#432: Bill Harris, PhD – Omega-3 Fatty Acids & Health

1. Detailed Study Notes
2. Transcript

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What can we actually conclude based on current evidence?

There are two main themes I want to highlight when considering this question:

1. Converging lines of evidence
2. Recommendations based on context

1: Converging lines of evidence

When evaluating the evidence base in order to answer a practical question, we don’t want to rely on one study type or one set of studies. Rather, we can look across the whole evidence base, and see if there is general agreement across different lines of evidence. Of course, some types of evidence carry much more weight, and that should be noted.

But if we take the topic of omega-3 intake and cardiovascular health for example. It would be a mistake to take a large omega-3 supplementation trial such as VITAL or the STRENGTH trial, see that the findings were regarded as null, and then extrapolate that to mean either omega-3 intake or status is unimportant for CVD risk reduction.

Rather a more prudent approach is to place that in context of other lines of evidence; epidemiology on the intake of omega-3 and CVD outcomes, shorter trials looking at the effect on biomarkers, associations between omega-3 index and CVD, mechanistic data showing biologically plausibility, etc.

And again, these are not all equally weighted, but understanding where the evidence leans in each area, we can put the finding of one supplement trial in that overall context. And it can prevent us throwing the baby out with the bathwater whenever a new trial comes along. Sometimes a new trial really does completely alter the picture, but caution is needed in how single studies are interpreted and extrapolated to various conclusions.

So with that in mind, consider the second aspect…

2: Recommendations based on context

The context being: Who? What dose? What outcome? What response to intake?

For primary prevention, the prudent and practical advice is to recommend at least one to two fish/seafood servings per week, which is consistent with current dietary guidelines. Following this recommendation would improve omega-3 intake and status in most individuals but would likely not be sufficient to reach an intake of 1 g/d of omega-3 fatty acids, a level that provides significant CV benefit for many patients.

A higher dose of omega-3 fatty acids (approximately 4 g/d of EPA and likely 4 g/d of EPA+DHA, as well) is also an effective adjunct for CV treatment in those with high TG who take statins.

Context: Background diet

• Current intake is relatively high in Japan (~1.3–2.5 g/d)
• Conversely, in the United States, Australia, Belgium, Germany, the United Kingdom, and Canada, average daily intake falls far short of the recommendation for CVD prevention (~500 mg/d EPA/DHA), with intakes approximating 100 to 290 mg/d or less

Context: what response to intake? i.e. effect on Omega-3 Status

• The O3I is an evidence-based marker of EPA and DHA intake as well as CVD risk.
• For CVD risk, a target range of 8% to 12% was proposed in 2004 for reduced risk of primary cardiac death, and subsequent research has confirmed this target as clinically relevant.
• A O3I below 4% seems to confer an increased risk of negative health outcomes.

In general, the best sources of omega-3 fatty acids are salmon, herring, anchovies, sardines, and rainbow trout. So those not consuming fish will rely on ALA sources such as chia, walnuts, etc.

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Understanding Fatty Acids

Fatty acids can be divided into four general categories: saturated, monounsaturated, polyunsaturated, and trans fats.

In saturated fatty acids, the carbon chain has the maximum number of hydrogen atoms attached to every carbon atom. If a pair of hydrogen atoms is missing because of a double bond between two carbon atoms, it is called an unsaturated fatty acid. A fatty acid with a single double bond is monounsaturated, whereas a fatty acid with more than one double bond is polyunsaturated.

Fatty acids of a certain length (18-20 carbons or more) are referred to as long-chain fatty acids.

Focusing on long-chain PUFAs, there are two main groups of interest:

1. Omega-3 (n-3) fatty acids
2. Omega-6 (n-6) fatty acids

Within any of the fatty acids classes discusses so far, there are several individual fatty acids. For example, some common examples include:

There are 2 essential fatty acids (‘essential’ meaning that we cannot make it endogenously):

1. ALA (n-3)
2. Linoleic acid (n-6)

The highlighted fatty acids above are three types of omega-3 fatty acid, namely:

• Alpha-linolenic acid (ALA): one of two essential fatty acids in the human diet. It acts as a precursor to linoleic acid (LA) and can be found in plant sources such as vegetable oils, certain nuts, flaxseeds and certain beans.
• Eicosapentaenoic acid (EPA): a long-chain omega-3 fatty acid, found in marine sources (seafood, fish oils and some microalgae).
• Docosahexaenoic acid (DHA): a long-chain omega-3 fatty acid, found in marine sources (seafood, fish oils and some microalgae).

ALA can be converted to EPA and ultimately DHA.

Studies using stable isotopes to trace ALA metabolism have revealed that beta-oxidation is the main fate of ingested ALA and that a relatively small proportion is metabolised to EPA and an even smaller proportion to DHA.

ALA has associations with health benefits prospectively in dietary assessments, but the recent FORCE consortium analysis of blood omega-3 levels found inverse associations with EPA/DHA, but not ALA.

How Much Omega-3 Do We Need?

• We don’t have a RDA, but rather there is an Adequate Intake (AI) value for the omega-3 fatty acids (because we don’t have the standard of evidence required to set a RDA).
• The AI for EPA + DHA (combined) is 250mg/d.
• It is estimated that less than 20% of the global population meet this need, with highest levels in Scandinavia and Japan and low levels in Europe/North America.
• Recommendations vary, both in terms of nutrient amounts (i.e. ~250 – 500 mg/d) and food-based inatkes (i.e. 1-2 portions of oily fish per week).
• