Tara Dall, MD Advanced Lipidology Diplomate American Board Clinical Lipidology

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1 Role of Omega-3 Fatty Acids in Cardiovascular Disease Prevention Tara Dall, MD Advanced Lipidology Diplomate American Board Clinical Lipidology 3 Types of Fat 1

2 Fat effect on cholesterol Saturated: most LDL-C, some neutral Trans Fatty Acids: LDL-C and HDL-C Monounsaturated: Maintain or LDL-C and or maintain HDL-C Polyunsaturated: Must be balanced need more omega-3: Triglycerides, LDL-C, small dense LDL-P most get too much omega-6 The Potential Cardiovascular Benefits of Omega 3s (EPA and DHA) Antilipid Antiarrhythymic Antiatherogenic Antithrombotic Anti-inflammatory Antihypertensive Omega 3 Fatty Acid Therapy Key ingredient for therapeutic benefit is Eicosapentaenoic (EPA, 2:5n-3) and Docosahexaenoic acid (DHA, 22:6n-3) Sources of EPA and DHA Alpha linolenic acid (ALA, 18:3n-3) in the diet EPA and DHA directly from the diet Dietary supplements Prescription omega-3 FA To reduce CV events, the dose of omega-3 FA therapy is ~1 g of EPA + DHA/day To lower TG levels, the dose of omega-3 therapy is ~4 g of EPA + DHA/day 2

Essential Fatty Acid Families ω-6 family H 3 C COOH C18:2 ω-6 Linoleic Corn Oil Safflower Oil Sunflower Oil H 3 C COOH C2:4 ω-6 Arachidonic More thrombotic and inflammatory metabolites ω-3 family H 3

3 Essential Fatty Acid Families ω-6 family H 3 C COOH C18:2 ω-6 Linoleic Corn Oil Safflower Oil Sunflower Oil H 3 C COOH C2:4 ω-6 Arachidonic More thrombotic and inflammatory metabolites ω-3 family H 3 C COOH C18:3 ω-3 -Linolenic Flaxseed Oil Canola Oil Soybean Oil H 3 C COOH C2:5 ω-3 Eicosapentaenoic (EPA) H 3 C COOH C22:6 ω-3 Docosahexaenoic (DHA) Less thrombotic and Oily Fish inflammatory Fish Oil Capsules metabolites Omega-6 to Omega-3 imbalance American diet 16-2 times as much omega-6 as omega-3. Cave men ranged from 1:1 to 5:1 World Health Organization (WHO) suggest 5:1 to 1:1 ratio for adults Omega-3 Plant omega-3 (ALA ) only 5-1% converted to EPA and DHA flax richest source in small amounts, canola oil, walnuts, leafy greens, soy foods Animal omega-3 (DHA & EPA) fatty fish (not fried) Salmon, Trout, herring, canned mackerel, sardines, shrimp 3

4 Cardiovascular Outcome Data for EPA and DHA DHA=docosahexaenoic acid; EPA=eicosapentaenoic acid. Omega-3 Fatty Acid Outcome Trials Studies have shown the cardiovascular benefit of consuming diets high in omega-3 Diet and Reinfarction Trial (DART) 1 Lyon Diet Heart Study 2 Indo-Mediterranean dit Diet Heart Study 3 Studies have shown the cardiovascular benefit of ALA Cardiovascular Health Study 4 Family Heart Study 5 Health Professionals Follow-up Study 6 Multiple Risk Factor Invervention Trial 7 Nurses Health Study 8 ALA=alphalinoleic acid. 1. Burr ML et al. Lancet. 1989;2: Leaf A. Circulation. 1999;99: Singh RB et al. Lancet. 22;36: Lemaitre RN et al. Am J Clin Nutr. 23;77: Djousse L et al. Am J Clin Nutr. 23;77: Ascherio A et al. BMJ. 1996;313: Dolecek TA. Proc Soc Exp Biol Med. 1992;2: Hu FB et al. Am J Clin Nutr. 1999;69:89-7. Japan EPA Lipid Intervention Study (JELIS) Incidence of nary Events %) Cumulative Major Coro (% Control EPA Hazard ratio =.81 (.69.95) p =.11 or statin + EPA (1.8 g/d) and followed for 5 years Yokoyama M. Presented at American Heart Association Scientific Sessions, Dallas, Texas, 14 November % Years 18,645 Japanese (7% women, mean age 61 years) randomized to statin alone 4

(%) Event rate 1 Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients 8 6 4 2 Major CHD Events * 19% Reduction P=.11 11 3.5 Statin 2.

CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; TC=total cholesterol. Yokoyama M et al. Lancet. 27;369:19-198. 2 1-1 -2-3 -4 LDL-C Lipid Effects Statin (n=9319) Statin + EPA 1.

5 (%) Event rate 1 Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients Major CHD Events * 19% Reduction P= Statin 2.8 seline (%) Change from ba *Sudden cardiac death, fatal and non-fatal MI, unstable angina, angioplasty, stenting, or CABG. CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; TC=total cholesterol. Yokoyama M et al. Lancet. 27;369: LDL-C Lipid Effects Statin (n=9319) Statin + EPA 1.8 g (n=9326) TC TG P<.1 Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS): Results (Primary and Secondary Prevention) In patients with a history of coronary artery disease (secondary prevention), major coronary events were reduced by 19% (P=.48) 158 [8.7%] in EPA group 197 [1.7%] in control group In patients with no history of coronary artery disease (primary prevention), major coronary events reduced by 18% (P=.132) 14 [1.4%] in EPA group 127 [1.7%] in control group EPA=Eicosapentaenoic acid. Yokoyama M et al. Lancet. 27;369: Relative Risk of Sudden Cardiac Death and Blood Omega- 3 Levels: Physicians' Health Study Relative e Risk % reduction in risk p for trend = Blood Omega-3 FA (%) by Quartile Mean: Albert CM et al. N Engl J Med 22:346:

GISSI-Prevenzione: Time Course of Clinical Events >11,3 post-mi patients were given usual care with or without 85 mg EPA+DHA for 3.5 years Total mortality reduced by 28% 1..99.98 n-3 PUFA Control.

95 Days 3 6 9 12 15 18 21 24 27 3 33 36 Marchioli R et al. Circulation 22;15:1897-193..53 (.32.88) p=.

6 GISSI-Prevenzione: Time Course of Clinical Events >11,3 post-mi patients were given usual care with or without 85 mg EPA+DHA for 3.5 years Total mortality reduced by 28% n-3 PUFA Control.59 (.36.97) (p=.27).97 p= (.54.96).96 p= Days Sudden death reduced by 47% (p=.136) Probability Probability (.22.99) p= Days Marchioli R et al. Circulation 22;15: (.32.88) p=.136 n-3 PUFA Control GISSI-Prevenzione: Effects of 85 mg/d of EPA+DHA on Serum Lipids mg/dl mg/dl Total Cholesterol n-3 Control HDL Cholesterol n-3 Control Months mg/dl mg/dl Marchioli R et al. Circulation 22;15: LDL Cholesterol n-3 Control Triglycerides n-3 Control Months Omega-3 FA and Risk for VT/VF in Patients with ICDs NO BENEFIT 2 patients with ICD and a recent history of sustained VT or VF 1.3 g/d EPA+DHA vs. placebo 2-year follow-up Endpoint: time to first ICD therapy for arrhythmia 6% with class III/IV HF None taking anti-arrhythmic drugs BENEFIT 42 with ICD implanted for cardiac arrest or sustained VT/VF 2.6 g/d EPA+DHA vs. placebo 1-year follow-up Endpoint: time to first ICD therapy or death 15% with class III/IV HF 35% taking anti-arrhythmic drugs Raitt MH et al. JAMA 25;293: Leaf A et al. Circulation 25;112:

Effect of EPA+DHA (81 mg/d 4 mo) on Heart Rate in 18 CHD Patients bp pm 9 85 8 75 7 65 6 55 5 Supine Standing Sitting at rest *74 vs 69 bpm, p<.

Heart Rate and Risk for Sudden Cardiac Death: Framingham Heart Study djusted Rate Biennial Age-a per 1 6 5 4 3 2 1 ***p<.1 ***Men 4.7 5.9 3.1 2.5 1.5 1.8 1.1 1.5.6 Women.

