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 acids Plant derived C18:2n-6 Linoleic acid COOEt COOH CH 3 C18:3n-3 -Linolenic acid COOH CH 3 Marine derived C20:4n-3 Arachidonic acid COOH CH 3 C20:5n-3 COOH Eicosapentaenoic acid CH 3 C22:5n-6 COOH Docosapentaenoic acid CH 3 C22:6n-3 COOH Docosahexaenoic acid Din JN et al. BMJ. 2004;328:30-35. Reprinted with permission from BMJ Publishing Group.

Major Dietary Sources of EPA and DHA U.S. Department of Agriculture, 2013. USDA National Nutrient Database for Standard Reference. EPA mg/100g DHA mg/100g EPA and DHA mg Anchovy 763 1292 2055 Herring, Atlantic 909 1,105 2,014 Salmon, farmed 862 1,104 1,966 Salmon, wild 411 1,429 1,840 Mackerel, Atlantic 504 699 1,203 Bluefish 323 665 988 Sardines, Atlantic 473 509 982 Trout 259 677 936 Golden bass (tilefish) 172 733 905 Swordfish 127 772 899 Tuna, white (albacore) 233 629 862 Mussels 276 506 782 Oysters, wild 274 210 484 King Mackerel 174 227 401 Tuna, light (skipjack) 91 237 328 Snapper 48 273 321 Flounder and sole 168 132 300 Clams 138 146 284 Grouper 35 213 248 Halibut 80 155 235 Lobster 117 78 195 Scallops 72 104 176 Blue Crab 101 67 168 Cod, Pacific 42 118 160 Shrimp 50 52 102 Catfish, farmed 20 69 89

Available Forms of Omega-3 Fatty Acids for Supplement and Pharmaceutical use Harris WS and Jacobson TA. In Clinical Lipidology: A Companion to Braunwald s Heart Disease: Expert Consult (2 nd edition) Editor Christie M. Ballantyne (2014, in press)

ECLIPSE STUDY: Epanova Compared to Lovaza in a Pharmacokinetic Single-dose Evaluation Kataoka Y et al. Future Cardiol. 2013;9:177-186

AHA Recommendations for Omega-3 FA Intake Population Patients without documented CHD Patients with documented CHD Patients needing triglyceride lowering 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 2 4 grams of EPA+DHA per day provided as capsules under a physician s care Kris-Etherton PM et al. Circulation 2002;106:2747-2757.

What Percent of Whale Blubber in Maui is EPA & DHA?

n-3 Fatty Acid Randomized Controlled Trials Assessing Cardiovascular Outcomes Trial, Year Population Interventions Compared DART 1989 GISSI-P 1999 2,033 men with recent MI (mean 41 days) 11,324 men with recent MI ( 3 mo) 2 servings/wk fatty fish (or fish oil capsules) vs other dietary advice Usual care plus 882 mg/day EPA+DHA, vitamin E, both or neither Duration years Lipid Effects Endpoints RR (95% CI) 2 No change in TC IHD events Total deaths 3.5 No change in TC, LDL-C or HDL- C; 5% decrease in TG Major CV events Non-fatal events Cardiac deaths Sudden deaths 0.84 (0.66-1.07) 0.71 (0.54-0.93) 0.90 (0.82-0.99) 0.98 (0.83-1.15) 0.78 (0.65-0.92) 0.74 (0.58-0.93) JELIS 2007 18,645 patients with total cholesterol 6.5 mmol/l (with and without CHD history) 1.8 g/day EPA vs usual care 4.6 No change in TC, LDL-C or HDL- C; 6% decrease in TG Coronary events Non-fatal events Coronary deaths Sudden deaths 0.81 (0.69-0.95) 0.81 (0.68-0.96) 0.94 (0.57-1.56) 1.06 (0.55-2.07) GISSI-HF 2008 6975 patients with heart failure 840 mg/day EPA+DHA vs placebo (not defined) 3.9 No change in TC, LDL-C or HDL- C; 5% decrease in TG Total death Death or hospitalization for CVD 0.91 (0 83-0 99) 0.94 (0.89-099) DART = Diet and Reinfarction Trial; GISSI-P = Gruppo Italiano per lo Studio della Soppravvivenza nel Infarto Miocardico Prevenzione; JELIS = Japan EPA Lipid Intervention Study; GISSI-HF = Gruppo Italiano per lo Studio della Soppravvivenza nel Infarto Miocardico Heart Failure Harris WS and Jacobson TA. In Clinical Lipidology: A Companion to Braunwald s Heart Disease: Expert Consult (2 nd edition) Editor Christie M. Ballantyne (2014, in press)

Recent n-3 Fatty Acid Randomized Controlled Trials Assessing Cardiovascular Outcomes RCT = randomized control trial; MI = myocardial infarction; IHD = ischemic heart disease; CV = cardiovascular; CHD = coronary heart disease; IGT Iimpaired glucose tolerance; IFG = impaired fasting glucose; NR = not reported; TC = total cholesterol; HDL = high density lipoprotein; LDL = low density lipoprotein; TG = triglycerides; SU.FOL.OM3 = Supplementation en Folates et Omega-3; ORIGIN = Outcome Reduction with Initial Glargine Intervention. Harris WS and Jacobson TA. In Clinical Lipidology: A Companion to Braunwald s Heart Disease: Expert Consult (2 nd edition) Editor Christie M. Ballantyne (2014, in press)

Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events: A Systematic Review and Meta-analysis (2012) Error bars indicate 95% CIs; PUFAs, polyunsaturated fatty acids; RR, relative risk. Rizos EC et al. JAMA. 2012;308(10):1024-1033.

