Interpreting Nutrition Research:A practitioner toolkit for clinical

success

Today’s talk objectives:

• To gain a deep understanding of why nutrition research often fails to produce expected results

• To understand how to critically review nutrition research to determine which nutrients really work – with a focus on brain health

• Understand how failures in research methods help us to be better clinicians

• Learn how to use this information to ensure success with your clinical protocols

Part 1: Why fish oils fail

(according to the research headlines)

Alarming headlines, butDO FISH OILS REALLY FAIL?

“Do fish oils REALLY keep the brain young? Study finds 'no evidence' that

omega-3 supplements slow mental decline”

“Is your omega-3 fish oil supplement any good - or a load

of old codswallop?”“Omega-3 supplements do little to protect you from heart diseases,

says new study”

“The benefits of omega-3 seem fishy”

“Experts cast doubt on omega-3”

“Insufficient evidence to support omega-3 as a treatment for depression”

– Cochrane review

“Fish oils are no benefit for diabetes”

Inconsistencies arising from dietary intervention studies give mixed results and create confusing messages (Von Schacky 2015; Harris 2015)

Poor heterogeneity in study designs, background diets, endpoint definitions, and baseline fish or omega−3 fatty acid intakes cloud meta-analysis outcomes

Patients recruited regardless of their baseline levels and treated with fixed doses

Recent RCTs (virtually all of which have been conducted in European or North American cohorts [low dietary fish intakes]) use relatively low doses (376–850 mg EPA & DHA) which at least partly explains their failure

CVD secondary-prevention populations - include many individuals who are already taking multiple heart medications such as statins, aspirin, and ACE inhibitors, which may obscure the effect of omega-3 fatty acids

The inter-individual variability in response to a fixed dose of EPA + DHA has been found to be large, i.e. to vary up to a factor of 13

Not all ‘fish oils’ are the same - addressing quality/concentration and purity

Study design to incorporate use of biomarkers?

Omega-3 dosing – ‘one size fits all?’

Effects of a single dose of EPA & DHA (3.4 g) taken with breakfast on the Omega-3 index (n =20)(Harris et al., 2013)

40 individuals with a baseline omega-3 index <5% (black bar) and post treatment (white bar) after a 6-week intervention with omega-3 EPA & DHA (0·5 g/d)

• The mean omega-3 index increased from 4·37% to 6·80% and inter-individual variability in response was high (varied by a factor of up to 13 inter-individually) (Kohler et al. 2010)

We are all biochemically unique – our needs for, production of and response to omega-3 differs considerably:

Many factors influence how we utilise omega-3 in supplement form, i.e.o Omega-3 baseline levelso Body weight, age, gender, etc

Supplement digestibility/bioavailability [rTG, EE, phospholipids]

Understanding the dose-response effects of EPA and DHA and ‘condition related’ requirements o EPA vs DHA – no longer viable to address them simply as ‘omega-3’

Tissue concentrations of these omega-3 fatty acids may be critical to achieving biological effects

Increasing omega-3 intake is not the same as increasing omega-3 levels!

The EPA/DHA dilemma

Although EPA and DHA are both long-chain polyunsaturated fatty acids (PUFAs), the molecules are often reported to produce biochemical and physiological responses that are qualitatively and quantitatively different from each other

The kinetics of EPA and DHA differ between different cell types

The marked differences between the effects of EPA and DHA indicate that it is an over-simplification to generalise the effects of omega-3 PUFA on cell function

It is the EPA in excess of DHA that is the active component in fish oil [treating depression]

Verlengia et al., 2004; Martins 2009; Sublette et al., 2011; Russell & Burgin-Maunder 2012

EPA and DHA utilisation differences

High DHA intake reduces delta-6-desaturase activity

Studies often report no increase in DHA levels with pure EPA supplementation – DHA saturation?