7 Effect of EPA+DHA (81 mg/d 4 mo) on Heart Rate in 18 CHD Patients bp pm Supine Standing Sitting at rest *74 vs 69 bpm, p<.1 Placebo Omega Minutes O Keefe JH Jr et al. Am J Cardiol 26;97: Heart Rate and Risk for Sudden Cardiac Death: Framingham Heart Study djusted Rate Biennial Age-a per ***p<.1 ***Men Women Quintile of Heart Rate Quintiles: Kannel WB et al. Am Heart J 1985;19: Omega-3 FA and Plaque Stability: Plaque Characteristics t Control Omega-3 Omega-6 8 ** 7 6 *p< ** ** IV V VI Thin AHA Type Cap Theis F et al. Lancet 23;361: Percent Patients awaiting carotid endarterectomy (n=188) were randomized to control, fish oil (omega-3), or sunflower oil (omega-6) supplementation for median 34, 46, and 43 days preprocedure Plaques in omega-3 patients appeared to be more stable 7

8 Data for Secondary Prevention in Patients With Heart Failure GISSI-HF: Design Prospective, multicenter, randomized, double-blind, placebo-controlled, parallel assignment Randomization 1 Patients with NYHA Class II IV IV heart failure (n=~7) Randomization 2 Patients with NYHA Class II IV heart failure and eligible for statin therapy (n=~525) P- OM3 1 g/day Placebo Rosuvastatin 1 mg/day Placebo Concomitant therapy: all treatments proven effective for the treatment of heart failure (ACE inhibitors, beta-blockers, diuretics, digo spironolactone, amiodarone, aspirin, and/or oral anticoagulants). ACE=angiotensin-converting enzyme; GISSI-HF=Gruppo Italiano p Studio della Sopravvivenza nell Infarto Miocardico Heart Failure Study; NYHA=New York Heart Association. Tavazzi L et al. Eur J Heart Fail. 24;6: GISSI-HF: Results Primary End Points End Point (Intention to treat) LOVAZA n=3494 (%) Placebo n=3481 (%) P value Adjusted Hazard Ratio All-cause mortality (95% CI ) All-cause mortality or hospitalization for CV causes (99% CI ) 999) All-cause mortality Absolute risk reduction of 1.8% Number needed to treat=56 for ~4 years Per protocol population (n=4994) LOVAZA 26% versus placebo 29% Adjusted hazard ratio (95% CI) =.86 ( ) P=.4 All-cause mortality or CV hospitalization Absolute risk reduction of 2.3% Number needed to treat=44 for ~4 years CI=confidence interval; CV=cardiovascular; GISSI-HF=Gruppo Italiano per Slide lo Source: Studio della Sopravvivenza nell Infarto Miocardico Heart Failure Study. GISSI-HF Investigators. Lancet. In Press. 8

9 GISSI-HF: Results Secondary End Points End Point LOVAZA, n=3494 (%) Placebo, n=3481 (%) Adjusted hazard ratio (95% CI) Death from CV causes (.81.99) Sudden cardiac death ( ) Hospitalized (.88-1.) Hospitalized for CV causes (.87.99) Hospitalized for heart failure ( ) Death from CV cause or ( ) hospitalization for any reason Fatal and non-fatal MI ( ) Fatal and non-fatal stroke ( ) CI=confidence interval; CV=cardiovascular; MI=myocardial infarction; GISSI-HF=Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico Heart Failure Study. GISSI-HF Investigators. Lancet. In Press. GISSI-HF: Summary Long-term administration of Prescription Omega 3 1 g/day reduced all-cause mortality and hospitalizations for CV reasons in a large population of patients with heart failure In the context of usual care Consistent across predefined subgroups Supported by per-protocol analysis No significant adverse events CV=cardiovascular; GISSI-HF=Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico Heart Failure Study. GISSI-HF Investigators. Lancet. In Press. Over the counter vs Prescription Omega 3 9

Omega-3 FA Less than 9 mg of n-6, n-7, and n-9 fatty acids Heavy metals not detectable Dioxins and

10 Prescription Omega-3 Acid Ethyl Esters (Lovaza formally Omacor) 9% Omega-3 EPA 465 mg DHA 375 mg Other Omega-3 6 mg Omega-6 8 mg Omega-7 and -9 8 mg Other FA 1 mg Composition of Prescription Omega-3 FA Less than 9 mg of n-6, n-7, and n-9 fatty acids Heavy metals not detectable Dioxins and halogenated polycarbons not detectable No Trans fatty acids High Dose Omega 3 FA 4g/day for Hypertriglyceridemia 1

Elevated Triglycerides Increase CHD Risk CHD Odd ds Ratio 12 1 8 6 4 2 TGs are independently associated with premature familial CHD* 11.4 1. 1.2 1.1 <1 1-149 15-199 2-299 3-499 5-799 Serum Triglycerides (mg/dl) 1.

