Manny Noakes Research Director CSIRO FOOD AND NUTRITION Omega-3 Nutrition- Fish versus Supplements

2 | n-3 LC PUFA intake LC PUFA n-3 reputed wide-ranging health benefits. Humans limited capacity to synthesize n-3 LC. Consumption of preformed n-3LC PUFA s needed. Seafood best dietary source. ~20% Australians consumed fish & seafood (Aus Health Survey 2011/12) Vegan, vegetarian and non fish consumers may be very low in n-3 LC PUFA Slide from W Stonehouse

Median n-3 LC PUFA intakes (mg/day) Meyer et al 2011 CountryPopulation Year of data collectionMedian intakes (mg/day) Greenland Eskimos ,000 Canada Inuit of Nunavik James Bay Cree Quebec ∼ Japan Kyushu SW island of Japan INTERLIPID study Aito Town INTERLIPID study Japanese living in Hawaii France All regions of France Nth Sth Europe 7 Centres in Europe Belgium Women living in Flanders Australia 1995 National Nutrition Survey Germany German Nutrition Survey USA USDA1994–1996 ∼ 115 Netherlands Rotterdam coronary calcification study |

Current Australian Guidelines NHMRC nutrient reference values (NRVs) in 2006 for omega-3 LCPUFA recommending both an adequate intake 160mg/day (men) and 90mg/day (women) and a suggested dietary target to prevent chronic disease – 600mg/day for men and 400mg/day for women. FSANZ also supports the consumption of omega-3 LCPUFA by allowing general-level health claims for heart health on commercially available food products. The food must contain a minimum of 50 mg EPA+DHA combined in a serving of food. Australian Dietary Guidelines recommend at least 2 serves of (any) fish per week. 4 | Slide from W Stonehouse

Health Claims for Heart Health 5 | EPA & DHA contribute to heart health FSANZ DHA & EPA contribute to normal function of the heart (0.25 g/d) DHA & EPA contribute to maintenance of normal blood pressure (3 g/d) DHA & EPA contribute to maintenance of normal blood triglyceride levels (2 g/d) DHA contributes to maintenance of normal blood triglyceride levels (2 g/d in combination with EPA) Supportive but not conclusive research shows consumption of EPA & DHA omega-3 fatty acids may reduce risk of coronary heart disease. EFSA FDA Slide from W Stonehouse

2008 Recommendations 6 |

8 |

Systematic reviews – literature between FISH OIL SUPPLEMENTS Are omega-3 LCPUFA supplements effective in the primary prevention of coronary heart disease? Are omega-3 LCPUFA supplements an effective intervention for the secondary prevention of CHD? Are omega-3 LCPUFA supplements effective in the prevention or treatment of heart failure? Are omega-3 LCPUFA supplements an effective intervention for lowering plasma triglycerides in hypertriglyceridaemic patients? FISH Is the reported consumption of omega-3 LCPUFA from fish associated with lower incidence of CHD events in primary prevention? Is the reported consumption of fish associated with a lower incidence of CHD in patients with existing CHD (i.e. secondary prevention)? Is the reported consumption of fish, or dietary patterns high in omega-3 LCPUFA associated with lower incidence of heart failure?

Fish Oil Studies 10 |

Are omega-3 LCPUFA supplements effective in the primary prevention of coronary heart disease? 11 | Kotwal et al 2012 Level 1 Omega 3 Fatty acids and cardiovascular outcomes: systematic review and meta-analysis Rizos et al 2012 Level 1 Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis Bosch et al 2012 Level 11 n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia Itakura et al 2011 Level 11 Relationships between plasma fatty acid composition and coronary artery disease Roncaglioni et al Level 11 n-3 fatty acids in patients with multiple cardiovascular risk factors There is no current evidence that omega-3 LCPUFA supplementation is beneficial or the primary prevention of CHD doses of EPA/DHA was 1-2 g

Copyright © American Heart Association, Inc. All rights reserved. 20 trials and > patients No effect of ω-3 fatty acids on composite cardiovascular outcomes Kotwal et al 2012 a systematic review and meta-analysis Level 1 Evidence

Are omega-3 LCPUFA supplements effective in the secondary prevention of coronary heart disease? 13 | 5 Level 1 meta-analyses were included: Kotwal et al.; Rizos et al.; Kwak et al.; Zhao et al., and Marik et al. The two meta-analyses published prior to 2010 provided evidence of benefit in patients with existing CHD, but the meta-analyses published after 2010 did not. 3 Level II RCTs included the OMEGA study (2010), Alpha to Omega study (2010) and GISSI Heart Failure (GISSI-HF) trial 2 trials provided 1 g EPA/DHA, one for 1 year (OMEGA and GISSI-HF), while the Alpha-Omega trial provided 400 mg EPA/DHA. The OMEGA trials did not find evidence of a beneficial effect There is no current evidence that omega-3 LCPUFA supplementation is beneficial for the secondary prevention of CHD.

