European Journal of Clinical Nutrition (2013), 1–5

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REVIEW

Fish oil omega-3 fatty acids and cardio-metabolic health, alone or
with statins
Anne Marie Minihane
The impact of the fish-derived omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cardiovascular
disease (CVD) and type 2 diabetes incidence and risk has been widely investigated. Although the balance of evidence suggests
substantial benefits with respect to CVD mortality, there is little evidence for an impact of these fatty acids on insulin sensitivity and
diabetes incidence, despite very promising data from animal models. The focus here will be the plasma lipid modulatory effects of
EPA and DHA and will include an exploration of the potential and demonstrated complementarity between statins and EPA/DHA on
overall CVD risk and the plasma cholesterol and triglyceride profile. Although there is some justification for greater general
population and patient EPA þ DHA intakes, an often overlooked major obstacle is that global fish stocks are limited and insufficient
to meet demands. The potential of emerging ‘non-fish foods’ to provide affordable and sustainable sources of EPA þ DHA will also
be briefly discussed.
European Journal of Clinical Nutrition advance online publication, 13 February 2013; doi:10.1038/ejcn.2013.19
Keywords: omega-3 fatty acids; fish oils; EPA and DHA; cardiovascular; insulin sensitivity; plasma lipids

INTRODUCTION
Each year cardiovascular disease (CVD) causes over four million
deaths in Europe and is responsible for 42% of total mortality in
men and 52% in women.1 Through more effective acute post
myocardial infarction and stroke management, extensive use of
revascularisation procedures, lifestyle changes and widespread
use of pharmacotherapy such as statins (HMGCoA reductase
inhibitors), CVD death rates have dropped considerably over the
past 30 years in northern and western Europe.1 However there are
concerns that CVD morbidity and eventually mortality will once
again rise due to the rapid escalation in the incidence of obesity
and type 2 diabetes (T2DM) that now occurs in 8.3% of adults
globally, with the number predicted to increase by 450% by 2030
(www.idf.org/diabetesatlas).
Over the last 50 years, a large amount of research has been
conducted on the cardiovascular benefits of the long-chain
omega-3 fatty acids found in fish, namely eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA), with 4400 papers on the
topic published in EJCN in its 25-year lifetime. Although not fully
consistent, the balance of evidence supports a role of EPA
and DHA in both the primary and secondary prevention of CVD.
The three-fold-increased CVD risk associated with adiposity and
diabetes2 is manifested through classical and emerging risk factors
such as insulin insensitivity, hypertrigylceridaemia, elevated small
dense low-density lipoprotein (LDL), inflammation and vascular
dysfunction, many of which are known to be responsive to
omega-3 fatty acid intervention.3,4
The purpose of this paper is to provide an overview of the
dietary sources, recommended intakes and sustainability of
omega-3 fatty acids, along with their impact alone or in
combination with statins on CVD and T2DM risk and on optimising
the plasma lipid profile.

Source and recommended intakes of omega-3 fatty acids
In the diet, a-linolenic acid (aLNA) derived mainly from seed oils
and the longer chain EPA and DHA from oily fish or fish oil
supplements represent the main omega-3 fatty acids. Habitual
intakes of aLNA of between 0.5–2.0% of dietary energy are
recommended.5 Although there is some suggestions that aLNA
may have independent cardioprotective benefits, its protection is
mainly thought to occur when it replaces saturated fat in the diet
or as a precursor for EPA and DHA synthesis.6 Although the
process of elongation and desaturation that converts the aLNA
(C18:3) to EPA and DHA is inefficient, with normally only 0.2–6%
conversion to EPA and 0–0.5% to DHA in humans,7,8 for non-fish
eaters, this pathway is responsible for the majority of tissue EPA
and DHA.9 Undoubtedly direct consumption of EPA and DHA is
the most effective means of improving status, with oily fish
providing 1.5–3.5 g per portion (Table 1). Alternatively, EPA and
DHA may be consumed as fish oil supplements or DHA-rich oil
supplements derived from microalgae oil that is suitable for
consumption by vegetarians. Omacor or MaxEPA represent
commonly prescribed sources of the long-chain omega-3 fatty
acids (Table 1).
With the exception of pregnant females, current omega-3 fatty
acid recommendations in adults are based on their cardioprotective actions. Although some variability exists, national and
international organisations typically recommend a minimum of
0.5 g EPA þ DHA per day to be achieved through consumption of
two portions of fish per week, one of which should be oily.10,11 In
the UK, the National Institute for Health and Clinical Excellence
(NICE) recommend that post-myocardial infarction patients
should be advised to consume at least 7 g of omega-3 fatty
acids per week from two to four portions of oily fish.12 For those
not achieving this intake from fish, a 1 g ‘omega-3 ethyl ester’

Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK. Correspondence: Professor A Marie Minihane, Department of Nutrition, Norwich Medical
School, University of East Anglia, Norwich NR4 7TJ, UK.
E-mail: a.minihane@uea.ac.uk
Received 7 January 2013; accepted 10 January 2013

EPA.04 g per day in non-fish-eating vegan. existing dwindling worldwide marine stocks. Consumption of SDA is low. The harvesting of Krill (small crustaceans. EPA þ DHA intakes of 0. but high production costs are a critical hurdle in terms of large-scale production.17 but it leads to a more efficient conversion to EPA than does aLNA.29 g/g capsule Elongase 20: 4n-3 Eicosatetraenoic acid Δ5 Desaturase 20: 5n-3 EPA Elongase 22: 5n-3 DPA Abbreviations: DHA.19 g/g capsule) 0. bKennedy et al. The initial step in the EPA/DHA biosynthesis pathway from aLNA. with consumption of this dose as either a standard fish oil or microalgae oil (see below) costing h3–5 and h20–25 per month respectively.01–0. For example.2 g per day.15 Although Krill has a large overall biomass.4 1. although in principal increased intakes of EPA and DHA above current intakes either alone or as an adjunct to prescribed medications is likely to produce significant health benefits. eicosapentaenoic acid.05 g per day. (2012). little impact on DHA status following SDA-soybean oil has been observed.2 0. namely its conversion to stearidonic acid (SDA). The recently developed transgenic SDA-soybean holds considerable potential regarding a viable source of EPA in humans.03 19 (0.02–0. an Australian study reported a median intake of 0. i. with commonly consumed oils such as rapeseed oil and soybean having B10% aLNA.8 1. Euphausia superba) in the Antarctic Ocean has produced an alternative source of marine EPA þ DHA largely used by the aquaculture industry.b Trouta Coda Plaicea Prawnsa Roast beef/pork/lamba Chickena Cod liver oil Omacor (Abbott HealthCare) MaxEPA (Seven Seas) 18: 3n-3 . Land plant foods are devoid of EPA and DHA as they lack the desaturase enzymes necessary for the bioconversion (Figure 1). 410-fold lower than the minimum recommended intake. are wholly inadequate to meet any substantial increase in demand. international treaties are in place to limit ‘over-fishing’ and European Journal of Clinical Nutrition (2013) 1 – 5 Δ6 Desaturase 24: 6n-3 Tetracosahexaenoic acid B-oxidation 22: 5n-3 DHA Figure 1. which produce one million tonnes of fish oils annually.05 0. these average consumption figures are misleading with regular oily fish consumers (o10% population) skewing the data to the right.18 & 2013 Macmillan Publishers Limited . EPA and DHA biosynthesis.1 0.6 1. catalysed by q6 desaturase is the rate-limiting step in the reaction. vegetarians and meat eaters. Furthermore.2–0.3 0.e.1 0.9 Cost and global sustainability of EPA and DHA: a need for ‘non-fish’ sources Affordability of fish and supplements is a recognised major barrier to EPA and DHA intake.03 g per day in adults with a mean intake of 0. This dose of 1 g per day of EPA and DHA for secondary prevention is equivalent to that recommended by the American Heart Association (AHA). seeds and nuts are a significant source of the shorter chain aLNA.84 g/g capsule 0. that is.5 g EPA þ DHA per day. However. given its fundamental role near the bottom of the marine food chain.Fish oil omega-3 fatty acids and cardio-metabolic health A Marie Minihane 2 Table 1. Main dietary and supplementary sources of long-chain omega-3 fatty acids Source Herringa Mackerela Salmon (wild)a Salmon (canned)a Sardines (canned)a Tuna.14 Elongase 24: 5n-3 Tetracosapentaenoic acid (Omacor) supplement is recommended.Linolenic acid Δ6 Desaturase EPA þ DHAg/100 g 18: 4n-3 Stearidonic acid 1. bluefinb Tuna (canned)a.8 1. intakes are likely to be o0. with supplemental studies indicating enhanced plasma and tissue EPA status. average population intakes of EPA and DHA are o0.19 g per day. docosahexaenoic acid. However. the vast majority of western populations.5 0. European Prospective Investigation into Cancer and Nutrition (EPIC) Norfolk cohort. Farmed marine microalgae (for example. Calculations based on a recent publication estimate that an expenditure of h6–21 per month14(depending on oily fish oil source) is required to provide the minimum of 0. ensure sustainability of the species.13 In the UK. For non-supplement users who eat oily fish less than once per month. although the complexities of the metabolic engineering of seed oils means that enhancing the levels of DHA in transgenic plants is a major challenge.3 1. Schizochytrium) provide a rich source of omega-3 fatty acids and in particular DHA16 suitable for vegetarians and vegans.11 Current estimates indicate that for most countries.2 1. a (BNF 1999).26 g per day were evident in fish-eaters with intakes of only 0. given that oily fish or fish oil supplement intake trends are bimodal. with a bioequivalency of B5:1 following SDA soybean intervention (Note: see the Journal of Nutrition Mar 2012 supplemental issue on ‘Heart Health Omega-3 for food: stearidonic acid (SDA) as a sustainable choice’). However. with higher amounts found in the less frequently consumed flaxseed oil (45–55%). The recently developed EPA-rich Camelina oil (wildflax) also hold tremendous promise. A limited number of human randomised controlled trials (RCTs) have demonstrated that its bioefficacy is comparable to traditional fish oils. in reality.

