The evidence base for the effective
clinical use of omega 3s
David Levy
Consultant P hysician, Diabetes & Endocrinology
Whipps Cross University Hospital
David.Levy@Whippsx.nhs.uk
Omega-3 fatty acids are used in two areas of clinical practice: as
prophylaxis in the period following myocardial infarction, and in patients
with severely elevated triglycerides (hypertriglyceridaemia), either as part
the metabolic syndrome or in one of the several mostly genetically
determined dyslipidaemias. The randomised controlled trial (RCT)
evidence is patchy and in patients with coronary artery disease not
consistent; in patients with hypertriglyceridaemia the evidence is more
solid, but outcome measures, such as incidence of heart disease, have not
yet been studied. However, there is much experimental evidence that
elevated triglycerides, particularly in the period of post-prandial stress,
exert many adverse effects on the vasculature, and when very high can
cause fatal acute pancreatitis. Most importantly from the patient
perspective, the side-effects of omega-3s, even when used in high doses,
appear to be mild.
Omega 3s in hypertriglyceridaemia
Depressed HDL cholesterol levels and elevated triglycerides frequently
coexist and are inversely correlated, so it is often difficult to disentangle
the role of elevated triglycerides alone, but major epidemiological studies,
such as PROCAM, have established the role of modestly elevated
triglycerides independent of HDL levels.
Both values, but not LDL cholesterol, are included in definitions of the
metabolic syndrome, and though contentious, it appears that significantly
abnormal levels are indeed associated with increased cardiovascular (CV)
risk. In two recent clinical RCTs (ACCORD lipid and FIELD) treatment
with fibric acid drugs reduced CV events in those with triglycerides >2.3
mmol/L, though in the overall study population, which had only slightly
elevated triglycerides, there were no benefits.
Triglyceride-induced pancreatitis
Severe hypertriglyceridaemia (triglycerides >10 mmol/L) is a risk factor
for not only vascular disease, but acute pancreatitis, a frequent cause of
hospital admission with severe abdominal pain; it can be fatal. Alcohol
excess, poorly controlled diabetes, some medications and a variety of
genetic causes – often in combination – predispose to severe
hypertriglyceridaemia.
Treatment of elevated triglycerides
Reduction in alcohol intake and carbohydrate-rich foods, together with
improved control of diabetes where applicable are the mainstays of
lifestyle modification, but most patients will require pharmacological
treatment. Of course we have to encourage our patients to eat lots of oily
fish, but in clinical practice the doses of omega-3s required to reduce
triglycerides are high and operate through multiple mechanisms, largely
in the liver. These include reducing production of VLDL, the triglyceride-
carrying apolipoprotein, increasing β oxidation within the liver, and
increasing peripheral clearance of VLDL particles.
Multiple actions of omega 3s in reducing VLDL/TGs
Increased  oxidation
Effect may increase with treatment duration (Thies et al 2003)
Jacobson TA. Am J Clin Nutr 2008;87(suppl):1981S-90S
Standard fish oil capsules contain about 400 mg of omega-3s, in an
approximate EPA/DHA ratio of 3:2. Very high strength prescription-only
preparations, for example Omacor (UK) or Lovaza (USA), now known
generically as omega-3-acid ethyl esters-90, contain 1g EPA+DHA per
capsule. Liquid fish oil, though cheaper, is often not tolerated at high
doses, though 10 mL of a high-strength preparation eg Seven Seas Extra
High Strength (UK), provides 2.3 g EPA+DHA. A high fish intake can
provide up to 2 g daily, but this is much more than most of the UK
population routinely eat, and even in the recent OMEGA study (2010)
carried out in Germany, fewer than 1% of the population ate fish daily,
and up to 5% never ate fish.
Can 1g daily intake be
achieved by eating fish?
1 g Omacor
daily is
equivalent to:
Omacor
38 g mackerel
53 g herring
70 g salmon
213 g shrimps
425 g eel
175 g tuna
275 g cod
Fish meal
eaten
Calories
1 capsule
kippered
mackerel
fillet grilled
fillet steamed
fresh, without
shells
smoked fillet
steaks, fresh
fillet in batter
9
89
105
137
251
834
243
687
Data from manufacturers of Omacor, 2002
In clinical practice, treatment is often started with a specific triglyceridereducing agent, for example, fibric acid drugs or niacin, to rapidly reduce
the risk of acute pancreatitis, and omega-3s added later and titrated in
dose. However, carefully used, omega-3s can be as effective as fibric acid
drugs, both yielding triglyceride reductions of about 25%, as can be seen
in the following figures, the second panel showing data from the VA-HIT
study published over a decade ago.