Are n-3 Fatty Acids Still Cardioprotective? Observational Studies Mechanism of Action Randomized Controlled Trials Meta-Analysis n-3 Dose: High vs. Low Design of Future Outcome Trials

Mozaffarian, D. et al. JAMA 2006;296:1885-1899.

Are n-3 Fatty Acids Still Cardioprotective? Mechanism of Action 1.Benefit of omega 3 s probably unrelated to changes in lipids - no Δ in lipids in JELIS - no Δ in lipids in GISSI-Prevenzione - no Δ in lipids in GISSI-Heart Failure 2. Many non-lipid mechanisms of action 3. The different cardiovascular benefits of omega 3 s are dependent on their doses, with antiarrythmic effects at low doses, and lipid lowering effects at higher doses

Are n-3 Fatty Acids Still Cardioprotective? Lipid Changes: 1. No evidence reducing TG s reduces CHD or CVD events 2. High dose omega 3 s (> 2-4 grams/day) are required to change lipid levels 3. No RCT evidence yet that lipid lowering doses of omega 3 s (>2-4g/day) reduce CHD risk or have better outcomes than low doses of omega 3 s (1-2g/day).

Are n-3 Fatty Acids Still Cardioprotective? Observational Studies Mechanism of Action Randomized Controlled Trials Meta-Analysis n-3 Dose: High vs. Low Design of Future Outcome Trials

The GISSI-Prevenzione Trial Post-MI Total Number of Patients 11,324 Omega 3 5,666 1 capsule/day Control 5,658 Vitamin E 2,836 Control 2,830 Vitamin E 2,830 Control 2,828 Hard endpoints. Duration: 3.5 years (start 1993) 172 centers in Italy involved, managed by the Mario Negri Institute

Probability GISSI-Prevenzione Trial: Early Effect on All-Cause Mortality GISSI-Prevenzione Trial: Early Effect on All-Cause Mortality 1.00 0.99 0.98 Omacor 0.97 0.96 0.59 (95% CI 0.36-0.97) P = 0.037 Control Omega 3 0.95 0 30 60 90 120 150 180 210 240 270 300 330 360 Days Marchioli R et al. Circulation 2002;105:1897-1903. Control Omega 3 RR P-Value All-Cause Mortality 10.6% 8.4% 21% 0.0064 Sudden Death 3.3% 1.8% 44% 0.0006 R Marchioli, et al., Circulation 2002; 105:1897-1903 Days 18

CONFIDENTIAL 2006

n > 18,000 (Japan) All administered statins 1 o & 2 o prevention 5 yr f/u 1,800 mg EPA/day Mean TG= 150 mg/dl Yokoyama M et al. Lancet 2007;370:215

Cohort Profile 18,645 Random allocation 14,981 Primary prevention 3,664 Secondary prevention 7,478 Control group 7,503 EPA group 1,841 Control group 1,823 EPA group

Event rate (%) Change from baseline (%) Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients Major CHD Events * Lipid Effects 10 8 6 19% Reduction P=0.011 20 10 0 Statin (n=9319) Statin + EPA 1.8 g (n=9326) 4 3.5 2.8-10 -20 P<0.0001 2-30 0 Statin -40 LDL-C TC TG *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. 2007;369:1090-8.

Cumulative Incidence of Major Coronary Events (%) Kaplan-Meier Estimates of Major Coronary Events 4-19% 3 Control 2 EPA No at Risk Control EPA 1 Hazard ratio: 0.81 (0.69-0.95) P=0.011 0 0 1 2 3 4 5 Years 9,319 8,931 8,671 8,433 8,192 7,958 9,326 8,929 8,658 8,389 8,153 7,924

Major Coronary Events Incidence No. of events (%) Control N=9,319 EPA N=9,326 P Value Hazard Ratio (95% CI) Major coronary events 324 (3.5) 262 (2.8) 0.011 0.81 (0.69-0.95) Sudden cardiac death 17 (0.2) 18 (0.2) 0.854 1.06 (0.55-2.07) Fatal MI 14 (0.2) 11 (0.1) 0.557 0.79 (0.36-1.74) Nonfatal MI 83 (0.9) 62 (0.7) 0.086 0.75 (0.54-1.04) Unstable angina 193 (2.1) 147 (1.6) 0.014 0.76 (0.62-0.95) CABG or PTCA 222 (2.4) 191 (2.1) 0.135 0.86 (0.71-1.05)

