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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 fatty - PowerPoint PPT Presentation
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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
Use your keypad to vote now!
?
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
Use your keypad to vote now!
?
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
Use your keypad to vote now!
NCEP ATP III. JAMA. 2001;285:2486-2497.
?
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
Use your keypad to vote now!
?
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%
Use your keypad to vote now!
NCEP ATP III. Circulation. 2002;106:3143-3421.
?
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
Use your keypad to vote now!
NCEP ATP III. Circulation. 2002;106:3143-3421.
?
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 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
Use your keypad to vote now!
?
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.
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
Use your keypad to vote now!
?
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