20.46 Elevated circulating triglyceride (TG) levels are thought to be the metabolic driver of the dyslipidaemic triad of the (ALP) that is associated with lower HDL-cholesterol levels and an increased number of LDL particles in the small dense LDL3 form (Figure 2). insulin of HbA1c was evident.44 However. & 2013 Macmillan Publishers Limited European Journal of Clinical Nutrition (2013) 1 – 5 . and in particular.19 the impact of EPA and DHA on cardiovascular risk has been investigated in a large number of human association studies and secondary prevention trials.and totalcholesterol. protein. In (ALP) men.7 years. CE Impact of increased triglyceride-rich lipoproteins on HDL & LDL metabolism.0–16. with the size effects on CVD risk between extreme quintiles comparable to that of LDL.47 Earlier studies using high doses of EPA and DHA (43 g per day) showed highly significant 20–50% reductions in fasting TG and associated modest increases in both LDL. This consistent TG-lowering effect of fish oil fatty acids.2 g EPA þ DHA per day for 12 weeks had no impact on insulin sensitivity. supportive of their cardioprotective benefits. Impact of EPA and DHA on insulin sensitivity and diabetes risk Earlier animal studies that provided considerable evidence of the insulin-sensitising impact of increased EPA and DHA intakes.27. vascular function and blood pressure. makes it difficult to conclude with any degree of certainty regarding the size effect of these intakes on individual CVD end-points. and intakes of 2–3 g per day thought to be needed to cause any meaningful reduction in the plasma inflammatory profile. we observed a 35 and 26% decrease in TG and LDL3 levels.43 In a recent meta-analysis of prospective cohort studies.22–27 The underlying physiological mechanisms mediating the effects include:28           Anti-arrhythmic29 Improved heart rate30 Reduced platelet aggregation and thrombosis24 Improved endothelial and overall vascular function31 Reduce blood pressure32 Anti-inflammatory33 Increased plaque stability34 Hypotriglyceridaemia35 Increased high-density lipoprotein (HDL)-cholesterol36 Decreased LDL337 Impact of EPA and DHA on triglycerides and the atherogenic lipoprotein phenotype Although the literature is not suggestive of on overall protective impact of EPA and DHA on insulin sensitivity and T2DM risk. which is referred to as the atherogenic lipoprotein phenotype (ALP). HL HDL Rapidly removed from circulation decreasing HDL-C Free cholesterol.35 with hyperlipidaemic individuals being particularly responsive.Fish oil omega-3 fatty acids and cardio-metabolic health A Marie Minihane 3 glucose and insulin metabolism. with follow-ups of 4. considerable heterogeneity in association was evident with an additional 2012 meta-analysis. nor circulating levels EPA and DHA biomarkers and incident T2DM was observed. indicating geographical differences in the associations