The document discusses factors that influence the bioavailability of omega-3 fatty acids from supplements. It finds that re-esterified triglyceride forms of omega-3s have higher bioavailability than ethyl-ester forms. The bioavailability of krill oil is similar to fish oil when doses are matched for EPA and DHA content. Higher doses of EPA and DHA from supplements are needed to raise omega-3 blood levels, with requirements varying based on starting levels, age, sex, weight, and activity levels.

1. Bioavailability of omega-3 supplements
Nina Bailey
BSc MSc PhD ANutr

2.  Fatty acid structure will affect the bioavailability of
omega-3 fatty acids
 Efficacy of the omega-3 fatty acid therapy is
influenced by bioavailability
 Ensuring maximal bioavailability is therefore crucial
to ensuring successful clinical outcomes

3. Common forms of omega-3

5.  Fatty acids must be digested before uptake:
Lipase breaks bonds in triglycerides
Phospholipase breaks bonds in phospholipids
Carboxylester lipase breaks bonds in ethyl esters
Monoglycerides
Free fatty acids
Lysophosphatides

6.  After absorption into enterocytes the
metabolism of long-chain fatty acids
involves re-esterification into:
Triglyceride (2-monoglyceride pathway)
Phospholipid (a-glycerophosphate pathway)
Formation of chylomicrons for further
transport

11. • Ethyl-Ester vs triglyceride
Numerous studies have assessed the absorption and bioavailability of ethyl-
ester fish oils in comparison to TG, with some early reporting similar
absorption rates for the two types of oil whilst others have suggested TG to
be superior
It appears that when a glycerol back bone is provided (by consuming
additional fat) EE are equally well absorbed as TG (Nordoy et al., 1991)
As the EPA content of natural TG is only 18%, the use of ethyl-ester (EE) is
common in both clinical trials and in pharmaceutical omega-3 products
because EE offers the concentrations required for therapeutic outcomes
Increasing interest/demand for rTG for both bioavailability
and concentration

12. Bioavailability of marine omega-3 fatty acid formulations
Participants (n = 72) randomly assigned to ~3.3 grams per day of
a blend of EPA and DHA daily for 2 weeks (Dyerberg et al., 2010)
• Re-esterified TG (rTG)
• Fish body oil (natural TG)
• Cod liver oil (natural TG)
• Free fatty acid (FFA)
• Ethyl-ester (EE)
• Corn oil (placebo)

13. Base line plasma levels of EPA and DHA
were measured in plasma total lipids
[cholesterol esters (CE), phospholipids (PL)
and triglycerides (TG)] and then again at
the end of the two week period.
The results showed that group taking the
fish oil in the EE form had the lowest
increase in EPA and DHA
Dyerberg et al., 2010

14. Raising the omega-3 index rTG vs. ethyl-ester
Double-blinded placebo-controlled trial (Neurobronner et al., 2010)
A total of 150 volunteers was randomly assigned to one of the three
groups:
• fish oil concentrate with EPA+DHA (1.01 g+0.67 g) given as rTG
• fish oil concentrate with EPA+DHA (1.01 g+0.67 g) given as ethyl ester
• corn oil (placebo group)
Volunteers consumed four gelatine-coated soft capsules daily over a
period of six months. The omega-3 index was determined at baseline (t(0))
after three months (t(3)) and at the end of the intervention period (t(6))

15. CONCLUSION:
A six-month supplementation of identical doses
of EPA+DHA led to a faster and higher increase
in the omega-3 index when consumed as rTG
than when consumed as ethyl esters (EE)
Raising the omega-3 index rTG vs. ethyl-ester
The omega-3 index increased significantly in both groups treated with omega-3
FAs from baseline to t(3) and t(6) (P<0.001). The omega-3 index increased to a
greater extent in the rTG group than in the EE group (t(3): 186 versus 161%
(P<0.001); t(6): 197 versus 171% (P<0.01))
Omega-3index(%)

16. Fish oil vs. krill oil
Krill are shrimp-like crustaceans of the species
Euphausia superba, found mostly in the
Antarctic and North Pacific Oceans