Might statins inhibit LC PUFA n-3? – possible mechanisms de Lorgeril et al BMC Medicine 2013 Statins increase arachidonic acid, the main n-6 fatty acid in cell membranes. This may in turn inhibit the protective effects of n-3 because n-6 and n-3 fatty acids are in competition through various pathways involved in the development and complications of CHD. Thus statins may inhibit n-3 by interfering in the n-3/n-6 interplay and favoring n |

Does Statin Use Mitigate the Benefit of Omega-3 Fatty Acids? Seth et al Meta-Regression of Randomized Trials Seth. 23 studies with 38,910 n-3 LCPUFA; 38,866 controls. Lower control group statin use (b = 0.222, P = 0.027) and higher DHA/EPA (b = , P = 0.033) ratio was associated with higher reduction in total mortality. 15 | Statin use may mitigate, and higher DHA/EPA ratio is associated with the beneficial effect of PUFA supplementation.

GISSI-HF trial 7,000 patients with functional Class II to IV heart failure were randomised to 1 g/day or placebo. Over a 3.9-year median follow-up, supplementation resulted in an absolute 9% reduction in mortality or admission to hospital (p=0.04). Benefit was greater in elderly and diabetic patients and those with impaired left ventricular function (sub-groups with greater absolute risk). 16 | Are omega-3 LCPUFA supplements effective in the prevention or treatment of heart failure? There is modest benefit from 1g n-3 LCPUFA in heart failure and in particular in those with greater absolute CHD risk. Around 300,000 Australians are living with heart failure, and every year around another 30,000 people are newly diagnosed with it

Are omega-3 LCPUFA effective for lowering plasma triglycerides in hypertriglyceridaemic patients? 2 positive meta-analyses Hartweg et al 2007 and Reiner et al Effective Dosage: Starting with 1200 mg/day DHA+EPA Increase if needed to: 4000 mg/day Checking patient’s response every 3-4 weeks when the dose is changed, until target TG levels reached. 17 | These data confirm high doses n-3 LCPUFA as a means for lowering plasma triglyceride levels.

Do Omega-3 LCPUFA Alter the Risk or Incidence of High Blood Pressure? 3 meta-analyses Appel et al 1993, Geleijnse et al 2002, Morris et al 1993 have shown that omega-3 LCPUFA reduce BP with the greatest effect in hypertensive patients -3.4 to -5.5 mmHg systolic BP -2.0 to -3.5 mmHg diastolic BP Dokholyan et al also suggested that greater than >3 g/day n-3 LCPUFA is required to reduce BP in patients with high- normal diastolic BP or stage 1 hypertension. 18 | Mori et al. showed that in overweight, mildly- hypercholesterolaemic patients, 4 g/day of encapsulated DHA, but not EPA, reduced 24-hour BP by -5.8/-3.3 mmHg.

EPA/DHA and blood pressure: a meta-analysis. Miller et al 2014 Effect of EPA+DHA on blood pressure in RCTs. 70 RCTs were included. The strongest effects in untreated hypertensives systolic blood pressure = mm Hg diastolic blood pressure = mm Hg BP also lowered among normotensives systolic blood pressure = mm Hg diastolic blood pressure = mm Hg 19 | Provision of EPA+DHA reduces systolic BP, while provision of ≥2g omega3 LCPUFA reduces diastolic BP.

Omega-3 and LCPUFA Rheumatoid Arthritis Patient-assessed pain, morning stiffness, number of painful and/or tender joints and non-steroidal anti- inflammatory drug (NSAID) consumption Large dosages EPA+DHA (>3g/d) needed for 3 months to see symptomatic benefits. 1yr trial, 5.5 g EPA+DHA/d – lower failure rate of 1 st -line therapy (Proudman et al. 2015) |

n-3 LCPUFA and Cognition 21 | Suggestive evidence DHA enhances learning and cognitive development in children; memory and reaction time particularly: Individuals with low habitual intake of LC n-3 Children with low literacy ability Age-related cognitive decline Stonehouse et al 2013 Stonehouse et al Meta-analyses – n-3 LCPUFA improved memory, attention & processing speed in adults with mild cognitive impairment / age-related cognitive decline Yurko-Mauro et al 2015 Mazereeuw et al 2012 Cooper et al 2015 Slide from W Stonehouse

n-3 LCPUFA & Depression Meta-analysis (Martins, 2009): Symptoms of depression significantly reduced with pure ethyl-EPA and high EPA (>50%) supplements. No effects seen with pure DHA or high DHA (>50%) supplements. Greatest effects in therapeutic populations (bipolar disorder and major depression) vs. mild-to-moderate depression Dose-response effect. 22 |

n-3 LCPUFA in depression Sublette et al trials 916 participants Sublette et al 2011 % EPA in the supplements was the fixed-effect predictor, dichotomized into 2 groups: EPA < 60% or EPA ≥ 60% of the total EPA + DHA Supplements with EPA ≥ 60% showed benefit on standardized mean depression scores (effect size = 0.532; P <.001) versus supplements with EPA < 60% (effect size = ; P =.756) Supplements with EPA < 60% were ineffective. 23 | Supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200 to 2,200 mg/d of EPA in excess of DHA, were effective against primary depression.