between EPA þ DHA status and intake and T2DM.45 The cardiovascular benefits of EPA and DHA Since the highly cited publications of Jørn Dyerberg and Hans Olaf Bang in Greenland Inuits. following supplementation with 3 g EPA þ DHA per day. there is significant evidence to suggest that fish oils are particularly effective at counteracting the dyslipidaemia associated with obesity and T2DM. In fact.21 the comprehensive literature is. in one of the largest RCTs conducted to date. Although two recent meta-analyses of RCTs have cast a ‘shadow of a doubt’ on the benefits of EPA and DHA on a range of cardiovascular end-points. As we have recently reviewed. and 25 670 cases. respectively. the LIPGENE study. the addition of 1.38. no association between intakes of fish or seafood or EPA and DHA. non-fasting TG levels are a highly significant risk factor for CVD.39 However. has led to the Responsiveness of the various CVD risk markers is very much dose-dependent with anti-arrhythmic actions evident at intakes as little as 200 mg per day. phospholipid. with a deleterious impact of fish oils on whole body More atherogenic relative to LDL1 and LDL2 ↑ small dense LDL3 LDL Enhanced inflammation HL TG CE CE CETP CE ↑ TRL TG HL Endothelial dysfunction ↑ small dense HDL3 CE enriched TRL remnants Sequesters cholesterol into artery wall TG Figure 2.41 but recent studies using more physiological fish oil intakes have observed no effect.and HDL-cholesterol.42 In a 2008 Cochrane review that included 23 RCTs. with no impact on HDL-cholesterol. TG. no significant impact of fish oils on plasma glucose. the distinct lack of adequately powered RCTs that have fed doses of EPA þ DHA of between 1–3 g per day.40 led to the suggestion that fish oils may positively modulate glucose and insulin metabolism in humans and thereby reduce T2DM risk and incidence. For example. the earlier human RCTs were suggestive of the opposite. in general.

17 Whelan J. with variable fatty acid composition is becoming increasingly feasible.57 Subsequent short-term studies have confirmed that statins in combination with fish oils/EPA concentrate has a more favourable impact on plasma lipoproteins size and lipid concentrations than statins alone. Khaw KT. 106: 2747–2757. REFERENCES 1 Nichols M. statin therapy is recommended for adults with clinical evidence of CVD and as part of a management strategy for the primary prevention of CVD in adults who have a X20% 10-year risk of developing CVD. Appel LJ. Arch Int Med 2012. 6 Pan A. Lewis JL. Transgenic oilseed crops as an alternative to fish oils. 19 Dyerberg J. The Stationary Office: Norwich. alpha-Linolenic acid and risk of cardiovascular disease: a systematic review and meta-analysis. 142: 592S–599SS. CONFLICT OF INTEREST The author declares no conflict of interest. Recommended dietary reference intakes. Milligan GC.52. 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