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European Journal of Clinical Nutrition (2013), 15

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www.nature.com/ejcn

REVIEW

Fish oil omega-3 fatty acids and cardio-metabolic health, alone or


with statins
Anne Marie Minihane
The impact of the sh-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 benets 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 prole. Although there is some justication for greater general
population and patient EPA DHA intakes, an often overlooked major obstacle is that global sh stocks are limited and insufcient
to meet demands. The potential of emerging non-sh foods to provide affordable and sustainable sources of EPA DHA will also
be briey discussed.
European Journal of Clinical Nutrition advance online publication, 13 February 2013; doi:10.1038/ejcn.2013.19
Keywords: omega-3 fatty acids; sh 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 benets of the long-chain
omega-3 fatty acids found in sh, 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), inammation 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 prole.

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 sh or sh oil
supplements represent the main omega-3 fatty acids. Habitual
intakes of aLNA of between 0.52.0% of dietary energy are
recommended.5 Although there is some suggestions that aLNA
may have independent cardioprotective benets, 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 inefcient, with normally only 0.26%
conversion to EPA and 00.5% to DHA in humans,7,8 for non-sh
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 sh
providing 1.53.5 g per portion (Table 1). Alternatively, EPA and
DHA may be consumed as sh 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 DHA per day to be achieved through consumption of
two portions of sh 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 sh.12 For those
not achieving this intake from sh, 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

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, bluefinb
Tuna (canned)a,b
Trouta
Coda
Plaicea
Prawnsa
Roast beef/pork/lamba
Chickena
Cod liver oil
Omacor (Abbott HealthCare)
MaxEPA (Seven Seas)

18: 3n-3
- Linolenic acid
6 Desaturase

EPA DHAg/100 g

18: 4n-3
Stearidonic acid

1.2
1.8
1.8
1.4
1.6
1.5
0.20.3
1.1
0.2
0.3
0.1
0.020.05
0.03
19 (0.19 g/g capsule)
0.84 g/g capsule
0.29 g/g capsule

Elongase
20: 4n-3
Eicosatetraenoic acid
5 Desaturase
20: 5n-3
EPA
Elongase
22: 5n-3
DPA

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid.


a
(BNF 1999). bKennedy et al. (2012).14

Elongase
24: 5n-3
Tetracosapentaenoic acid

(Omacor) supplement is recommended. 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).11
Current estimates indicate that for most countries, average
population intakes of EPA and DHA are o0.2 g per day. However,
given that oily sh or sh oil supplement intake trends are
bimodal, these average consumption gures are misleading with
regular oily sh consumers (o10% population) skewing the data
to the right. For non-supplement users who eat oily sh less than
once per month, that is, the vast majority of western populations,
intakes are likely to be o0.05 g per day, i.e. 410-fold lower than
the minimum recommended intake. For example, an Australian
study reported a median intake of 0.03 g per day in adults with a
mean intake of 0.19 g per day.13 In the UK, European Prospective
Investigation into Cancer and Nutrition (EPIC) Norfolk cohort,
EPA DHA intakes of 0.26 g per day were evident in sh-eaters
with intakes of only 0.010.04 g per day in non-sh-eating vegan,
vegetarians and meat eaters.9
Cost and global sustainability of EPA and DHA: a need for
non-sh sources
Affordability of sh and supplements is a recognised major barrier
to EPA and DHA intake. Calculations based on a recent publication
estimate that an expenditure of h621 per month14(depending on
oily sh oil source) is required to provide the minimum of 0.5 g
EPA DHA per day, with consumption of this dose as either a
standard sh oil or microalgae oil (see below) costing h35 and
h2025 per month respectively.
Furthermore, 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 signicant health
benets, in reality, existing dwindling worldwide marine stocks,
which produce one million tonnes of sh oils annually, are wholly
inadequate to meet any substantial increase in demand. The
harvesting of Krill (small crustaceans, Euphausia superba) in
the Antarctic Ocean has produced an alternative source of marine
EPA DHA largely used by the aquaculture industry. A limited
number of human randomised controlled trials (RCTs) have
demonstrated that its bioefcacy is comparable to traditional sh
oils.15 Although Krill has a large overall biomass, given its
fundamental role near the bottom of the marine food chain,
international treaties are in place to limit over-shing and
European Journal of Clinical Nutrition (2013) 1 5

6 Desaturase
24: 6n-3
Tetracosahexaenoic acid
B-oxidation
22: 5n-3
DHA

Figure 1.