Fish/Dietary Studies 24 |

Is consumption of omega-3 LCPUFA from fish associated with lower incidence of CHD events in primary prevention? de Goede et al, 2010 Marine (n-3) fatty acids, fish consumption, and the 10-year risk of fatal and nonfatal coronary heart disease in a large population of Dutch adults with low fish intake Joensen et al 2011 Marine n-3 polyunsaturated fatty acids in adipose tissue and the risk of acute coronary syndrome Mozaffarian et al 2013 Plasma phospholipid long- chain omega-3 fatty acids and total and cause- specific mortality in older adults: a cohort study Musa-Veloso et al Impact of low v. moderate intakes of long-chain n-3 fatty acids on risk of coronary heart disease –benefit with >250 mg omega-3 LCPUFA from fish reducing the risk of sudden cardiac death by 35% Streppel et al 2008 Long-term fish consumption and n-3 fatty acid intake in relation to (sudden) coronary heart disease death: the Zutphen study 25 | There is good evidence that increased consumption of fish or dietary patterns with omega-3 LCPUFA are associated with the primary prevention of coronary heart disease (Level 111) Prospective cohort studies

Is consumption of fish associated with lower incidence of heart failure? Meta-analysis -7 prospective cohort studies - 176,441 subjects with 5,480 cases of heart failure. High fish intake protective against developing HF. Cardiovascular Health Study - 4,738 US adults >65y. Highest quintile had 32% lower risk compared to those who consumed fish < or = to 1/month (p trend 0.009). A 14.3-year follow-up -The Atherosclerosis Risk in Communities (ARIC) study - plasma phospholipid omega-3 LCPUFA (especially EPA) at baseline inversely correlated with heart failure in women but not in men (P<0.001). 26 | Prospective cohort studies These observational data are supportive of a modest inverse association between fish consumption and heart failure. Level III

27 | Is consumption of fish associated with lower CHD in patients with existing CHD (i.e. secondary prevention)? Evidence from prospective cohort studies Only two applicable new studies. Manger et al. 2010, Dietary intake of n-3 long-chain PUFA and coronary events in Norwegian patients with coronary artery disease. Pottala et al 2010 Blood EPA and DHA predict all-cause mortality in patients with stable coronary heart disease: the Heart and Soul study. Evidence support s the consumption of fish including oily fish for secondary prevention of CHD. Level III

Are Omega-3 LCPUFA from Fish Associated with Lower Stroke Risk? Mozaffarian et al. (2013) reported total plasma phospholipid omega-3 LCPUFA were inversely related to ischaemic stroke risk (p=0.043) with a 37% reduction in the highest versus the lowest quintile, but there was no significant effect on haemorrhagic stroke (p=0.86). DHA most strongly associated with reduction in ischaemic stroke and DPA with reduction in stroke death. Larsson et al., meta-analysis of fish consumption and stroke in 15 prospective studies, - increment of 3 servings of fish/week associated with a 6% lower incidence of total stroke. Interventions with fish oil supplementation have not demonstrated any reduction in stroke. 28 | These data suggest that fish intake is associated with lower stroke risk.

Key Findings: Omega-3 LCPUFA supplements - neither a beneficial nor adverse effect demonstrated in primary or secondary prevention of CHD. The evidence continues to be positive for the role of omega-3 LCPUFA in the treatment of hypertriglyceridaemia The evidence continues to be positive for the role of omega-3 LCPUFA as a benefit to prevent heart failure. Higher fish intake was associated with lower incident rates of heart failure in addition to lower sudden cardiac death, stroke and myocardial infarction.

2015Recommendations FISH Dietary intake of fish consistently found to be of benefit for the protection from heart disease and stroke. Higher fish intake was associated with lower incident rates of heart failure,o lower sudden cardiac death, stroke and myocardial infarction. Heart Foundation recommends all Australians include 2-3 three serves fish (including oily fish)/week as part of a heart healthy eating pattern. This amount of fish provides between mg per day of combined docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). SUPPLEMENTS Omega-3 LCPUFA supplements can be considered in patients with heart failure in additional to standard therapy. Omega-3 LCPUFA supplements are effective in the treatment of hypertriglyceridaemia. 30 |