17. Krill oil – USPs
• The long-chain fatty acids in Krill are absorbed
and carried to the body’s cells in phospholipid
form
• Phospholipids form the structural basis of cell
membranes and are more effectively utilised by
the body

18. • The DHA content of krill is similar to that of oily fish,
but the EPA content is generally higher
• Krill oil also contains the carotenoid Astaxanthin, a
naturally occurring antioxidant that gives krill oil its
red/pink colour and that acts as a natural preservative
• The growing interest in krill as an alternative source of
omega-3 is leading to an increase in krill oil products

20. • The message that krill may provide benefits similar to
fish oil has been growing rapidly although there are
still relatively few human studies conducted on krill
• Initial indications suggest that krill oil can reduce
inflammation and cardiovascular risk factors including
cholesterol and triglycerides
• Studies confirming the specific benefits of fish oil
currently run into the thousands, compared to only a
handful on krill oil

21. • Much of the marketing of krill oil focus on its
superior bioavailability with consumer targeted
messages such as, ‘less is more’
• MegaRed Krill oil 300mg ‘one-a-day-capsule’
delivers 36mg EPA and 16.5mg DHA
• But are the omega-3 fatty acids in krill oil more
bioavailable than those found in standard fish
body oil?

22.  Krill vs fish oil in ‘like for like’ dosing (Maki et al., 2009)
2g krill oil vs 2g fish oil
Results: comparable uptake of EPA and DHA
 Comparing krill with fish oil (Ulven et al., 2011)
3.0g krill oil vs 1.8g fish oil
Results: comparable uptake of EPA and DHA but no significant difference in
omega-3 levels with higher intake of krill – doesn’t support the ‘less is more’
 Krill vs fish oil in ‘like for like omega-3’ dosing (Ramprasath et al., 2013)
Uptake of EPA and DHA as krill oil superior to fish oil ?? Issue with study bias!!

23. Incorporation of EPA and DHA into plasma phospholipids in
response to different omega-3 fatty acid formulations
Double-blinded cross over (Schuchardt et al., 2011)
n = 12 (males)
Single dose of:
• 7.0g krill oil (1050 mg EPA: 630mg DHA)
• 3.4g fish oil ethyl-ester (1008mg EPA: 672mg)
• 3.4g fish oil triglyceride (1008mg EPA: 672mg)

25. • Main findings
– The omega-3 concentrations in plasma phospholipids were at
their highest 24 hours after consumption of all three EPA and
DHA containing oils
– EPA and DHA were absorbed in the following order
Krill oil > triglyceride > ethyl ester
– krill oil contained high amounts of EPA and DHA as free fatty
acids rather than as total phospholipid (22% EPA and 21% DHA)
– However, due to high standard deviation values, there were no
statistically significant difference in uptake between the three
treatments

26.  Although superior bioavailability of omega-3 in krill oil over fish oil is
suggested , none of the studies have managed to show significant
improvement in absorption of omega-3 fatty acids with krill oil over
fish oil
 At the most, data from a bioavailability study in humans showed a
tendency for higher bioavailability for EPA after krill oil consumption
compared with fish oil (Schuchardt et al., 2013), however this study
tested an acute single dose of omega-3 PUFA over 48h
 Neurobronner’s six month study gives a better indication of
bioavailability by addressing the omega-3 index suggesting that rTG is
superior to EE

27. Use of Ethyl-esters in clinical settings
Currently all pharmaceutically available omega-3 products are in the
form of EE
• Vascepa (Cardiovascular)
• Lovaza (Cardiovascular)
• Omacor (Cardiovascular)
• Miraxion (Huntington’s)

28. Ethyl-EPA studies
JELIS study found
 1.8g/day of ethyl-EPA in just under 20,000
hypercholesterolaemic subjects randomised to EPA +
statins or statins alone = 19% reduced incidence of
major CVD
 That increasing EPA and reducing AA to EPA ratio were
both useful in preventing coronary artery disease