EPA and DHA biosynthesis.

ensure sustainability of the species. Farmed marine microalgae


(for example, Schizochytrium) provide a rich source of omega-3
fatty acids and in particular DHA16 suitable for vegetarians and
vegans, but high production costs are a critical hurdle in terms of
large-scale production.
Land plant foods are devoid of EPA and DHA as they lack
the desaturase enzymes necessary for the bioconversion
(Figure 1). However, seeds and nuts are a signicant source of
the shorter chain aLNA, with commonly consumed oils such as
rapeseed oil and soybean having B10% aLNA, with higher
amounts found in the less frequently consumed axseed oil
(4555%). The initial step in the EPA/DHA biosynthesis pathway
from aLNA, namely its conversion to stearidonic acid (SDA),
catalysed by q6 desaturase is the rate-limiting step in the reaction.
Consumption of SDA is low,17 but it leads to a more efcient
conversion to EPA than does aLNA. The recently developed
transgenic SDA-soybean holds considerable potential regarding a
viable source of EPA in humans, with supplemental studies
indicating enhanced plasma and tissue EPA status, 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, little impact on DHA status following
SDA-soybean oil has been observed. The recently developed
EPA-rich Camelina oil (wildax) also hold tremendous promise,
although the complexities of the metabolic engineering of seed
oils means that enhancing the levels of DHA in transgenic plants is
a major challenge.18
& 2013 Macmillan Publishers Limited

Fish oil omega-3 fatty acids and cardio-metabolic health


A Marie Minihane

3
glucose and insulin metabolism,41 but recent studies using more
physiological sh oil intakes have observed no effect. For example,
in one of the largest RCTs conducted to date, the LIPGENE study,
the addition of 1.2 g EPA DHA per day for 12 weeks had no
impact on insulin sensitivity.42 In a 2008 Cochrane review that
included 23 RCTs, no signicant impact of sh oils on plasma
glucose, insulin of HbA1c was evident.43 In a recent meta-analysis
of prospective cohort studies, with follow-ups of 4.016.7 years,
and 25 670 cases, no association between intakes of sh or
seafood or EPA and DHA, nor circulating levels EPA and DHA
biomarkers and incident T2DM was observed.44 However,
considerable heterogeneity in association was evident with an
additional 2012 meta-analysis, indicating geographical differences
in the associations between EPA DHA status and intake and
T2DM.45

The cardiovascular benets of EPA and DHA


Since the highly cited publications of Jrn Dyerberg and Hans Olaf
Bang in Greenland Inuits,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.
Although two recent meta-analyses of RCTs have cast a shadow
of a doubt on the benets of EPA and DHA on a range of
cardiovascular end-points,20,21 the comprehensive literature is, in
general, supportive of their cardioprotective benets.2227 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-inammatory33
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, there
is signicant evidence to suggest that sh oils are particularly
effective at counteracting the dyslipidaemia associated with
obesity and T2DM, which is referred to as the atherogenic
lipoprotein phenotype (ALP).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). As we have recently
reviewed, TG, and in particular, non-fasting TG levels are a highly
signicant risk factor for CVD, with the size effects on CVD risk
between extreme quintiles comparable to that of LDL- and totalcholesterol.47
Earlier studies using high doses of EPA and DHA (43 g per day)
showed highly signicant 2050% reductions in fasting TG and
associated modest increases in both LDL- and HDL-cholesterol,35
with hyperlipidaemic individuals being particularly responsive. In
(ALP) men, we observed a 35 and 26% decrease in TG and
LDL3 levels, respectively, following supplementation with 3 g
EPA DHA per day, with no impact on HDL-cholesterol. This
consistent TG-lowering effect of sh oil fatty acids, 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, and intakes of 23 g per day thought to
be needed to cause any meaningful reduction in the plasma
inammatory prole, vascular function and blood pressure.27,38,39
However, the distinct lack of adequately powered RCTs that have
fed doses of EPA DHA of between 13 g per day, makes it
difcult to conclude with any degree of certainty regarding the
size effect of these intakes on individual CVD end-points.
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,40 led
to the suggestion that sh oils may positively modulate glucose
and insulin metabolism in humans and thereby reduce T2DM risk
and incidence. In fact, the earlier human RCTs were suggestive of
the opposite; with a deleterious impact of sh 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.