In some cases [depression/neurodevelopmental disorders] high DHA supplementation has been shown to worsen health outcomes

12 week intervention with 1.8 g omega-3 (1.2g EPA + 0.6g DHA) in young healthy males aged 18-25

During the washout period, EPA and DHA levels decreased back to baseline levels, with EPA levels rapidly returned to baseline levels within 2 weeks of stopping fish oil supplementation, while serum DHA returned to baseline levels only by the end of the washout period

Suggests high EPA requirements

Roke & Mutch 2014

Time (weeks)

The unique benefits of pure EPA

EPA (unlike DHA) reduces the pro-inflammatory activity of AA in a number of ways

EPA is an inhibitor of the enzyme delta-5-desaturase that produces AA

EPA directly displaces AA from cell membranes

EPA competes with AA for the enzyme PLA2 necessary to release AA from the membrane phospholipids

EPA competes with COX and LOX enzymes to prevent the conversion of AA to its eicosanoids

As such, studies show that EPA plus DHA oils are less effective at reducing inflammation than pure EPA oils

BUT - does your fish oil deliver?

Strength/concentration of the active ingredient within the total oil volume

Bioavailability of the omega-3 form used

Accurate ‘dosing’ – as [mg/kg/day] determined according to the baseline omega-3 index

For an intervention to be successful you need to raise omega-3 levels and reduce the inflammatory capacity of omega-6 AA

A combination of factors determine omega-3 intervention success:

TG EE rTG PL

The power of rTG omega-3

Dyerberg et al., 2010 graph shows the % increase in serum EPA+DHA content following 2 weeks of EPA and DHA supplementation Av. 3.3g per day.

rTG oil delivered biggest increase in serum lipid content in the lowest volume of oil and lowest total dose of EPA+DHA (all others delivered 200mg EPA + DHA or more)

Importance of oil concentration Higher concentrations increase cellular omega-3 levels more than the same

dose provided at a lower concentrationBrunton and Collins 2007

Importance of dose plus concentration Higher dose high concentrations from rTG fish oil increase cellular omega-3

levels up to 5x more than krill oil and 3x more than standard fish oil

Laidlaw et al., 2014 Comparison of manufacturer- recommended dose of rTG, EE concentrated fish oils with Krill oil (PL) and salmon oil (TG)

Subjects (n = 35) were randomly assigned to consume one of four products, in random order, for a 28-day period, followed by a 4-week washout period

Subsequent testing of the remaining three products, followed by 4-week washout periods, continued until each subject had consumed each of the products

Laidlaw et al., 2014

A randomised clinical trial to determine the efficacy of manufacturers’ recommended doses of omega-3 fatty acids from different sources in facilitating cardiovascular disease risk reduction

Part 2 : Nutrition research and the brain

Brain studies are extremely difficult to conduct

Why??

Focus, attention and cognitive performance

Omega-3 increases blood flow to the brain supplying oxygen and fuel, essential for neurotransmitter production and function, memory, learning, cognition, and brain and neurone cell structure

Benefits restricted to those with sub-optimal omega-3 intake – surprised?!

DHA is for memory and learning if intake is low

EPA in excess of DHA for cognitive performance, in particular attention

Total omega-3 needed to be >400mg

‘DHA only’ often resulted in detrimental effects to cognition

Many benefits of DHA associated with increased blood flow

>1month intervention needed for benefits to be seen

Amino Acids. 2000;19(3-4):635-42.A taurine and caffeine-containing drink stimulates cognitive performance and well-being.Seidl R1, Peyrl A, Nicham R, Hauser E.

The findings clearly indicate that the mixture of three key ingredients of Red Bull Energy Drink used in the study (caffeine, taurine, glucuronolactone) have positive effects upon human mental performance and mood.

Psychopharmacology (Berl). 2001 Nov;158(3):322-8.An evaluation of a caffeinated taurine drink on mood, memory and information processing in healthy volunteers without caffeine abstinence.Warburton DM1, Bersellini E, Sweeney E.RESULTS:

In both studies, the caffeinated, taurine-containing beverage produced improved attention and verbal reasoning, in comparison with a sugar-free and the sugar-containing drinks. The improvement with the verum drink was manifested in terms of both the mean number correct and the reaction times. Another important finding was the reduction in the variability of attentional performance between participants.

