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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
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
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 (2nd 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
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
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
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)
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)
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.
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.
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
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
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
CONFIDENTIAL
©2006
• 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
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
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
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
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
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)
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.
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.
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.
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, 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.
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
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 --
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.