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

High vs. Low Dose? - National Lipid Association · 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

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Page 1: High vs. Low Dose? - National Lipid Association · 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 and Cardiovascular Disease:

High vs. Low Dose?

Terry A. Jacobson M.D., F.N.L.A.

Emory University Atlanta, GA

Page 2: High vs. Low Dose? - National Lipid Association · 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

Structure of Omega-3 and

Omega-6 Fatty Acids

Din JN et al. BMJ. 2004;328:30-35.

Reprinted with permission from BMJ Publishing Group.

COOEt

Omega-6 fatty acids Omega-3 fatty acids

COOH

CH3

COOH CH3

Plant derived

C18:2n-6 Linoleic acid

C18:3n-3 -Linolenic acid

Marine derived

COOH CH3 C20:5n-3 Eicosapentaenoic acid

COOH

CH3

C20:4n-3 Arachidonic acid

COOH

CH3

C22:5n-6 Docosapentaenoic acid

COOH CH3 C22:6n-3 Docosahexaenoic acid

Page 3: High vs. Low Dose? - National Lipid Association · 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

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

Page 4: High vs. Low Dose? - National Lipid Association · 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

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 (2nd edition) Editor Christie M. Ballantyne (2014, in press)

Page 5: High vs. Low Dose? - National Lipid Association · 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

ECLIPSE STUDY: Epanova Compared to Lovaza in a

Pharmacokinetic Single-dose Evaluation

Kataoka Y et al. Future Cardiol. 2013;9:177-186

Page 6: High vs. Low Dose? - National Lipid Association · 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

AHA Recommendations for Omega-3

FA Intake

Kris-Etherton PM et al. Circulation 2002;106:2747-2757.

Population Recommendation

Patients without documented CHD

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)

Patients with documented CHD

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

2–4 grams of EPA+DHA per day provided

as capsules under a physician’s care

Page 7: High vs. Low Dose? - National Lipid Association · 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

What Percent of Whale Blubber

in Maui is EPA & DHA?

Page 8: High vs. Low Dose? - National Lipid Association · 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

n-3 Fatty Acid Randomized Controlled Trials

Assessing Cardiovascular Outcomes

Trial, Year Population Interventions Compared

Duration years

Lipid Effects Endpoints RR (95% CI)

DART 1989

2,033 men with recent MI (mean 41

days)

2 servings/wk fatty fish (or fish oil capsules) vs other dietary

advice

2 No change in TC IHD events Total deaths

0.84 (0.66-1.07) 0.71 (0.54-0.93)

GISSI-P 1999

11,324 men with recent

MI (≤ 3 mo)

Usual care plus 882 mg/day

EPA+DHA, vitamin E, both or neither

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

0.90 (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 (2nd edition)

Editor Christie M. Ballantyne (2014, in press)

Page 9: High vs. Low Dose? - National Lipid Association · 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

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 (2nd edition) Editor Christie M.

Ballantyne (2014, in press)

Page 10: High vs. Low Dose? - National Lipid Association · 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

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.

Page 11: High vs. Low Dose? - National Lipid Association · 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

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 JAMA. 2012;308(10) 1024-

1033.

Page 12: High vs. Low Dose? - National Lipid Association · 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

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

Page 13: High vs. Low Dose? - National Lipid Association · 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

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

Page 14: High vs. Low Dose? - National Lipid Association · 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

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

Page 15: High vs. Low Dose? - National Lipid Association · 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

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).

Page 16: High vs. Low Dose? - National Lipid Association · 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

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

Page 17: High vs. Low Dose? - National Lipid Association · 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

5,666

The GISSI-Prevenzione Trial Post-MI

• Hard endpoints. Duration: 3.5 years (start 1993)

• 172 centers in Italy involved, managed by the Mario Negri Institute

Total Number of Patients

11,324

Vitamin E

2,836

Control

2,830

Vitamin E

2,830

Control

2,828

Control

5,658 1 capsule/day

Page 18: High vs. Low Dose? - National Lipid Association · 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

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

GISSI-Prevenzione Trial: Early Effect on All-Cause Mortality

GISSI-Prevenzione Trial:

Early Effect on All-Cause Mortality

GISSI-Prevenzione Trial:

Early Effect on All-Cause Mortality1.00

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 = 0.037

Omacor

Control

Marchioli R et al. Circulation 2002;105:1897-1903.

