Bioavailability of omega-3 supplements

Nina BaileyBSc MSc PhD ANutr

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

Common forms of omega-3

Fatty acids must be digested before uptake:

Lipase breaks bonds in triglyceridesPhospholipase breaks bonds in phospholipidsCarboxylester lipase breaks bonds in ethyl esters

MonoglyceridesFree fatty acidsLysophosphatides

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

• 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

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)

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

Raising the omega-3 index rTG vs. ethyl-esterDouble-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))

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-esterThe 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))

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Fish oil vs. krill oil

Krill are shrimp-like crustaceans of the species Euphausia superba, found mostly in the Antarctic and North Pacific Oceans

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

• 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

• 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

• 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?

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!!

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)

• 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 orderKrill 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

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

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)

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

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

Using biomarkers to determine fatty acid status

• AA to EPA ratio

• Omega-3 index

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)

The omega-3 index: a dose response

Harris & Von Schacky, 2004

Omega-3 index - biomarker of cardiovascular health

Harris & Von Schacky, 2004Albert et al., 2002

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

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

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/day75 kg requires 1.2 g omega-3/day55 kg requires 0.9 g omega-3/day

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

Igennus recommend the following guidelines to optimise the bioavailability of ethyl-EPA

Smaller capsulesUnlike 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-dosingHigh 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 foodCapsules 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

ninab@igennus.comwww.igennus.comdrninabailey.co.uk

01223 42143407527384229