11 Elevated Triglycerides Increase CHD Risk CHD Odd ds Ratio TGs are independently associated with premature familial CHD* < Serum Triglycerides (mg/dl) *Triglyceride odds ratio adjusted for HDL-C; n=653 (Family History=early CHD), n=129 (control). CHD=coronary heart disease; HDL-C=high-density lipoprotein cholesterol; TG=triglyceride. Hopkins PN et al. J Am Coll Cardiol. 25;45: Triglyceride Level Predicts CHD Risk Meta-Analysis of 29 Studies (N = 262,525) Groups CHD Cases CHD Risk Ratio* (95% CI) Duration of follow-up 1 years 592 <1 years 4256 Sex Male 7728 Female 1994 Fasting status Fasting 7484 Nonfasting 2674 Adjusted for HDL Yes 4469 No 5689 Overall CHD Risk Ratio* 1.72 ( ) Decreased Increased Risk 1 Risk 2 *Individuals in top versus bottom third of usual log-triglyceride values, adjusted for at least age, sex, smoking status, lipid concentrations, and blood pressure (most). CHD=coronary heart disease. Sarwar N et al. Circulation. 27;115: Lipid and Lipoprotein Metabolism in the Normal Person Glycerol Cholesteryl ester Apo B DGAT2 Triglyceride Fatty acids VLDL (Very low density lipoprotein) TG:Cholesterol=5:1 ratio Liver 11

Lipid and Lipoprotein Metabolism in the Normal Person Muscle and adipose tissue

Hepatocyte Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Increased

Liver Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Muscle and adipose

12 Lipid and Lipoprotein Metabolism in the Normal Person Muscle and adipose tissue Fatty acids Lipoprotein lipase Lipase Bloodstream IDL LDL LDL receptor VLDL Liver Hepatocyte Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Increased triglyceride secretion Cholesteryl ester Triglycerides VLDL TG:Cholesterol 5:1 Liver Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Muscle and adipose tissue Lipoprotein lipase Lipase Bloodstream LDL Decreased conversion to LDL VLDL Liver 12

Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Bloodstream Lipase LDL Small, dense LDL Increased VLDL HDL Rapid degradation Small, dense HDL HDL Lipase Free fatty acids Triglycerides Apo B

13 Lipid and Lipoprotein Metabolism in Hypertriglyceridemia Bloodstream Lipase LDL Small, dense LDL Increased VLDL HDL Rapid degradation Small, dense HDL HDL Lipase Free fatty acids Triglycerides Apo B Liver NCEP Guidelines: Patient Types Based on Fasting Triglyceride Levels Patient Type (category) Very high Fasting TG Level (mg/dl) 5 High Borderline high Normal <15 Continue TLC even if lipid-lowering drug therapy is started NCEP=National Cholesterol Education Program; TG=triglyceride; TLC=therapeutic lifestyle changes. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report Executive Summary. 21; NIH Publication No NCEP Guidelines: Treatment Objectives for Elevated Triglycerides Primary Objective Very High TG TG 5 mg/dl High TG LDL goal mg/dl *VLDL-C levels are influenced by triglyceride levels. Secondary Objective LDL-C & non HDL-C non HDL-C (VLDL-C*, LDL-C) HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; NCEP=National Cholesterol Education Program; TG=triglyceride; VLDL-C=very low-density lipoprotein cholesterol. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report Executive Summary. 21; NIH Publication No

Pharmacologic Treatment Options for Triglyceride Reduction Omega 3 Statins Fibrates Niacin Prescription Omega 3 (Lovaza )for Triglyceride Lowering The effects of 4 g of Lovaza per day were assessed

levels were between 5 and 2 mg/dl were enrolled in these two studies of 6 and 16 weeks duration Harris WS et al. J Cardiovasc Risk 1997;4:385-391. Pownall HJ et al. Atherosclerosis 1999;143:285-297.