Meta-analysis of 72 placebo-controlled studies of
effect of omega 3 supplements on triglycerides
5
P<0.0001
P<0..0001
0
% change
-5
Placebo
-10
n-3FA
-15
Difference
-20
-25
-30
TG <2
TG ≥2
Redrawn from Harris WS. Clin Nutr 1997; 65 (suppl): 1645S-54S
VA-HIT (gemfibrozil)
Changes from baseline (%)
15
10
7.5
4.0 3.6
5
9.6
1.8
0
-5
-2.1 -2.8
-10
-15
-20
Placebo
-25
Gemfibrozil
-24.5
-30
l
ro
ste
e
l
o
Ch
L
LD
-c
ol
s
ter
s
ide
er
ole
c
h
y
c
igl
LTr
HD
l
ro
ste
e
l
ho
Adapted from Rubins et al. N Engl J Med 1999; 341: 410-418
Effect of omega-3s on lipid profile
In a meta-analysis of placebo-controlled studies using omega-3
supplements in two groups with relatively low and high triglycerides (<2
and >2 mmol/L, respectively), it can be seen that both LDL and HDL
cholesterol levels increase. The effect on HDL may not be statistically
significant in the high-triglyceride group, and the effect on LDL may be
mediated through an increase in larger, less atherogenic particles.
Meta-analysis of 72 placebo-controlled studies of
n-3 FA supplements on lipids and lipoproteins
LDL cholesterol Total cholesterol
10
HDL cholesterol
P<0.001
NS
8
% change
6
P<0.02
P<0.008
Placebo
4
n-3FA
P<0.009
2
Difference
NS
0
-2
TG <2
TG ≥2
TG <2 TG ≥2
TG <2 TG ≥2
Redrawn from Harris WS. Clin Nutr 1997; 65 (suppl): 1645S-54S
Omega-3s in the prevention of cardiac events
Building on the epidemiological evidence that people eating diets rich in
omega-3s had fewer coronary events, the GISSI Prevenzione Study
(1999) was the first properly conducted RCT in patients within 3 months
of a heart attack. The cardiac studies of omega-3s have generally used
much lower doses – usually 1 g EPA+DHA daily – than in triglyceride
reduction. However, in GISSI-P the pattern of lipid changes was similar
to that seen in the meta-analysis of high-dose omega-3s, but perhaps as
expected with low dose omega-3s, there was only a modest decrease in
triglycerides. However, there was a significant reduction in
cardiovascular events, especially sudden death, attributed to membranestabilising properties of omega-3s that reduced arrhythmias. On the basis
of this study, in the UK high-strength omega-3s (1g/day) are licensed for
post-MI prophylaxis starting within 3 months of the index event.
Lipid profile in GISSI-P (MI within 3
months)
TC
LDL-C
HDL-C
TG
12
10
8
% change
6
4
Control
2
Omega 3s
0
-2
-4
-6
GISSI-Prevenzione Investigators. Lancet 1999; 354: 447-455
More recently, the JELIS study (2008) carried out in a Japanese
population, found that combined low-dose statin and high-dose omega-3
(EPA, 2.4 g/day) reduced events in those patients who had already had a
cardiovascular event (secondary prevention) – but interestingly,the
intervention did not reduce sudden cardiac death, possibly because this
was a population with an already very high intake of omega-3s. There
were unusual features of this study, for example, a very high baseline
serum cholesterol level (mean 7.1 mmol/L) in a population traditionally
thought to have an exceptionally favourable lipid profile. However, those
with the highest number of risk factors (central obesity, low HDL
cholesterol and/or elevated triglycerides, hypertension, elevated total
cholesterol) had the greatest benefit in event reduction. All but one of
these is used in internationally-agreed definitions of the metabolic
syndrome.
