statin
Gemfibrozil +
++++
Fenofibrate
Niacin
+++
Omega-3 acid ethyl esters —

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
The calcium score of 125 on EBCT indicates the likely presence of coronary artery disease in this 40-year-old man with a family history of premature cardiac disease.
The results of a thallium stress test show some impairment of myocardial perfusion due to a small, reversible abnormality of the inferior wall.
Prior attempts to manage blood lipids have been hindered by intolerable adverse events.
EBCT = electron beam computed tomography.

48. Case Study 2 (cont’d) Total cholesterol: 177 mg/dL HDL: 27 mg/dL
LDL: 120 mg/dL
TG: 151 mg/dL
Although total cholesterol is at a desirable level, 177 mg/dL, the patient’s HDL is very low and his TG level is in the borderline range.
Other risk factors, particularly a family history of premature cardiovascular disease and the likely presence of coronary artery disease, increase the risk of a CVD event before age 50. As we saw in slide 11, “TG are independently associated with premature familial CHD.”
The patient has experienced unacceptable AEs with previous therapies to control dyslipidemia
Hopkins PN et al. J Am Coll Cardiol. 2005;45:

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
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50. PCE Takeaways

51. 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

52. PCE Takeaways (cont’d)
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

53. 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

54. ? 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
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