14 Pharmacologic Treatment Options for Triglyceride Reduction Omega 3 Statins Fibrates Niacin Prescription Omega 3 (Lovaza )for Triglyceride Lowering The effects of 4 g of Lovaza per day were assessed in two randomized, placebo-controlled, double-blind, parallelgroup studies 84 adult patients (42 on Lovaza, 42 on placebo) with very high triglyceride levels Patients whose baseline triglyceride levels were between 5 and 2 mg/dl were enrolled in these two studies of 6 and 16 weeks duration Harris WS et al. J Cardiovasc Risk 1997;4: Pownall HJ et al. Atherosclerosis 1999;143: Omega-3 Ethyl Esters and Lipid Levels in Patients with Triglycerides >5 mg/dl Baseline (mg/dl) 6% 4% 2% % -2% -4% TG 816 P<.1 HDL-C 22 P= Non- HDL-C 27 P= Chol 296 P= VLDL-C 175 P< % Placebo Pooled analysis: Harris WS et al. J Cardiovasc Risk 1997;4: Pownall HJ et al. Atherosclerosis 1999;143: LDL-C 89 P< Omega-3 Acid Ethyl Esters (4 g/day) 14

With POM3 LOVAZA 4 g/day (n=15) Mean Baseline 871 21 116 3 Gemfibrozil 12 mg/day (n=13) 622 126 122 n lipid tion (%) Change in concentrat 1-1 -3 +3% +34% -37% -46% -33% -39% -4% -4% -5 TG

15 Why Can Treatment With LOVAZA Increase LDL-C, and What Is the Clinical Significance? Normalizing Lipid and Lipoprotein Metabolism Muscle and adipose tissue Lipoprotein lipase Lipase Bloodstream Proper conversion to LDL LDL VLDL Liver LDL-C Shifts Are Not Specific to Treatment With POM3 LOVAZA 4 g/day (n=15) Mean Baseline Gemfibrozil 12 mg/day (n=13) n lipid tion (%) Change in concentrat % +34% -37% -46% -33% -39% -4% -4% -5 TG VLDL-C LDL-C TG VLDL-C LDL-C 12-week, randomized, double-blind, double-dummy trial N=3 patients with TG levels between 356 and 2492 mg/dl LDL-C=low-density lipoprotein cholesterol; TG=triglyceride; VLDL-C=very low-density lipoprotein cholesterol. Stalenhoef AF, et al. Atherosclerosis. 2;153:

16 Addition of POM3 4 g/day in Patients With High Triglycerides Taking Simvastatin LDL-C by Baseline LDL-C Tertile LDL-C Tertile 1 LDL-C Tertile 2 LDL-C Tertile 3 ( mg/dl) ( mg/dl) ( mg/dl) aseline (%) Median change from ba LDL-C=low-density lipoprotein cholesterol, TG=triglyceride. Data on file. GlaxoSmithKline. LOVAZA 4 g/day + simvastatin 4 mg/day Placebo + simvastatin 4 mg/day n=43 n=41 n=4 n=46 n=39 n=45 Eligible subjects included men and women with LDL-C levels 1% above their NCEP ATP III goal and with TG levels mg/dl after an 8-week lead-in phase of diet and simvastatin 4 mg/day. POM3 4 g/day Significantly Decreased Non HDL-C 1,2 alues (mg/dl) Median va % VLDL-C IDL-C LDL-C 215 P=.13 LDL-C Goal in Patients With -1 Risk Factor* 3 Baseline End of Therapy *LDL-C goals vary based on risk factors. HDL-C=high-density lipoprotein cholesterol; IDL-C=intermediate-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; VLDL-C=very low-density lipoprotein cholesterol. 1. Prescribing Information for LOVAZA. 2. Data on file, GlaxoSmithKline. 3. NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report Executive Summary. 21; NIH Publication No Adding POM3 4 g/day to Simvastatin Increased LDL Particle Size* LDL particle eline (%) Median change in size from base Post-hoc Analysis of Median Change in LDL Particle Size 1. n=16 LOVAZA 4 g/day + simvastatin 4 mg/day Placebo + simvastatin 4 mg/day.51 P=.66 between groups. n=12 *Measured by nuclear magnetic resonance (NMR). LDL=low-density lipoprotein. Data on File, GlaxoSmithKline. 16

