Health Promoting

Benefits of Omega-3s

Harry B. Rice, PhD

Vice-President Regulatory & Scientific Affairs
27 April 2017
 Throughout Life,
Omega-3s are Valuable

Fetal growth Brain Growth Brain Growth Regulating Neurological

Inflammation Cell
Maternal Visual Preservation
stores Development Cardiovascular
Protecion Regulating
Inflammation

Cardiovascular
Protection
Heart
Health
Early Omega-3 Heart Health
Research
It all Began in the 70s with Hans Olaf
Bang and Jørn Dyerberg*

The studies were meant to generate hypotheses that could

be further investigated with interventional studies**

Jørn Dyerberg

*Lancet 1971;1(7710):1143-5.
**INFORM 2015;26(1):25-27.
 Diet and Reinfarction Trial (DART)

• 1989
• RCT
• 2033 men with previous history of MI
• Results: consumption of two servings/week fatty fish
• Reduced risk of death by ischemic heart disease
• Reduced all-cause mortality by 29%

*Lancet 1989;334(8666):757-761.
 GISSI-Prevenzione

• 1999
• RCT
• 11,324 adults with
history of recent MI
• Randomized to receive
850 mg EPA/DHA vs no
intervention
• Results: EPA/DHA
reduced the risk of all-
cause mortality, sudden
death, coronary death
and cardiovascular
death. Reprinted, with permission, from GISSI-Prevenzione Investigators, 1999

*Lancet 1999;354(9177):447–455.
 Japan EPA Lipid Intervention Study (JELIS)

• 2007
• 18,645 patients with
hypercholesterolemia
(70% female)
• Randomized to receive
statin alone or statin +
1,800 mg/d EPA
• 5-year duration
• EPA group had 19%
reduced risk for major
adverse coronary events
Reprinted, with permission, from Yokoyama et al., 2007

*Lancet 2007;369(9567):1090-1098.
 GISSI-HF

• 2008
• 7,000 patients with class II-
IV heart failure
• Randomized to receive
either 1 g Lovaza (850-882
mg EPA+DHA), Rosuvastatin
(10 mg), Both, or Dual
placebo
• Results: O-3 Groups
• ↓ total mortality
• ↓ in CVD mortality Reprinted, with permission, from the GISSI-HF Investigators, 2008

*Lancet 2008;372:1223-1230..
 O-3 Conundrum
In contrast to earlier investigations*, some recent studies
have not demonstrated significant effects of the long-chain
omega-3s, EPA and DHA, on cardiovascular disease (CVD)
risk/events.

*e.g. GISSI-Prevenzione, Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS), GISSI-HF, Diet
and Reinfarction Trial (DART)
 Studies in Question

• OMEGA (2010)
• Alpha Omega (2010)
• SU.FOL.OM3 (2010)
• ORIGIN (2012)
• Strand et al. (2013)
• Risk and Prevention Study (2013)
• FORWARD Trial (2013)
 References
Alpha Omega Trial Group (2010). n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 363:2015-26.

GESICA Investigators (2013). Omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: results of
the FORWARD( Randomized Trial to Assess Efficacy of PUFA for the Maintenance of Sinus Rhythm in Persistent Atrial
Fibrillation) trial. J Am Coll Cardiol 61:463-468.

OMEGA Study Group (2010). OMEGA, a randomized, placebo-controlled trial to test the effect of highly purified omega-3 fatty
acids on top of modern guideline-adjusted therapy after myocardial infarction. Circulation 122:2152-2159.

ORIGIN Trial Investigators (2012). n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 367:309-
318.

Strand E Pedersen ER Svingen GF Schartum-Hansen H Rebnord EW Bjørndal B Seifert R Bohov P Meyer K Hiltunen JK Nordrehaug
JE Nilsen DW Berge RK and Nygård O (2013). Dietary intake of n-3 long-chain polyunsaturated fatty acids and risk of myocardial
infarction in coronary artery disease patients with or without diabetes mellitus: a prospective cohort study. BMC Med 11:216.

SU.FOL.OM3 Collaborative Group (2010). Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised
placebo controlled trial. BMJ 341:c6273.

The Risk and Prevention Study Collaborative Group (2013). n–3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors. N
Engl J Med 368:1800-1808.
 WHY?
Increase in
Omega-6 Intake

Higher
O-3 Background
Assessment Omega-3 Intake
Method Treatment
Omega-3
Duration too
Dosage
Short

Expanded/Com
Too Few posite
Subjects Maintenance on Endpoints
Aggressive
Cardiovascular
Drug Treatment
 Context is Key
Harris WS. Are n-3 fatty acids still cardioprotective? Curr Opin Clin Nutr Metab Care.
2013;16:141-9.
James MJ, Sullivan TR, Metcalf RG, Cleland LG. Pitfalls in the use of randomised controlled
trials for fish oil studies with cardiac patients. Br J Nutr. 2014;112:812-20.