29. Vascepa™ trials:
• ANCHOR & MARINE looked at role of EPA on inflammatory markers
associated with CVD and atherosclerosis in hypertriglyceridaemic
patients taking statins for cholesterol control
• Both studies randomised subjects to 12 weeks of taking 4 or 2g EPA or
placebo daily
• Results showed 4g EPA reduced TGs, non-HDL cholesterol and other
markers of atherosclerosis without increasing total LDL
• The ANCHOR study used predominantly (>70%) diabetic subjects and
showed 4g EPA daily significantly improved lipid profiles and lipid related
markers without negatively impacting glycaemic control

30. Using biomarkers to determine fatty acid status
• AA to EPA ratio
• Omega-3 index

31. The omega-3 index
 The omega-3 index is defined as the content of EPA and DHA in the cell
membrane of RBCs, expressed as a weight percentage of total fatty
acids and reflects tissue fatty acid composition
 The omega-3 index in RBC correlates highly with the EPA+DHA content
in both plasma and whole blood, but RBC EPA+DHA is better correlated
to long-term fatty acid intake and is a more suitable biomarker for the
nutritional status of an individual
 RBC EPA+DHA also correlates to EPA and DHA content of cardiac muscle
 Responsive to increasing intakes and the half-life of EPA+DHA in RBCs is
4–6 times longer than in serum, with concentrations returning to
baseline 16 weeks after supplementation (Harris & Von Schacky, 2004)

32. The omega-3 index: a dose response
Harris & Von Schacky, 2004

33. Omega-3 index - biomarker of cardiovascular health
Harris & Von Schacky, 2004
Albert et al., 2002

34.  The amount of EPA+DHA needed to achieve a target omega-3 index is
poorly defined, as are the determinants of the omega-3 index in response to
a change in EPA+DHA intake
 A randomised, placebo-controlled, double-blind, parallel-group study
(n=115)
 One of 5 doses (0, 300, 600, 900, 1800 mg) of EPA+DHA (as rTG) was given
daily as placebo or fish oil supplements for 5 months
 Develop a predictive model of the omega-3 index in response to EPA+DHA
supplementation and identify factors that determine the response
Flock et al., 2013
RBC omega‐3 fatty acid content in response to fish oil supplementation:
A dose–response randomised controlled trial

35.  Variability was influenced by baseline omega-3 index, age, sex and physical
activity
 Lower omega-3 index status and older age each predicted greater increases in
omega-3 index
 Increased physical activity level was associated with a higher omega-3 index
 Female subjects had a non-significant increase in omega-3 compared to males
 However, body weight was the greatest influencer

37. Using the body‐weight‐adjusted values to increase the omega-3
index from 4.3% to 8% (change of 3.7% = 0.016mg/kg EPA+ DHA)
An individual weighing:
95 kg requires 1.5 g omega-3/day
75 kg requires 1.2 g omega-3/day
55 kg requires 0.9 g omega-3/day

38. Summary
• There is little evidence to support the bioavailability claims
related to krill oil and many of the health benefits attributed to
krill oil may arise from its high Astaxanthin content
• Given the cost of krill oil compared to standard fish oils, krill oil
may not currently offer a cost effective substitute for highly
concentrated omega-3 product
• The majority of bioavailability data favours phospholipid, re-
esterified triglyceride and free fatty acid over triglyceride and
ethyl-ester

39. Igennus recommend the following guidelines to optimise the bioavailability of ethyl-EPA
 Smaller capsules
Unlike our competitors, we keep our capsules small, making them not only easier to swallow but
to encourage and highlight the importance of split dosing
 Split-dosing
High doses of EPA should be distributed throughout the day. Not only does this help with
digestion and uptake of the fatty acids within the oil, but it also ensures that blood levels are
sustained throughout the day
 Taking the supplements with food
Capsules should never be taken on an empty stomach. Taking E-EPA with food (and ideally in the
presence of other dietary oil/fat) will increase the body’s natural ability to digest and absorb the
fatty acids
 Inclusion of vitamin E
We add vitamin E to all of our EPA products to protect the free fatty acids from oxidation both
pre and post digestion

40. ninab@igennus.com
www.igennus.com
drninabailey.co.uk
01223 421434
07527384229