• L-Theanine + taurine calm and focus the mind via GABA and dopamine activation

• Caffeine stimulates the brain, increasing energy, alertness and information processing speed

• L-Theanine + caffeine enhance focus and reduce distractibility

Mood balance

Omega-3

• EPA and DHA are essential for mood-regulating neurotransmitter production and function

• EPA reduces inflammation, which directly attacks and degrades serotonin, leading to low mood and depression

Reproducing ‘bad’ science http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004692.pub4/full

Depression Sublette 2011 Meta-analysis http://www.ncbi.nlm.nih.gov/pubmed/21939614

Grosso et al., 2014

http://www.ncbi.nlm.nih.gov/pubmed/24805797

Serotonin

TDOIDO

IFN-g, TNF-a, IL-1, IL-6

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

+

+

+

KMO

5-HTP

Neuronal damage Depression

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Cortisol

IDO

Sleep disturbance

IFN-g, TNF-a, IL-1, IL-6

+

Serotonin

TDOIDO

IFN-g, TNF-a, IL-1, IL-6

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

+

+

+

KMO

5-HTP

Neuronal damage Depression

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Cortisol

IDO

Sleep disturbance

IFN-g, TNF-a, IL-1, IL-6

+

EPA

Serotonin

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

KMO

5-HTP

Neuronal damage Depression

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Sleep disturbance

EPA

Serotonin

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

KMO

5-HTP

Neuronal damage Depression

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Sleep disturbance

EPA

Serotonin

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

KMO

5-HTP

Neuronal damage Depression

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Sleep disturbance

EPA

Serotonin

Kynurenine

Quinolinic acidNMDA agonist

3-Hydroxykynurenine

KMO

5-HTP

Elevated Mood

Kynurenic acidNMDA antagonist

NMDA receptor

Tryptophan

Regulated sleep

EPA

EPA and DHA utilisation differencesRoke & Mutch 2014

Time (weeks)

• Half the DHA dose = same enrichment and longer lasting elevation within the cells of the brain compared with EPA

• Conditions requiring EPA MUST dose with excess EPA at least 3:1

Vitamin D

• acts as a mood stabiliser

• low levels increase risk of anxiety and depression

• Studies show mixed results (in some case worsening) in managing depression

Should vitamin D supplements be recommended to prevent chronic diseases? BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h321

Bottom line:

Do not recommend vitamin D supplements to prevent chronic disease because clear evidence of benefit does not currently exist and adverse effects cannot be excluded

‘all studies without flaws demonstrated a statistically significant improvement in depression with Vitamin D supplements…… the effect size was comparable to that of anti-depressant medication.’

NB: Only effective in those who are deficient AND dose given must result in a changed serum Vit D level http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011048/

Cognitive decline

BUT almost all studies of omega-3 use to boost cognitive function have shown little or no benefits – why?

• Study population• Dose given• EPA or DHA • Cognitive tests chosen • Duration of intervention time • Is it already too late?

B vitamins

• B1,2,3 and 5– support mitochondria of the brain and CNS– aid detoxification pathways– reduce inflammation

• B6, B12 and folate in their most active and bioavailable forms – homocysteine recycling – elevated levels = significant risk factor for age-related cognitive decline

What else?

Brain studies are extremely difficult to conduct

Why??

What's the optimal length of time for this intervention

Which nutrients should be used? Single, isolated nutrients or blends….

What dose do we give?

What's the right population for this study and intervention?

What else might be affecting the participants’ brains?

Part 3 : translating this into successful personalised nutrition

and clinical practice

There are still numerous gaping holes in research which, for now, prevent firm conclusions being made.

So - what can we learn from the negative studies and what we can do in clinic to ensure therapeutic success?

1: Choosing the right dose for EACH participant

It is increasingly apparent that the right dose for the right person is vital in ensuring study success.

Before the study even begins we must know each individual participant’s baseline level of the nutrient being investigated and, where possible, dose according to pre-determined and validated dosing guidelines.