The JELIS Study: Conclusions The addition of eicosapentaenoic acid (EPA) to low-dose statin therapy significantly reduced the incidence of major coronary events, largely driven by a reduction in unstable angina, when compared with patients taking statins alone The benefits in secondary prevention were greater than those in primary prevention

Are Omega s Still Cardioprotective?: Why Current Trials Failed n-3 PUFA do not reduce CVD events n-3 PUFA have little benefit on top of aggressive medical treatments including statins, antiplatelet agents, etc. n-3 PUFA trials have been inadequately powered to detect a clinically meaningful effect on CHD deaths, the endpoint most likely to be effected based on both epidemiological and clinical trial data n-3 PUFA background therapy has increased due to increased fish consumption and greater use of fish oil supplements n-3 PUFA doses in clinical trials, have been too low (0.5-1.0 g EPA and DHA) to effect long term plaque stabilization (2-4gms) n-3 PUFA have a limited benefit on CHD deaths after a threshold intake has been reached of 250 mg/day.

Are Omega s Still Cardioprotective?: Why Current Trials Failed Populations consuming little or no fish intake have not been studied n-3 PUFA therapy has not been tested at doses required to significantly effect lipoproteins (triglycerides, non-hdl-c, apo B, or apo C-III) n-3 PUFA therapy has not been tested in individuals with high triglycerides or with other related lipid abnormalities (low HDL-C) despite a suggestion of potential large benefit in post-hoc analysis of randomized trials

Are n-3 Fatty Acids Still Cardioprotective? Observational Studies Mechanism of Action Randomized Controlled Trials Meta-Analysis n-3 Dose: High vs. Low Design of Future Outcome Trials

JELIS: Change from Baseline in Omega 3 Fatty Acid Levels (ug/ml) Itakura, H et al. J. Atheroscler. Thromb. 2011, 18 : 99 107.

JELIS: Relationship between On-Treatment EPA Concentration and Adjusted Major Coronary Events Itakura, H et al. J. Atheroscler. Thromb. 2011, 18 : 99 107.

JELIS:! % of Patients Achieving EPA 150ug/ml: Control Group (10%) vs EPA Group (61%) Itakura, H et al. J. Atheroscler. Thromb. 2011, 18 : 99 107.

Are Omega s Still Cardioprotective?: Why Current Trials Failed n-3 PUFA do not reduce CVD events n-3 PUFA have little benefit on top of aggressive medical treatments including statins, antiplatelet agents, etc. n-3 PUFA trials have been inadequately powered to detect a clinically meaningful effect on CHD deaths, the endpoint most likely to be effected based on both epidemiological and clinical trial data n-3 PUFA background therapy has increased due to increased fish consumption and greater use of fish oil supplements n-3 PUFA doses in clinical trials, have been too low (0.5-1.0 g EPA and DHA) to effect long term plaque stabilization (2-4 gms) n-3 PUFA have a limited benefit on CHD deaths after a threshold intake has been reached of 250 mg/day.

Definition of Insanity Insanity is doing the same thing over and over again and expecting different results.

Are n-3 Fatty Acids Still Cardioprotective? Observational Studies Mechanism of Action Randomized Controlled Trials Meta-Analysis n-3 Dose: High vs. Low Design of Future Outcome Trials

Summary of Key OMEGA-3 Outcomes Studies GISSI study JELIS study REDUCE-IT Population Italian Japanese International N 11,324 18,645 ~8,000 Male: Female 85% male 31% male - Risk profile OM-3 formulation & dosage Recent MI ( 3 mths; median 16 days) Omacor 1 g/day (EPA/DHA) 40 80% 1 o prevention; TC 6.5 mmol/l; excluded MI 6 months Epadel 1.8 g/day (pure EPA) Established vascular dx Diabetes (+) TG 200-499mg/dl EPA-E 4 g/day Follow-up 3.5 years 4.6 years 4-5 years Statin use Endpoint Result LDL-C 4.7% baseline/45.5% at end Death, non-fatal MI, stroke RRR 10%/15% (2- or 4- way analysis) Increased ~3% > control groups All on Low Dose Background Statins MACE RRR 19% No Difference Between both groups All on Background Statins (LDL-C goal) MACE Powered for 15% RRR SCD RR = 0.74/0.55 RR= 1.06 -- --

Summary: Are n-3 Fatty Acids Still Cardioprotective? Although recent n-3 fatty acid intervention studies have not demonstrated a beneficial effect on total cardiovascular outcomes, the totality of evidence suggests that CHD mortality is reduced at a low doses Properly designed clinical trials are needed assessing populations with low background n-3 fatty acid intake and using higher n-3 fatty acid doses (2-4gms) to either affect lipids or other mechanisms involved in plaque stabilization The risk-benefit ratio of n-3 fatty acids for reducing risk for cardiovascular disease still remains favorable in the right patient at the right dose.