17 Does Treatment With LOVAZA Affect Lipoprotein-associated Phospholipase A 2 (Lp-PLA 2 )? Lp-PLA 2 Is Associated With Risk of CHD WOSCOPS (2) WHI (21) ARIC LDL<13 mg/dl (24) Rotterdam (25) Mayo Heart Study (25) KAROLA (25) Intermountain Heart (26) PROSPER (26) PROVE-IT (26) THROMBO (26) CHS (26) MALMO (27) PEACE (27) Risk Ratio for CHD Events CHD=coronary heart disease; Lp-PLA 2=Lipoprotein-associated Phospholipase A 2. Corson MA, et al. Am J Cardiol. 28;11(suppl):41F-5F. Adding LOVAZA 4 g/day to Statins: Change in Lp-PLA 2 edian change (%) Me P=.2 between groups. LOVAZA 4 g/day + simvastatin 4 mg/day Median tr reatment difference (%) All P<.1* LOVAZA 4 g/day + atorvastatin 1 mg (week -8) LOVAZA 4 g/day + atorvastatin 2 mg (week 8-12) Placebo + simvastatin 4 mg/day LOVAZA 4 g/day + atorvastatin 4 mg (week 12-16) Eligible subjects included men and women with Eligible subjects included men and women with fasting non LDL-C levels 1% above their NCEP ATP III goal and with TG HDL-C >16 mg/dl and TG 25 mg/dl and 599 mg/dl. levels mg/dl after an 8-week lead-in phase of diet and simvastatin 4 mg/day. *P-value=Difference in median % change from baseline between LOVAZA plus atorvastatin and respective placebo plus atorvastatin groups. HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; Lp-PLA 2=lipoprotein-associated phospholipase A 2; TG=triglyceride. Data on file, GlaxoSmithKline. 17

AHA Recommendations for Omega-3 FA Intake Population Patients without documented CHD Patients with documented CHD Recommendation Eat a variety of (preferably oily) fish at least twice a week.

18 AHA Recommendations for Omega-3 FA Intake Population Patients without documented CHD Patients with documented CHD Recommendation Eat a variety of (preferably oily) fish at least twice a week. Include oils and foods rich in -linolenic acid (flaxseed, canola, and soybean oils; flaxseeds; and walnuts) Consume ~1 g of EPA+DHA per day, preferably from oily fish. EPA+DHA supplements could be considered in consultation with the physician Patients needing triglyceride lowering 4 grams of EPA+DHA per day provided as capsules under a physicians care Kris-Etherton PM et al. Circulation 22;16: Fish as a Source of Omega-3 Fatty Acids Fish consumption 1 Risk of heavy metal contaminants Risk of other environmental contaminants The FDA recommends no more than 12 ounces of low-mercury fish/week 2 Calories per serving 3 Type of fish Approximate ounces needed to equal LOVAZA 4 g/day 1 Tuna (light, canned, drained) Mackerel Pacific cod Lobster Scallop Salmon (Atlantic, farmed) Catfish (farmed) The intakes of fish given above are very rough estimates because oil content can vary markedly (>3%) with species, season, diet, and packaging and cooking methods. 1. Kris-Etherton PM et al. Circulation. 22;16: U.S. Department of Health and Human Services and U.S. Environmental Protection Agency Consumer Advisory. Available at: Accessed August 7, U.S. Department of Agriculture, Agricultural Research Service. 27. USDA National Nutrient Database for Standard Reference, Release 2. Nutrient Data Laboratory Home Page. Available at: Accessed September 16, 28. Ways to Get 1 g/d EPA+DHA Fish oz salmon, sardines, mackerel per day Dietary Supplements -Low Potency:3 mg EPA+DHA/g (Typical drug store capsules; 3 g/d) - Mid Potency: 5 7 mg EPA+DHA/g (Mail-order, online, etc; 2 g/d Drugs - High Potency: 85 mg EPA+DHA/g (Omega-3 acid ethyl esters; 1 g/d) Cod Liver Oil - 1 tsp (RDA for vitamin D; 2 RDA for vitamin A) 18

19 Summary High TG levels are associated with atherogenic dyslipidemia and CHD and very high TG levels are associated with pancreatitis. Treatment options for high TG include the following: TLC for weight reduction/control Statins to achieve LDL-C goal Addition of fibrates, niacin, or fish oils to achieve non HDL-C goal Omega-3 FA therapy 1 g/day is an option for CHD patients Treatment options for very high TG include the following: TLC for weight reduction/control Fibrates, niacin, and/or fish oils for TG lowering Availability of a prescription grade omega 3-FA with consistent quality should prove to be useful for the medical management of TG-related disorders Potential Triglyceride-Lowering Mechanisms of Omega-3 FA Cell membrane Mitochondria CPT-I, -II Acyl-CoA dehydrogenase Peroxisome Acyl-CoA oxidase (rodents only?) NEFA Hormone-Sensitive Lipase Adipose TG FA Uptake + В-oxidation + Acyl-CoA Glucose Uptake Acetyl-CoA Acyl-CoA carboxylase synthase FA synthase FA Acetyl CoA Lipogenesis Β-oxidation DAG TG DGAT Glycerol-3-P Lyso PA PA PAP + Phospholipids Harris WS and Bulchandani D. Curr Opin Lipidol 26; 17: Apo B-1 + VLDL Degradation Should blood omega-3 fatty acid levels be considered as a potential risk factor for sudden cardiac death? If so, what would high- and low-risk levels be? 19

