Scientific Basis for a Public Health Recommendation for EPA/DHA

Transcription

1 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

2 Omega-3s are One of the Most Research Compounds in Health and Nutrition The Body of Evidence: Randomized, Controlled Trials in Humans Source: Pubmed, as of April 28, 2015

3 New Scientific Papers Published on EPA and DHA, Even with more than 28,000 published papers and 3,100 human clinical trials, we are still only beginning to discover the complete role EPA and DHA play in human health New Human RCTs Published on EPA and DHA, Source: Pubmed as of April 28, 2015

4 Proteins EPA and DHA Fatty Acids Phospholipids Fatty 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 Source: Norwegian Scientific Committee for Food Safety

5 Proteins EPA and DHA Fatty Acids Phospholipids Fatty Acids Eicosanoids and Docosanoids Mitochondria 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 Source: Norwegian Scientific Committee for Food Safety

6 Proteins EPA and DHA Fatty Acids Phospholipids Fatty Acids Eicosanoids and Docosanoids Mitochondria Enzymes EPA and DHA have four known biological functions. Modulate enzyme activity, including inhibiting protein kinases and preventing increases in calcium and potassium in cells Source: Norwegian Scientific Committee for Food Safety

7 Proteins EPA and DHA Fatty Acids Phospholipids Fatty Acids DNA Eicosanoids and Docosanoids Enzymes EPA and DHA have four known biological functions. Regulate expression of genes involved in inflammation, cell proliferation, cell death, and oxidative stress Mitochondria Source: Norwegian Scientific Committee for Food Safety

8 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 Cardiovascular Protection

9 Heart Health

10 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): **INFORM 2015;26(1):25-27.

11 Seminal O-3 Heart Health Research 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):

12 Seminal O-3 Heart Health Research 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 allcause mortality, sudden death, and coronary death. Reprinted, with permission, from GISSI-Prevenzione Investigators, 1999 *Lancet 1999;354(9177):

13 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 Total mortality reduced by 28% (p=0.027) Days Probability 0.59 ( ) p= ( ) p=0.027 n-3 PUFA Control Sudden death reduced by 47% (p=0.0136) Days Probability 0.47 ( ) p=0.048 Marchioli R et al. Circulation 2002;105: ( ) p= n-3 PUFA Control Slide Source: Lipids Online Slide Library

14 Seminal O-3 Heart Health Research Japan EPA Lipid Intervention Study (JELIS) ,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):

15 Japan EPA Lipid Intervention Study (JELIS) Cumulative Incidence of Major Coronary Events (%) Control EPA Years 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 Yokoyama M. Presented at American Heart Association Scientific Sessions, Dallas, Texas, 14 November % Hazard ratio = 0.81 ( ) p = Slide Source: Lipids Online Slide Library

16 Seminal O-3 Heart Health Research GISSI-HF ,000 patients with class II- IV heart failure Randomized to receive either 1 g Lovaza ( 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:

17 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)

18 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)

19 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:

20 References Alpha Omega Trial Group (2010). n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 363: 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: 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: ORIGIN Trial Investigators (2012). n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 367: 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:

21 WHY? Increase in Omega-6 Intake Omega-3 Dosage O-3 Assessment Method Treatment Duration too Short Higher Background Omega-3 Intake Too Few Subjects Maintenance on Aggressive Cardiovascular Drug Treatment Expanded/Co mposite Endpoints

22 Context is Key Harris WS. Are n-3 fatty acids still cardioprotective? Curr Opin Clin Nutr Metab Care. 2013;16: 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: 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.

23 Doctor Infographic

24 Meta-Analyses of Cardiac Death Meta-Analysis # Studies Included Wen et al., % Casula et al., % Delgado-Lista, % Kotwal et al., % Rizos et al., % Kwak et al., % Trikalinos, % Chen et al., % Marik et al., % Zhao et al., % Leon et al., % Coronary Death Risk Reduction

25 Blood Pressure RCT Meta-Analysis Systolic Model # Data Points WGMD Lower 95% CI Upper 95% CI All studies Hypertensive subjects Normotensive subjects Diastolic Model # Data Points WGMD Lower 95% CI Upper 95% CI All studies Hypertensive subjects Normotensive subjects 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:

26 Is it me or is it EPA+DHA?

27 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.

28 Relative Risk of Sudden Death from Cardiac Causes According to Base-Line Blood Level of Long-Chain n-3 Polyunsaturated Fatty Acids Quartile Blood Omega-3 Fatty Acid (%) by Quartile Relative Risk N Engl J Med 2002;346:1113-8

29 Relative Risk of Sudden Cardiac Death and Blood Omega-3 Levels: Physicians' Health Study Relative Risk % reductio n in risk p for trend = Mean: Blood Omega-3 FA (%) by Quartile Albert CM et al. N Engl J Med 2002:346: Slide Source: Lipids Online Slide Library

30 Research in Progress

31 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 D 3 (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?

32 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 1 st occurrence of any component of the composite endpoint (includes cardiovascular death)

33 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.

34 Public Health

35 Public Health Impact of Low EPA/DHA Intake is serious High Sodium Intakes 102,000 Annual US Deaths Preventable from Changes in Dietary Factors Heart Disease Deaths from Low EPA and DHA Intakes 84,000 High Trans Fat Intakes 82,000 Alcohol Use 64,000 Low PUFA & High SFA Intakes 15,000 Low Intakes of Fruits and Vegetables 58,000 Source: Danaei et al. (2010) PLoS Med 6(4): e

36 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 Preventable Heart Disease Deaths from Low EPA and DHA Intakes 84,000 All Heart Attacks and Strokes 514,000 Source: US Centers for Disease Control and Prevention, 2009

37 Extrapolated to the world, this is more than 2 million people Source: GOED Analysis

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

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

40 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 *Lancet 2012;380:

41 O-3s May Add Years to Your Life 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 mg of EPA + DHA per day. *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:

42 Safety

43 Upper Level of Intake (UL) 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 )

44 Guidelines on Nutrition Labelling (CAC/GL ) Nutrient Reference Value (NRV) The establishment of general population NRVs should take into account upper level (UL) of intake established by recognized authoritative scientific bodies.

45 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, CFR 184 Substances Affirmed as Generally Recognized as Safe: Menhaden Oil Final Rule

46 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.

47 Norwegian Scientific Committee for Food Safety (VKM) Evaluated positive/negative human health effects from n-3 PUFAs in food supplements and fortified foods 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

48 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

49 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.

50 EFSA's Conclusions Available 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.

51 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 fishand 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.

52 Spherix Conclusions 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 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.

53 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.

54 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?

55 SUSTAINABILITY

56 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

57 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.

58 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 Reduction Fisheries: SFP Fisheries Sustainability Overview Sustainable Fisheries Partnership Foundation. 35 pp. Available from

59 Questions?