HL
HDL

Rapidly removed from circulation


decreasing HDL-C

Free cholesterol, phospholipid, protein, CE

Impact of increased triglyceride-rich lipoproteins on HDL & LDL metabolism.

& 2013 Macmillan Publishers Limited

European Journal of Clinical Nutrition (2013) 1 5

Fish oil omega-3 fatty acids and cardio-metabolic health


A Marie Minihane

4
AHA recommending 24 g EPA DHA per day as an effective
hypotrigylceridaemic dose.11 Although it was originally thought
that such high intakes were necessary to bring about meaningful
changes in TG, more recent RCTs have indicated that lower intakes
can also be effective. In the FINGEN study, supplementation with
0.7 and 1.8 g EPA DHA per day resulted in group mean
reductions in TG of 8% and 11%, with APOE4 carriers (25%
Caucasians) and men being particularly responsive.48
There has also been considerable interest in establishing the
individual impact of EPA versus DHA on plasma lipid and other
CVD biomarkers, in particular in an era where the production of
tailor-made transgenic oils, with variable fatty acid composition is
becoming increasingly feasible. Available evidence is suggestive
that both EPA and DHA are TG-lowering with slightly greater
reductions with DHA.4951 DHA also appears to most effective at
increasing the size of both LDL and HDL particles.50,51
Fish oils as an adjunct to statins
Large clinical trials over the past two decades have established
statins as a cost-effective, efcacious and rst-line lipid lowering
therapy.52,53 In the UK, 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.54 In patients at high risk of
CVD events, there is currently a great deal of interest in the use of
combined therapies driven by the observations that high-risk
statin-treated patients often continue to have high rates of
cardiovascular events, and the fact that TG levels are high
correlates of residual risk in patients on statins.53,55,56 A number of
adjunct lipid modulating therapies are available, including brates,
niacin and sh oils, with combined therapies in particular
recommended in patients with TG X500 mg/dl (7 mmol/l). The
benet of a combined statin plus sh oil has the effect of
potentiating the TG-lowering, anti-inammatory and vascularmodulating impact of both compounds with statins ameliorating
the LDL-C elevation evident following high-dose sh oils in
hyperlipidaemic individuals.35,37
In the Japan EPA Lipid Intervention Study (JELIS), 18 645
hypercholesterolaemic patients (total cholesterol 46.5 mmol/l)
were assigned to statins or statins 1.8 g EPA per day. At 4.6-year
follow-up, a 19% reduction in major coronary events was evident
in the EPA-supplemented group along with a reduction in
unstable angina and non-fatal coronary events.26 In subgroup
analysis in patients with elevated TG (42.1 mmol/l) and low
HDL-cholesterol (o1.1 mmol/l), a greater risk of coronary heart
disease (hazards ratio, 95% condence interval of 1.71, 1.112.64)
was evident with a 53% reduction following EPA intervention.57
Subsequent short-term studies have conrmed that statins in
combination with sh oils/EPA concentrate has a more favourable
impact on plasma lipoproteins size and lipid concentrations than
statins alone.58,59

CONCLUSION
Multiple cardiovascular risk factors are positively affected by sh
oil fatty acids. The lipid modulatory, and in particular, TG-lowering
impact of EPA and DHA have been consistently described, with a
relatively comprehensive understanding of dose-response relationships, at least at a population level. Although modest
reductions in population LDL-cholesterol levels are evident over
the last 25 years,60 raised TG levels are becoming increasingly
prevalent due to its association with obesity and insulin resistance.
Accumulating evidence, in particular, the output from the JELIS
trial suggests that a statin EPA/DHA intervention may be a
particularly effective therapy, and especially in those with elevated
TG levels. In these individuals, it is likely that EPA/DHA will
counteract a substantial portion of the residual risk following
European Journal of Clinical Nutrition (2013) 1 5

statin intervention alone. However, further long-term studies with


clinical end-points are needed to conrm the synergistic benets
of statins and omega-3 supplements on cardiovascular incidence
and mortality. A more widespread use of omega-3 fatty acids will
require the availability of a sufcient affordable supply, which
could potentially be provided by novel transgenic seeds oils. The
bioefcacy of these new oils, relative to sh oils, has not yet been
comprehensively studied.

CONFLICT OF INTEREST
The author declares no conict of interest.

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