Risk for Primary Cardiac Arrest and Red Blood Cell EPA+DHA Level Odds Ratio 1..8.6.4.2 9% reduction in risk *p<.5 vs Q1. 3.3% 4.3% 5.% 6.

Omega-3 Index A measure of the amount of EPA+DHA in red blood cell membranes expressed as the percent of total fatty acids There are 64 fatty acids in this model membrane, 3 of which are EPA

20 Risk for Primary Cardiac Arrest and Red Blood Cell EPA+DHA Level Odds Ratio % reduction in risk *p<.5 vs Q1. 3.3% 4.3% 5.% 6.5% Mean RBC EPA+DHA by Quartile Adapted from Siscovick DS et al. JAMA 1995;274: Omega-3 Index A measure of the amount of EPA+DHA in red blood cell membranes expressed as the percent of total fatty acids There are 64 fatty acids in this model membrane, 3 of which are EPA or DHA 3/64 = 4.6% Omega-3 Index = 4.6% Harris WS et al. Prev Med 24;39: Relationship Between Reported Intake of Tuna and Other Non-fried Fish and the Omega-3 Index (n=163) dex (%) Omega-3 In <1/mon (13%) 1 3/mon (42%) 1/wk (18%) >1 2/wk (15%) Frequency of Intake (% of Population) Sands SA et al. Lipids 25;4: >2/wk (12%) 2

21 Omega-3 Index: Study Estimates Greatest Protection 1% GISSI-P:~9 1% 8% CHS: 8.8% DART:~8 9% Least Protection 6% SCIMO: 8.3% 5 epi studies:~8% 8.1% PHS: 3.9% SCIMO: 3.4% Seattle: 3.3% 4% 2% PHS: 7.3% Seattle: 6.5% Harris WS et al. Prev Med 24;39: Proposed Omega-3 Index Risk Zones: Relative Risk for Death from CHD Undesirable Intermediate Desirable % 4% 8% 1% Percent of EPA + DHA in RBC Harris WS et al. Prev Med 24;39: The Omega-3 Index: How Does It Compare with Traditional CHD Risk Factors? Physicians Health Study RR SC CD Relative Risk for Sudden Cardiac Death by Risk Factor P for < < trend CRP Hcy TC LDL HDL TG TC/ HDL ω-3 FA Q1 Q2 Q3 Q4 Albert CM et al. Circulation 22;15: Albert CM et al. N Engl J Med 22;346:

22 Omega-3 and CHD: Summary EPA and DHA have cardioprotective properties; effects of ALA are unclear Mechanisms of action - TG lowering: via a combination of inhibited hepatic TG synthesis/secretion and enhanced VLDL-TG clearance - Reduced risk for sudden cardiac death: via an increased resistance to ischemia-induced ventricular arrhythmias The Omega-3 Index (RBC EPA+DHA) has the potential to be a new risk factor for CHD death AHA-recommended intakes range from 2 (preferably oily fish) meals/wk (1 prevention), to ~1 g/d (2 prevention), to 2 4 g/d (triglyceride lowering) Omega-3 FA may be obtained from oily fish, cod liver oil, dietary supplements, and a pharmaceutical preparation Tara Dall, MD Diplomate, American Board Clinical Lipidology Advanced Lipidology Delafield, ld WI 22

Omega 3 s and Cardiovascular Disease: High vs. Low Dose? Terry A. Jacobson M.D., F.N.L.A. Emory University Atlanta, GA

Omega 3 s and Cardiovascular Disease: High vs. Low Dose? Terry A. Jacobson M.D., F.N.L.A. Emory University Atlanta, GA Structure of Omega-3 and Omega-6 Fatty Acids Omega-6 fatty acids CH 3 Omega-3 fatty