Marchioli R, Levantesi G. n-3 PUFAs in cardiovascular disease. Int J Cardiol. 2013;170:S33-

8.
Rice HB, Bernasconi A, Maki KC, Harris WS, von Schacky C, Calder PC. Conducting omega-3
clinical trials with cardiovascular outcomes: Proceedings of a workshop held at ISSFAL
2014. Prostaglandins Leukot Essent Fatty Acids. 2016;107:30-42.
von Schacky C. Omega-3 fatty acids in cardiovascular disease--an uphill battle.
Prostaglandins Leukot Essent Fatty Acids. 2015;92:41-7.

Wu JH, Mozaffarian D. omega-3 fatty acids, atherosclerosis progression and cardiovascular

outcomes in recent trials: new pieces in a complex puzzle. Heart. 2014;100:530-3.
Totality of the Scientific
Evidence
 Blood Pressure Meta-Analysis
RCTs
Systolic
# Data Lower Upper
Model Points WGMD 95% CI 95% CI

All studies 93 -1.52 -2.25 -0.79

Hypertensive
subjects 15 -4.51 -6.12 -2.83
Normotensive
subjects 73 -1.25 -2.05 -0.46

Diastolic
# Data Lower Upper
Model Points WGMD 95% CI 95% CI

All studies 92 -0.99 -1.54 -0.44

Hypertensive
subjects 15 -3.05 -4.35 -1.74
Normotensive
subjects 72 -0.62 -1.22 -0.02

Miller PE Van Elswyk M and Alexander DD (2014). Long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and blood pressure: a
meta-analysis of randomized controlled trials. Am J Hypertens. 27:885-896.
 CHD Meta-Analysis
RCTs and Prospective Cohorts
Model SRRE Lower 95% CI Upper 95% CI
CHD Risk
(RCTs) all studies 0.94 0.85 1.05
CHD Risk
(RCTs) LDL > 130 mg/dL 0.86 0.76 0.98
CHD Risk
(RCTs) TGs > 150 mg/dL 0.84 0.72 0.98
CHD Risk
(Prospective Cohorts) 0.82 0.74 0.98

Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC (2017). A Meta-Analysis of Randomized Controlled Trials and Prospective Cohort Studies of
Eicosapentaenoic and Docosahexaenoic Long-Chain Omega-3 Fatty Acids and Coronary Heart Disease Risk. Mayo Clin Proc. 92:15-29.
 Cardiac Death Meta-Analysis
RCTs
Model SRRE Lower 95% CI Upper 95% CI
Cardiac Death Risk
all studies 0.921 0.864 0.982
Cardiac Death Risk
>1 g/day EPA+DHA 0.709 0.508 0.990
Cardiac Death Risk
LDL > 130 mg/dL 0.829 0.726 0.947
Cardiac Death Risk
TGs > 150 mg/dL 0.826 0.723 0.944
Cardiac Death Risk
<40% statin use 0.864 0.794 0.940

Maki KC, Palacios O, Bell M, Toth PP (in preparation). Use of Supplemental Long Chain Omega-3 Fatty Acids and Risk for Cardiac Death: An Updated Meta-
Analysis and Review of Research Gaps.
Is it me or is it
EPA+DHA ?
 Fish Vs EPA+DHA
• No head-to-head comparison exists.
• There are strong documented benefits for both fish and
isolated fatty acids.
• Intake of EPA+DHA from either oily fish or fish oil pills
results in increases in the Omega-3 Index.
 Relative Risk of Sudden Death from Cardiac
Causes According to Base-Line Blood Level of
Long-Chain n-3 Polyunsaturated Fatty Acids

Quartile 1 2 3 4
Blood Omega-3 Fatty 3.58 4.76 5.63 6.87
Acid (%) by Quartile
Relative Risk 1.00 0.52 0.19 0.10

N Engl J Med 2002;346:1113-8

 Relative Risk of Sudden Cardiac Death and
Blood Omega-3 Levels: Physicians' Health
Study

1
90%
reductio
0.8 n
Relative Risk

in risk
p for trend = 0.001
0.6

0.4

0.2

0
1 2 3 4
Blood Omega-3 FA (%) by Quartile
Mean: 3.58 4.76 5.63 6.87
Albert CM et al. N Engl J Med 2002:346:1113-1118. Slide Source:
Lipids Online Slide Library
www.lipidsonline.org
 Luric Study
Omega-3 Index and risk for all-cause mortality over 10 years
in 3259 patients undergoing diagnostic cardiac catheterization

Model 1: adjusted for age

and gender

Model 2: additionally
adjusted for BMI, LDL-C,
HDL-C, logTG,
hypertension, diabetes
mellitus, smoking, alcohol
intake, physical exercise
and lipid lowering therapy.

Kleber ME, Delgado GE, Lorkowski S, März W, von Schacky C (2016). Omega-3 fatty acids and mortality in patients referred for
coronary angiography. The Ludwigshafen Risk and Cardiovascular Health Study. Atherosclerosis. 252:175-81.
Slide Content Courtesy of William Harris, PhD
 Women’s Health Initiative Memory
Study P for trend

Omega-3 Index
and risk for
death from any
cause over 14.9
years in 6501
post-
menopausal
women

Harris WS, Luo J, Pottala JV, Espeland MA, Margolis KL, Manson JE, Wang L, Brasky TM, Robinson JG (2017). Red blood cell
polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study. J Clin Lipidol. 11:250-9.
Slide Content Courtesy of William Harris, PhD
 Fatty Acids and Outcomes
Research Consortium (FORCe)
Question: Are EPA and DHA related to first CHD events?

