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Scientific Basis for a Public Health Recommendation for EPA/DHA

Harry B. Rice, Ph.D.VP, Regulatory & Scientific Affairs CRN-I Symposium - Kronberg im Taunus November 20, 2015

Source: Pubmed, as of April 28, 2015

The Body of Evidence: Randomized, Controlled Trials in Humans

Omega-3s are One of the Most Research Compounds in Health and Nutrition

Source: Pubmed as of April 28, 2015

New Scientific Papers Published on EPA and DHA, 1967-2014

Even with more than

28,000published papers and

3,100human clinical trials,we are still only

beginningto discover the

complete role EPA and DHA play in

human health

New Human RCTs Published on EPA and DHA, 1967-2014

Source: Norwegian Scientific Committee for Food Safety

Proteins

PhospholipidsFatty Acids

EPA and DHA have four known biological functions.They are incorporated as structural components of cell membranes, increasing fluidity and allowing for proper functioning of proteins

EPA and DHA Fatty

Acids


Proteins


EPA and DHA have four known biological functions.They are oxidized to generate bioactive metabolites called eicosanoids and docosanoids that help regulate inflammation in the body

EPA and DHA Fatty

Acids

Eicosanoids and

Docosanoids

Mitochondria


Proteins


EPA and DHA have four known biological functions.Modulate enzyme activity, including inhibiting protein kinases and preventing increases in calcium and potassium in cells

EPA and DHA Fatty

Acids

Eicosanoids and

Docosanoids

Mitochondria

Enzymes


Proteins


EPA and DHA have four known biological functions.Regulate expression of genes involved in inflammation, cell proliferation, cell death, and oxidative stress

EPA and DHA Fatty

Acids

Eicosanoids and

Docosanoids

Mitochondria

DNA

Enzymes

Throughout Life, Omega-3s are Valuable

Fetal growth

Maternal stores

Brain Growth

Visual Development

Brain Growth Regulating Inflammation

Cardiovascular Protecion

Neurological Cell

Preservation

Regulating Inflammation

CardiovascularProtection

HeartHealth

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.

Seminal O-3 Heart Health ResearchDiet 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.

Seminal O-3 Heart Health ResearchGISSI-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, and coronary death.

*Lancet 1999;354(9177):447–455.

Reprinted, with permission, from GISSI-Prevenzione Investigators, 1999

Slide Source:Lipids Online Slide Librarywww.lipidsonline.org

Total mortalityreduced by 28%(p=0.027)

Sudden deathreduced by 47%(p=0.0136)

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

GISSI-Prevenzione: Time Course of Clinical Events

>11,300 post-MI patients were given usual care with or without 850 mg EPA+DHA for 3.5 years

Days

Prob

abili

ty

0 30 60 90 120 150 180 210 240 270 300 330 360

Prob

abili

ty

0 30 60 90 120 150 180 210 240 270 300 330 360

n-3 PUFAControl

n-3 PUFAControl

Days

0.59 (0.36–0.97)p=0.037

0.72 (0.54–0.96)p=0.027

0.47 (0.22–0.99)p=0.048 0.53 (0.32–0.88)

p=0.0136

0.950.960.970.980.991.00

0.950.960.970.980.991.00

Seminal O-3 Heart Health ResearchJapan 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

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

Reprinted, with permission, from Yokoyama et al., 2007


Cum

ulat

ive

Inci

denc

e of

M

ajor

Cor

onar

y Ev

ents

(%

)

Yokoyama M. Presented at American Heart Association Scientific Sessions, Dallas, Texas, 14 November 2005.

Japan EPA Lipid Intervention Study (JELIS)

18,645 Japanese (70% women, mean age 61 years) randomized to statin alone or statin + EPA (1.8 g/d) and followed for 5 years

0 1 2 3 4 5 Years

ControlEPA

–19%

Hazard ratio = 0.81 (0.69–0.95)p = 0.011

0

1

2

3

4

Seminal O-3 Heart Health ResearchGISSI-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

*Lancet 2008;372:1223-1230..

Reprinted, with permission, from the GISSI-HF Investigators, 2008

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)

Studies in Question OMEGA

• randomized, placebo-controlled, double-blind, multicenter trial testing the effects of omega-3-acid ethyl esters-90 (1 g/d for 1 year) on the rate of sudden cardiac death in survivors of acute myocardial infarction, if given in addition to current guideline-adjusted treatment

• Conclusions: “Guideline-adjusted treatment of acute MI results in a low rate of sudden cardiac death and other clinical events within 1 year of follow-up, which could not be shown to be further reduced by the application of omega-3 fatty acids.”

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.

ReferencesAlpha 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 NordrehaugJE 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 randomisedplacebo 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.

Too Few Subjects

Omega-3 Dosage

Expanded/Composite

Endpoints

Treatment Duration too

Short

WHY?

Maintenance on Aggressive Cardiovascular

Drug Treatment

Higher Background

Omega-3 Intake

O-3 Assessment

Method

Increase in Omega-6

Intake

Context is Key

Harris WS. Are n-3 fatty acids still cardioprotective? Curr Opin Clin Nutr MetabCare. 2013;16:141-9.