Sub-group analysis of primary prevention
patients in JELIS
P<0.05
JELIS Investigators. Atherosclerosis 2008; 200: 135-140
Definition of metabolic syndrome – IDF, 2005
METABOLIC SYNDROME
Central
Obesity
Waist circumference
Male > 94 cm
Female > 80 cm
Must have
Triglycerides
HDL-cholesterol
Blood pressure
Blood glucose
> 1.69
Male < 0.9
Female < 1.1
≥ 130/ 85
≥5.6
+
any 2 of these
Interestingly, subsequent analysis also showed that secondary prevention
stroke patients (those who had already suffered a stroke) had a reduced
risk of further stroke, but this effect was not seen in those who had not
had a previous stroke. A note of caution: in the most recent secondary
prevention study in myocardial infarction patients, OMEGA (2010)
conducted between 2003 and 2007, neither sudden death nor
cardiovascular events were reduced after a year of 1g/d omega-3s, but as
in so many recent secondary prevention studies, the event rate was
exceptionally low, and OMEGA was considered to be statistically
underpowered.
However, even in the recent GISSI-HF (heart failure) study (2008), The
Lancet was able to conclude on its front page:
GISSI-HF
GISSI-HF: The Lancet, 4 October 2008
Patients with significant heart failure were treated with 1g/d of omega-3s
together with optimum modern heart failure treatments. The risk
reduction was small, around 10% in relative terms or a 2% absolute
reduction, but heart failure is one of the burgeoning epidemics of our time,
and the significant reduction in hospitalisation for heart failure with this
treatment was a welcome outcome in this study. In GISSI-Prevenzione,
patients with more severe left ventricular dysfunction (ejection fraction
<50%) benefited more, and sudden deaths were significantly reduced in
this group compared with those who had better preserved function.
Notably, in the same GISSI-HF trial, a potent statin (rosuvastatin)
conferred no benefit.
Future prospects in diabetes
At least two RCTs are in progress in these higher risk patients; both are
probably sufficiently powered to demonstrate benefit or otherwise.
Trials in progress in Type 2 diabetes
 ASCEND (A Study of Cardiovascular Events
iN Diabetes)
 n=10000; primary prevention diabetes: 2x2
randomisation to aspirin 100 mg daily and 1g n3FA. Follow up 5 years: still in recruitment
 ORIGIN (Outcome Reduction with Initial
Glargine INtervention)
 Secondary prevention: glargine vs conventional
glycaemic treatment; 1g n3-FA vs placebo.
Recruitment from 2003, results early 2010
If I had been writing this a few years ago I would probably have placed
omega-3s as second line treatment for hypertriglyceridaemia, but they are
valuable as first-line in ambulatory patients with modestly elevated
triglycerides (fibrates remain drugs of choice for reliable triglyceride
reduction in patients with severe hypertriglyceridaemia). Certainly,
alternatives to fibrates must be considered in the light of the largely
negative results of recent trials (notably FIELD and ACCORD Lipid). In
addition, omega-3s are highly acceptable to patients, many of whom,
especially if they have diabetes, already have long lists of medications.
As well as encouraging them to increase their dietary omega-3 intake,
they can easily supplement with 2-4 grams of fish oils daily if required.
Although prescription omega-3s are not licensed for combination
treatment with other lipid-modifying agents, they have a unique mode of
action, quite different from that of the statins, with which they are
routinely prescribed in post-MI patients, and RCTs have reported adverse
effects that are no more frequent than in placebo-treated patients.
Conclusions
 General agreement that pharmacological doses of
omega 3s should be used in significant
hypertriglyceridaemias to reduce risk of acute
pancreatitis (and probably CV events – though no
RCTs possible)
 Omega 3s probably second line after fibrate (hazards
of statin + fibrate)
 Cogent case for their first line use in Type 2 diabetes
with TG in light of disappointing results of FIELD
study (effects on glycaemia are clinically trivial)
Conclusions
 Accumulating evidence that pharmacological doses of
omega 3s (not far off doses achievable by diet) are of
benefit in:
 MI within 3 months
 Heart failure
 Angina (DART-2)
 Strong hint (with limits from JELIS analyses) of
benefit in:
 Severe hypercholesterolaemia
 Primary prevention in metabolic syndrome (with TG and
HDL) and those with multiple CV risk factors
 Secondary prevention of stroke