Translated into a practical clinical setting, testing (genotype and phenotype)is key to understand biochemical individuality and whether or not your client actually needs, and will indeed benefit from, a specific nutrient intervention.

Using established dosing guidelines where available - such as that calculated using the omega-3 index biomarker and body weight – can at least help us to achieve health-protective levels of a nutrient in our clients, from which we can try to establish the therapeutic dose.

2: What plasma or cellular levels need to be reached in order to have a clinical effect in this specific area of health?

Whilst there is still no known ‘ideal’ plasma level of each and every nutrient for each and every condition, the severity of deficiency tells us whether the nutrient in question is likely to contribute to clinical results and how high we should commence the dose.

Remember - the lower the baseline levels (and the bigger/heavier they are), the more a person will need to take in order to raise their plasma levels to that associated with health benefits.

Those with the lowest baseline levels are likely to have the highest level of dysfunction. Raising their levels closer to ‘ideal’ should help them to notice a tangible benefit to their health. People with closer-to-adequate plasma levels may still benefit but the scale of improvement is likely to be smaller and may therefore go unnoticed.

Using current levels and dosing between known therapeutic doses and upper tolerable limits will help to get quicker positive results.

3: How does the body prioritise which clinical benefit it needs most?

If the client or study participant has more than one condition with high requirements of this particular nutrient how do we determine how the body will prioritise distribution?

If you have 3 major organ systems all requiring additional support and you give a relatively modest dose of a nutrient which is known to contribute to all of these systems, then perhaps most, or all, of that nutrient gets shuttled to the organ with the greatest need.

How do we dose correctly if more than one system is crying out for the nutrient?

We need to look at the body as a whole when designing single nutrient studies for single clinical benefits to determine if an endogenous competition might be the reason for our negative outcome!

4: One nutrient alone does not always have the power to significantly benefit one area of health

This is really key and is the reason humans have evolved to eat food, not nutrients.

Our organs and systems are extremely complex and it is impossible to isolate just one nutrient as being ‘most’ important for function.

It is likely that looking at the overall benefits of a combination of nutrients is much more useful than looking at each nutrient’s impact alone.

The positive research for specific diets, for example the MIND diet in supporting healthy cognitive ageing and the DASH diet for heart and metabolic health, is much better established than most isolated nutrients.

5: Choose the right participants for this study and choose what specific outcome suits them best?

If you want to be sure your client, or participant, will respond it is clear you need to a) choose a nutrient that they actually need b) use a population who require the targeted benefit.

There’s no point in targeting someone with depression knowing it has inflammatory roots and choosing to give them glucosamine to treat non-existent joint pain and then expecting their joint pain to improve!

In the AERDS2 study it is clear, for a number of reasons, that both omega-3 and the population chosen were not ideal for the desired outcomes to be tested. The participants were not malnourished, poorly educated or financially disadvantaged - all factors known to correlate with fish consumption and increased risk of brain function decline.

6 and 7: When and for how long is optimal for this intervention?

Understanding what factor, and at which point in the life cycle, has the ability to impact on long-term health outcomes is vital in determining the likelihood of positive outcomes from clinical studies.

If the ‘damage’ has already been done, an intervention may only prevent worsening of symptoms, rather than result in benefits and…

If the intervention is not given for the optimal length of time it may never reach significance.

The order and length of interventions we choose to use in our day-to-day clinics will determine if, and to what extent, a client will respond.

Creating a plan of action: Where do I start?

1. Which symptoms and systems are of

most concern to you AND your client?

2. What strategies can you

implement?

3. What

impact

could this

have?

5. So where do I start?

4. Does this change the

benefit gained or

perceived?

Choosing the right intervention:

Questions you need to ask

Is the intervention you choose right for the client?

Is the nutrient right at this time in their treatment plan?

What else might be affecting whether or not this nutrient could be effective?

What other demands might there be in the body for this nutrient?

What are their current levels of this nutrient?

What other nutrients are needed to make sure this nutrient can work in the desired area?