Days

R Marchioli, et al., Circulation 2002; 105:1897-1903 18

Omega 3

Page 19: High vs. Low Dose? - National Lipid Association · 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

CONFIDENTIAL

©2006

Page 20: High vs. Low Dose? - National Lipid Association · 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

• n > 18,000 (Japan) • All administered statins • 1o & 2o prevention • 5 yr f/u • 1,800 mg EPA/day • Mean TG= 150 mg/dL

Yokoyama M et al. Lancet 2007;370:215

Page 21: High vs. Low Dose? - National Lipid Association · 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

14,981 Primary prevention 3,664 Secondary prevention

18,645 Random allocation

7,503 EPA

group

7,478 Control

group

1,823 EPA

group

1,841 Control

group

Cohort Profile

Page 22: High vs. Low Dose? - National Lipid Association · 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

Addition of Eicosapentaenoic Acid (EPA) to Statin Therapy in Japanese Patients

*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.

3.5 2.8

0

2

4

8

10

Statin

Major CHD Events*

Statin (n=9319)

Statin + EPA 1.8 g (n=9326)

Event ra

te (

%)

Lipid Effects

TC LDL-C TG

P<0.0001

Change f

rom

baselin

e (

%)

-40

-30

-20

-10

0

10

20

19% Reduction

P=0.011 6

Page 23: High vs. Low Dose? - National Lipid Association · 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

No at Risk

Control

EPA

0 1 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

Cu

mu

lati

ve I

ncid

en

ce o

f M

ajo

r

Co

ron

ary

Even

ts

(%)

4

P=0.011

EPA

Control 3

2

1

0

Hazard ratio: 0.81 (0.69-0.95)

- 19% - 19%

Kaplan-Meier Estimates of Major Coronary Events

2 3

Page 24: High vs. Low Dose? - National Lipid Association · 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

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)

Page 25: High vs. Low Dose? - National Lipid Association · 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

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

Page 26: High vs. Low Dose? - National Lipid Association · 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

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 (2nd edition) Editor Christie M.

Ballantyne (2014, in press)

Page 27: High vs. Low Dose? - National Lipid Association · 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
Page 28: High vs. Low Dose? - National Lipid Association · 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
Page 29: High vs. Low Dose? - National Lipid Association · 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

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, anti-platelet 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.

Page 30: High vs. Low Dose? - National Lipid Association · 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

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, anti-platelet 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.

Page 31: High vs. Low Dose? - National Lipid Association · 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

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, anti-platelet 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.

Page 32: High vs. Low Dose? - National Lipid Association · 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

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

Page 33: High vs. Low Dose? - National Lipid Association · 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

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

Page 34: High vs. Low Dose? - National Lipid Association · 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

JELIS: Change from Baseline in Omega 3

Fatty Acid Levels (ug/ml)

Itakura , H et al. J. Atheroscler. Thromb. 2011, 18 : 99 – 107.

Page 35: High vs. Low Dose? - National Lipid Association · 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

JELIS: Relationship between On-Treatment EPA

Concentration and Adjusted Major Coronary Events

Itakura , H et al. J. Atheroscler. Thromb. 2011, 18 : 99 – 107.

Page 36: High vs. Low Dose? - National Lipid Association · 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

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.

Page 37: High vs. Low Dose? - National Lipid Association · 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

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, anti-platelet 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.

Page 38: High vs. Low Dose? - National Lipid Association · 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

Definition of

Insanity

“Insanity” “is

doing the same

thing over and

over again and

expecting different

results.”

Page 39: High vs. Low Dose? - National Lipid Association · 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

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

Page 40: High vs. Low Dose? - National Lipid Association · 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

Summary of Key OMEGA-3 Outcomes Studies

40

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 Recent MI (≤ 3 mths;

median 16 days)

80% 1o prevention; TC ≥ 6.5 mmol/l; excluded

MI ≥ 6 months

Established vascular dx Diabetes (+)

TG 200-499mg/dl

OM-3 formulation & dosage Omacor 1 g/day

(EPA/DHA) Epadel 1.8 g/day (pure

EPA) EPA-E 4 g/day

Follow-up 3.5 years 4.6 years 4-5 years

Statin use 4.7% baseline/45.5% at

end All on Low Dose

Background Statins All on Background Statins

(LDL-C goal)

Endpoint Death, non-fatal MI,

stroke MACE MACE

Result RRR 10%/15% (2- or 4-

way analysis) RRR 19% Powered for 15% RRR

LDL-C Increased ~3% > control

groups No Difference

Between both groups --

SCD RR = 0.74/0.55 RR= 1.06 --

Page 41: High vs. Low Dose? - National Lipid Association · 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

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.