In a consortium of 19 studies, biomarkers of EPA and DHA were

associated with a significantly lower risk of fatal CHD.
• EPA [RR 0.91 (95% CI, 0.82-1.00)]
• DHA [RR 0.90 (95% CI,0.84-0.96)](

Del Gobbo LC, et al (2016) ω-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19
Cohort Studies. JAMA Intern Med 176:1155-66
Research in Progress
 Research in Progress
VITamin D and OmegA-3 Trial (VITAL)

• 25,874 men and women across the U.S.

• Does taking daily dietary supplements of vitamin D3
(2000 IU) or Omacor® (omega-3 fatty acid ethyl esters), 1
g/d, reduce the risk for developing cancer, heart disease,
and stroke in people who do not have a prior history of
these illnesses?
 Research in Progress
Outcomes Study to Assess STatin Residual Risk
Reduction With EpaNova in HiGh CV Risk PatienTs
With Hypertriglyceridemia (STRENGTH)
• randomized, double-blind, placebo-controlled (corn oil),
parallel group design that will enroll approximately
13,000 patients with hypertriglyceridemia and low HDL
and high risk for CVD to be randomized 1:1 to either
corn oil + statin or Epanova® (omega-3 carboxylic acids)
+ statin, once daily, for approximately 3-5 years
• primary outcome: time to 1st occurrence of any
component of the composite endpoint (includes
cardiovascular death)
 Research in Progress
Reduction of Cardiovascular Events With EPA -
Intervention Trial (REDUCE-IT)

• Objective: to evaluate whether Vascepa® (icosapent

ethyl), combined with a statin therapy, is superior to
statin therapy alone, when used as a prevention in
reducing long-term cardiovascular events in high-risk
patients with mixed dyslipidemia.
Safety & Upper Limits
 EPA/DHA Are Safe!

Over the years, national regulatory authorities around the

world have conducted safety assessments for EPA+DHA.
Importantly, all have concluded that an increased risk of
bleeding is NOT an issue of concern.
 Safety & Upper Limits
Reviewed in 2010
• Only three case reports observed interactions with anticoagulants
Australia • NO randomized controlled trials observed bleeding
• No upper limit established

Reviewed in 2011
• Concluded it was not possible to identify clear adverse effects
Norway • Possible drug interactions only observed above 6.9g/day EPA+DHA
• No upper limit established, but up to 6.9g/day confirmed as safe

Reviewed in 2012
European • No upper limit could be established, but studies up to 5g/day considered
Union • No bleeding observed and no drug interactions observed
• 5g/day EPA+DHA established as No Adverse Event Level

Established Decades Ago

United • Arbitrary upper limit established because less evidence existed
States • Established through GRAS process
• 3g EPA+DHA per day upper limit
 OPERA Study
Omega-3 Treatment Resulted in Less Bleeding

Patients undergoing open heart surgery in 28 centers were given either placebo or 10 grams
EPA+DHA over 3-5 days presurgery and 2 grams/day until discharge.

Mozaffarian D, Marchioli R, Macchia A, Silletta MG, Ferrazzi P, Gardner TJ, Latini R, Libby P, Lombardi F, O'Gara PT, Page RL,
Tavazzi L, Tognoni G; OPERA Investigators (2012). Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for
Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA. 2012 Nov 21;308(19):2001-11.
Slide Content Courtesy of William Harris, PhD
 Recent Analysis Provides Additional Safety
Support
• Analysis of 8 clinical intervention studies conducted with enteral
medical nutrition products containing fish oil as omega-3 source
addressed the occurrence of bleeding-related adverse events and
effects on key coagulation parameters.

• In all patients considered (over 600), with moderate to severe disease,

with or without concomitant use of antithrombotic agents, there was no
evidence of increased risk of bleeding with omega-3s.

Jeansen S, Witkamp RF, Garthoff JA, van Helvoort A, Calder (ePub ahead of print 29 March 2017). Fish oil LC-PUFAs do not affect
blood coagulation parameters and bleeding manifestations: Analysis of 8 clinical studies with selected patient groups on omega-3-
enriched medical nutrition. Clin Nutr.
alwaysomega3s.com
Doctor Infographic
Are You Getting Enough?
Brain Health
GOED Intake
Recommendations
Public Health
 Globally, EPA/DHA Intake is
Insufficient

*BMJ 2014;348:g2272.
 Globally, EPA/DHA Intake is
Insufficient

*BMJ 2014;348:g2272.
 Blood Levels of EPA and DHA Correlate
with Insufficient Intake

Stark KD, Van Elswyk ME, Higgins MR, Weatherford CA, Salem N Jr.. Global survey of the omega-3 fatty acids, docosahexaenoic acid and
eicosapentaenoic acid in the blood stream of healthy adults. Prog Lipid Res. 2016 Jul;63:132-52.
 Questions?
[email protected]