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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.

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Presentation on theme: "Hypertriglyceridemia and Cardiovascular Disease Management: The Role of Omega-3 Fatty Acids Ronald A. Codario, MD Assistant Clinical Professor of Medicine."— Presentation transcript:

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? 1. Frequently 2. Sometimes 3. Seldom 4. 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? 1. Very confident 2. Somewhat confident 3. Not confident Use your keypad to vote now! ?

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

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. 2001;285:2486-2497.

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: <10% 10%-20% >20% Low Moderate High CHD = coronary heart disease. NCEP ATP III. JAMA 2001;285:2486–2497.

9 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 Endothelial Dysfunction Visceral adiposity Hypertriglyceridemia

10 Dyslipidemias Are Prominent in Metabolic Syndrome* NCEP ATP III. JAMA. 2001;285:2486-2497. Risk FactorDefining Level (Adults) TG150 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 pressure130/85 mm Hg Fasting glucose100 mg/dL * Diagnosis is established when 3 of these risk factors are present.

11 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. ?

12 ATP III Lipid Classifications Total cholesterol (mg/dL) <200 Desirable 200-239 Borderline high 240High LDL (mg/dL) <100 Optimal 130-159 Borderline high 160-189 High HDL (mg/dL) <40 (M)Low <50 (F) Low 60High TG (mg/dL) <150 Normal 150-199 Borderline high 200-499High 500Very high NCEP ATP III. JAMA. 2001;285:2486-2497.

13 Key Question Elevated TGs at a level requiring intervention present 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! ?

14 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 women 2 Relative Risk for CHD TGs in VLDL and IDL Men Women Framingham Heart Study Meta-analysis of 17 prospective studies 0.0 0.5 1.0 1.5 2.0 2.5 50100150200250300350400 VLDL = very low density lipoproteins, IDL = intermediate density lipoprotein.

15 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 <3030-3940-4950+ <200 200-299 300 HDL (mg/dL) Odds Ratio 5.7 6.1 17.2 2.2 3.1 4.3 1.3 3.7 6.7 1.01.1 7.9 Triglycerides (mg/dL)

16 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 Relative Risk 100160220 LDL-C (mg/dL) 85 65 45 25 HDL-C (mg/dL) Data from Framingham Heart Study (Men)

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. Circulation. 2002;106:3143-3421.

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 non–lipid-based CVD risk factors with lifestyle modifications and pharmacotherapy NCEP ATP III. JAMA. 2001;285:2486-2497.

19 Pharmacotherapy Commonly Used to Reduce CVD Risk and/or Alter Risk Factors Therapeutic TargetDrug 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

20 Key Question 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 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 VLDL IDL LDL 1.Non-HDL-C = total cholesterol – HDL 2. Non-HDL-C is the sum of all the atherogenic particles 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 Cushings disease Lipodystrophy Pregnancy Medication use (eg, corticosteroids, beta-blockers, retinoids, thiazide diuretics, antiretroviral therapy) NCEP ATP III. Circulation. 2002;106:3143-3421.

24 Key Question Results of studies have shown that statins can reduce TG levels on average by what percentage? 1.30% 2.55% 3. >60% Use your keypad to vote now! NCEP ATP III. Circulation. 2002;106:3143-3421. ?

25 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. DrugReduction in TG Level Statins 1 Up to 30% Fibrates 1 20%-50% Niacin 1 20%-50% Fish oil (omega-3 acid ethyl esters) 1 30%-40% Fibrate + statin 2 *~40% Niacin + statin 1 ~40% *Administer with caution due to risk of myopathy and rhabdomyolysis.

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 patients 1 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.

28 Niacin for Lipid Management Raises HDL-C levels and reduces CHD risk, used alone or in combination with statins 1-3 Recommended by NCEP ATP III in combination with statins for patients with high TG or low HDL 4 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.

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;343:191-197; 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.

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 (>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. Am Fam Physician. 2004;70:133-140.

32 Key Question The NCEP ATP III guidelines recommend drug intervention to reduce TG levels at which level of risk? 1. Very high500 mg/dL 2. High200-499 mg/dL 3. Borderline high150-199 mg/dL 4. Normal<150 mg/dL Use your keypad to vote now! NCEP ATP III. Circulation. 2002;106:3143-3421. ?

33 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 Probability 330210 150 60 090180270 Days 30120 240300 360 0.59 (95% CI, 0.36-0.97) P =.037 Omega-3 Acid Ethyl Esters (850 mg/d) Control

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; 2002:VII-3-VII-5, Appendix III-A. Patient Risk Category Fasting TG Level (mg/dL) Very high500 High200-499 Borderline high150-199 Normal<150

35 American Heart Association Recommendations Patient PopulationRecommendation 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 HypertriglyceridemiaConsume 2-4 g of EPA plus DHA daily in capsules by prescription Kris-Etherton et al. Circulation. 2002;106:2747-2757.

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; 297:611-619.

37 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) P <.0005 P <.005 P <.025 P <.025* NS 350-401128-164 Simvastatin 10-40 mg/d (average 32 mg/d)

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. 2007;30:S4-S41. Grundy SM et al. Circulation. 2004;110:227-239.

39 Focused Treatment for Hypertriglyceridemia NCEP ATP III. Circulation. 2002;106:3143-3421. Serum TG (mg/dL) Primary Goal Secondary GoalIntervention <150Lower LDLNone 150-199Lower LDLNone Lifestyle changes Evaluate for metabolic syndrome 200-499Lower LDLLower non–HDL-C Modify lifestyle Evaluate for metabolic syndrome Consider drug therapy

40 Focused Treatment for Hypertriglyceridemia (contd) NCEP ATP III. Circulation. 2002;106:3143-3421. Serum TG (mg/dL) Primary Goal Secondary Goal Intervention >500Lower 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

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;70:133-140.

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? 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! ?

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/m 2 ; 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? 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 Use your keypad to vote now! ?

50 PCE Takeaways

51 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

52 PCE Takeaways (contd) 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

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? 1. Very likely 2. Likely 3. Somewhat likely 4. Not likely Use your keypad to vote now! ?

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