James MJ, Sullivan TR, Metcalf RG, Cleland LG. Pitfalls in the use of randomisedcontrolled 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.

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.

Doct

or In

fogr

aphi

c

Meta-Analyses of Cardiac Death

Meta-Analysis # StudiesIncluded

Coronary DeathRisk Reduction

Wen et al., 2014 10 12%

Casula et al., 2013 8 32%

Delgado-Lista, 2012 13 9%

Kotwal et al., 2012 13 14%

Rizos et al., 2012 15 9%

Kwak et al., 2012 11 9%

Trikalinos, 2012 14 11%

Chen et al., 2011 10 19%

Marik et al., 2009 6 13%

Zhao et al., 2009 8 29%

Leon et al., 2008 11 20%

Blood Pressure RCT Meta-Analysis

Systolic

Diastolic

Model# Data Points WGMD

Lower 95% CI

Upper 95% CI

All studies 93 -1.52 -2.25 -0.79Hypertensive subjects 15 -4.51 -6.12 -2.83Normotensive subjects 73 -1.25 -2.05 -0.46

Model# Data Points WGMD

Lower 95% CI

Upper 95% CI

All studies 92 -0.99 -1.54 -0.44Hypertensive subjects 15 -3.05 -4.35 -1.74Normotensive 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.

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 FattyAcid (%) by Quartile

3.58 4.76 5.63 6.87

Relative Risk 1.00 0.52 0.19 0.10

N Engl J Med 2002;346:1113-8


Blood Omega-3 FA (%) by Quartile

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

Albert CM et al. N Engl J Med 2002:346:1113-1118.

Rela

tive

Ris

k

90%reductionin risk

p for trend = 0.001

3.58 4.76 5.63 6.87Mean:

1 2 3 40

0.2

0.4

0.6

0.8

1

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?


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)


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.

Public Health

High Sodium Intakes102,000

Heart Disease

Deaths from Low EPA and DHA Intakes

84,000

High Trans Fat Intakes

82,000

Alcohol Use64,000

Low Intakes of

Fruits and Vegetables

58,000

Low PUFA

&High SFA

Intakes

15,000

Annual US Deaths Preventable from Changes in Dietary Factors

Source: Danaei et al. (2010) PLoS Med 6(4): e1000058.

Public Health Impact of Low EPA/DHA Intake is serious

All Heart Attacks and Strokes

514,000

Preventable Heart

Disease Deaths from Low EPA and DHA Intakes

84,000

Source: US Centers for Disease Control and Prevention, 2009

More than 16% of all deaths from heart attacks and strokes in the United States may be prevented by increasing intakes to 250mg per day

Extrapolated to the world, this is more than 2 million people

Source: GOED Analysis

*BMJ 2014;348:g2272.

Globally, EPA/DHA Consumption is Insufficient

Globally, EPA/DHA Consumption is Insufficient

*BMJ 2014;348:g2272.

Increasing Global Burden of Disease

DALY (disability-adjusted life-year) - measure of overall disease burden, expressed as the number of years lost due to ill-health, disability or early death.

• In 2010, the attributable burden of a diet low in seafood omega-3s (EPA & DHA) was 1.1% of global DALYs.

• 22% of ischaemic heart disease DALYs attributed to low seafood omega-3 intake.

• Diets low in EPA+DHA accounted for 1,043,085 deaths in 1990 and 1,389,896 deaths in 2010.

*Lancet 2012;380:2224-2260

O-3s May Add Years to Your Life

*Mozaffarian D Lemaitre RN King IB Song X Huang H Sacks FM Rimm EB Wang M and Siscovick DS (2013). Plasma Phospholipid Long-Chain ω-3 Fatty Acids and Total and Cause-Specific Mortality in Older Adults: A Cohort Study. Ann Intern Med 158:515-525.

• Prospective cohort study of ~2700 subjects in 4 U.S. communities

• Higher circulating individual and total ω3-PUFA levels were associated with lower total mortality, especially CHD death, in older adults.

• Individuals in the highest (versus lowest) quintile lived an average of 2.22 more years after age 65.

• The findings support an average target dietary range of 250-400 mg of EPA + DHA per day.

Safety

For EPA and DHA, there is inconsistent or missing guidance on tolerable upper intake levels (ULs), the “maximum level of habitual intake from all sources of a nutrient judged to be unlikely to lead to adverse health effects in humans.”

Guidelines on Nutrition Labelling (CAC/GL 2-1985)

Upper Level of Intake (UL)

The establishment of general population NRVs should take into account upper level (UL) of intake established by recognized authoritative scientific bodies.

Guidelines on Nutrition Labelling (CAC/GL 2-1985)

Nutrient Reference Value (NRV)

U.S. Food & Drug Administration (FDA)

In 1997 the FDA determined that intakes of EPA+DHA from Menhaden Oil up to 3 g/d are safe for the general population

*Federal Register Vol. 62, No. 108: Thursday, June 5, 1997. 21CFR §184 Substances Affirmed as Generally Recognized as Safe: Menhaden Oil Final Rule

Institute of Medicine (IOM)

• Insufficient evidence to set a UL

Food and Nutrition Board, Institute of Medicine of the National Academies. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Washington D.C.: The National Academies Press, 2002/2005.