?

Start here:

Planning for success:

factors to consider

• Choose an optimal starting dose• Limit changes to other factors that could affect positive outcomes

or reduce the likelihood of noticing a benefit• Make sure the client can be and is committed to compliance• Don’t overwhelm the system with single nutrient interventions;

optimise the baseline diet and lifestyle and target systems, not symptoms, initially

• Introduce new nutrients slowly, review regularly, and routinely stop intake to make sure the nutrients chosen are individually beneficial and contributing significantly at that point in the protocol

• Plot it out!

Tools

Planning how the whole process of support might look, including:

what to give and when, relative to the specific organ system and outcome of greatest concern, from the outset of treatment,

together with recognising the importance of compliance to certain interventions beyond just a few months,

as well as not being afraid to revisit treatment options at different times in a treatment plan

is essential to creating a successful support plan.

Pharmepa® RESTORE & MAINTAIN™

The fastest, most effective, clinical omega-3 intervention

‘RESTORE’ pure EPA

‘MAINTAIN’EPA, DHA and GLAMinimum 3-6 months

Therapeutic role of Pharmepa®RESTORE & MAINTAIN™

AA to EPA ratio Inflammatory regulation Symptoms of inflammatory illness Optimum brain, cell, heart, immune

and CNS function Optimum wellbeing

Omega-3 index AA to EPA ratio Long-term general and cellular health Heart, brain and eye health Reduce risk of chronic illness and help

protect against inflammatory disease

Sophie TullyBSc MSc DipPT Nutrition Education Manager

sophiet@igennus.com07908368173

http://igennus.com/professionals/

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Hull MA, Sandell AC, Montgomery AA, Logan RF, Clifford GM, Rees CJ, Loadman PM, Whitham D: A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial. Trials 2013, 14:237.

Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM: Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. Journal of the American Heart Association 2013, 2:e000513.

Harris WS: The omega-3 index: clinical utility for therapeutic intervention. Current cardiology reports 2010, 12:503-508.

Harris WS: Pushing the limits with omega-3 fatty acids. Trends in cardiovascular medicine 2015.

Harris WS, Von Schacky C: The Omega-3 Index: a new risk factor for death from coronary heart disease? Preventive medicine 2004, 39:212-220.

Harris WS, Varvel SA, Pottala JV, Warnick GR, McConnell JP: Comparative effects of an acute dose of fish oil on omega-3 fatty acid levels in red blood cells versus plasma: implications for clinical utility. Journal of clinical lipidology 2013, 7:433-440.

Kohler A, Bittner D, Low A, von Schacky C: Effects of a convenience drink fortified with n-3 fatty acids on the n-3 index. The British journal of nutrition 2010, 104:729-736.

Martins JG: EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. Journal of the American College of Nutrition 2009, 28:525-542.Puri BK, Leavitt BR, Hayden MR, Ross CA, Rosenblatt A, Greenamyre JT, Hersch S, Vaddadi KS, Sword A, Horrobin DF, et al: Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Neurology 2005, 65:286-292.

Puri BK, Bydder GM, Counsell SJ, Corridan BJ, Richardson AJ, Hajnal JV, Appel C, McKee HM, Vaddadi KS, Horrobin DF: MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment. Neuroreport 2002, 13:123-126.

Russell FD, Burgin-Maunder CS: Distinguishing health benefits of eicosapentaenoic and docosahexaenoic acids. Marine drugs 2012, 10:2535-2559.

Sublette ME, Ellis SP, Geant AL, Mann JJ: Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. The Journal of clinical psychiatry 2011, 72:1577-1584.

Surette ME: The science behind dietary omega-3 fatty acids. CMAJ : Canadian Medical Association journal = journal de l'Association medicale Canadienne 2008, 178:177-180.

Verlengia R, Gorjao R, Kanunfre CC, Bordin S, de Lima TM, Martins EF, Newsholme P, Curi R: Effects of EPA and DHA on proliferation, cytokine production, and gene expression in Raji cells. Lipids 2004, 39:857-864.