European Journal of Clinical Nutrition (2013) 67, 536–540
& 2013 Macmillan Publishers Limited All rights reserved 0954-3007/13
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 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 (2013) 67, 536–540; doi:10.1038/ejcn.2013.19; published online 13 February 2013
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: [email protected]
Received 7 January 2013; accepted 10 January 2013; published online 13 February 2013
Fish oil omega-3 fatty acids and cardio-metabolic health
A Marie Minihane
537
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
Δ6 Desaturase
EPA þ DHAg/100 g
18: 4n-3
Stearidonic acid
1.2
1.8
1.8
1.4
1.6
1.5
0.2–0.3
1.1
0.2
0.3
0.1
0.02–0.05
0.03
19 (0.19 g/g capsule)
0.84 g/g capsule
0.29 g/g capsule
Elongase
20: 4n-3
Eicosatetraenoic acid
Δ5 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 fish or fish oil supplement intake trends are
bimodal, these average consumption figures are misleading with
regular oily fish consumers (o10% population) skewing the data
to the right. For non-supplement users who eat oily fish 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 þ DHA intakes of 0.26 g per day were evident in fish-eaters
with intakes of only 0.01–0.04 g per day in non-fish-eating vegan,
vegetarians and meat eaters.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. 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 0.5 g
EPA þ DHA per day, 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.
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 significant health
benefits, in reality, existing dwindling worldwide marine stocks,
which produce one million tonnes of fish 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 þ DHA largely used by the aquaculture industry. A limited
number of human randomised controlled trials (RCTs) have
demonstrated that its bioefficacy is comparable to traditional fish
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-fishing’ and
& 2013 Macmillan Publishers Limited
Δ6 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 significant 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 flaxseed oil
(45–55%). 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 efficient
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 (wildflax) 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
European Journal of Clinical Nutrition (2013) 536 – 540
Fish oil omega-3 fatty acids and cardio-metabolic health
A Marie Minihane
538
glucose and insulin metabolism,41 but recent studies using more
physiological fish 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 þ DHA per day for 12 weeks had no
impact on insulin sensitivity.42 In a 2008 Cochrane review that
included 23 RCTs, no significant impact of fish oils on plasma
glucose, insulin of HbA1c was evident.43 In a recent meta-analysis
of prospective cohort studies, with follow-ups of 4.0–16.7 years,
and 25 670 cases, no association between intakes of fish 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 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,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 benefits of EPA and DHA on a range of
cardiovascular end-points,20,21 the comprehensive literature is, in
general, supportive of their cardioprotective benefits.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, there
is significant evidence to suggest that fish 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
significant 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 significant 20–50% 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 þ DHA per day, with no impact on HDL-cholesterol. This
consistent TG-lowering effect of fish 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 2–3 g per day thought to
be needed to cause any meaningful reduction in the plasma
inflammatory profile, vascular function and blood pressure.27,38,39
However, the distinct lack of adequately powered RCTs that have
fed doses of EPA þ DHA of between 1–3 g per day, makes it
difficult 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 fish 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 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.
HL
HDL
Rapidly removed from circulation
decreasing HDL-C
Free cholesterol, phospholipid, protein, CE
Impact of increased triglyceride-rich lipoproteins on HDL & LDL metabolism.
European Journal of Clinical Nutrition (2013) 536 – 540
& 2013 Macmillan Publishers Limited
Fish oil omega-3 fatty acids and cardio-metabolic health
A Marie Minihane
539
AHA recommending 2–4 g EPA þ 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 þ 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.49–51 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, efficacious and first-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 fibrates,
niacin and fish oils, with combined therapies in particular
recommended in patients with TG X500 mg/dl (7 mmol/l). The
benefit of a combined statin plus fish oil has the effect of
potentiating the TG-lowering, anti-inflammatory and vascularmodulating impact of both compounds with statins ameliorating
the LDL-C elevation evident following high-dose fish 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 þ 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% confidence interval of 1.71, 1.11–2.64)
was evident with a 53% reduction following EPA intervention.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.58,59
CONCLUSION
Multiple cardiovascular risk factors are positively affected by fish
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 þ 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
& 2013 Macmillan Publishers Limited
statin intervention alone. However, further long-term studies with
clinical end-points are needed to confirm the synergistic benefits
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 sufficient affordable supply, which
could potentially be provided by novel transgenic seeds oils. The
bioefficacy of these new oils, relative to fish oils, has not yet been
comprehensively studied.
CONFLICT OF INTEREST
The author declares no conflict of interest.
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