• Evaluated positive/negative human health effects from n-3 PUFAs in food supplements and fortified foods

Norwegian Scientific Committee for Food Safety (VKM)

Norwegian Scientific Committee for Food Safety (VKM). Evaluation of negative and positive health effects of n-3 fatty acids as constituents of food supplements and fortified foods. 2011.

VKM’s Conclusions

• It was not possible to identify clear adverse effects from EPA and DHA up to the dosage 6.9 g/day, and no tolerable upper intake level could be established.

Norwegian Scientific Committee for Food Safety (VKM). Evaluation of negative and positive health effects of n-3 fatty acids as constituents of food supplements and fortified foods. 2011.

European Food Safety Authority (EFSA)

In June 2011, the European Commission asked EFSA to review the existing scientific data on the possible link between the intake of n-3 PUFAs and adverse health effects and to advise the Commission on a UL for the general population and, if appropriate, vulnerable subpopulations.

EFSA Panel on Dietetic Products, Nutrition and Allergies (2012). Scientific Opinion related to the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA J 10(7):2815.

EFSA's ConclusionsAvailable data are insufficient to establish a UL for the n-3 LCPUFAs (individually or combined) for any population group.“At observed intake levels, consumption of n-3 LCPUFA has not been associated with adverse affects in healthy children or adults.”

It was not possible to identify clear adverse effects from EPA and DHA up to the dosage 5.0 g/day, and no tolerable upper intake level could be established.

EFSA Panel on Dietetic Products, Nutrition and Allergies (2012). Scientific Opinion related to the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA J 10(7):2815.

GOED's Assessment

GOED commissioned Spherix Consulting (Bethesda, MD U.S.A.) to prepare a weight of the evidence hazard identification and characterization of the n-3 fatty acids, EPA, DHA and DPA in general with specific reference to fish-and algal-derived oils containing 20% or more of EPA + DHA + DPA as native triacylglycerides (TAGs), reconstituted TAGs or ethyl esters.

Spherix Consulting, Inc. for and on behalf of the Global Organization for EPA and DHA Omega-3s (GOED) (2012). Hazard characterization of the long-chain polyunsaturated n-3 fatty acids, DHA, EPA and DPA. Unpublished, but available upon request.

• No studies were identified that are appropriate to define specific intake levels or intake/response relationships that can be used to define a UL for the investigated effects.

• Conclusion is in line with past conclusions from IOM (2005), VKM (2011) and EFSA (2012).

Spherix Conclusions

Spherix Consulting, Inc. for and on behalf of the Global Organization for EPA and DHA Omega-3s (GOED) (2012). Hazard characterization of the long-chain polyunsaturated n-3 fatty acids, DHA, EPA and DPA. Unpublished, but available upon request.

Highest Observed Intake• In the absence of an UL, consideration should be given to

an alternative, yet equally representative, value – highest observed intake (HOI).

• In 2005, a workshop convened jointly by FAO of the UN and the WHO was held with the purpose of discussing a model for nutrient risk assessment.

• Of particular interest were nutrients without reported adverse health effects. For such nutrients, the HOI level was introduced as a strategy to provide guidance to risk managers.

• “The HOI is derived only when no adverse health effects have been identified. It is the highest level of intake observed or administered as reported within (a) study(ies) of acceptable quality.”

Highest Observed Intake

Given that the HOI is grams per day and the zone of consensus is mg per day for otherwise healthy individuals, is it really necessary to determine the UL for n-3 PUFAs?

SUSTAINABILITY

Sustainability

The 2015 U.S. Dietary Guidelines Advisory Committee examined the sustainability of fish production.

The DGAC concurs with the FAO report (State of World Fisheries and Agriculture) that consistent evidence demonstrates that capture fisheries increasingly managed in a sustainable way have remained stable over several decades. However, on average, capture fisheries are fully exploited and their continuing productivity relies on careful management to avoid over-exploitation and long-term collapse.

*Scientific Report of the 2015 Dietary Guidelines Advisory Committee

Sustainability

For many, the word exploit has a negative connotation. In describing the state of fisheries, exploit is not considered negative until we talk about being overexploited. FAO defines fully exploited as follows –

The fishery is operating at or close to an optimal yield level, with no expected room for further expansion.

Sustainability

According to the most recent report of the Sustainable Fisheries Partnership, the fisheries that supply 85% of omega-3 oils just received a rating of B or higher on a scale from A through F.

*Veiga, P., P. Sousa, B. Lee-Harwood, S. Segurado, and C. Schmidt. 2015. Reduction Fisheries: SFPFisheries Sustainability Overview 2015. Sustainable Fisheries Partnership Foundation. 35 pp. Availablefrom www.fishsource.com

http://www.fishsource.com/

[email protected]

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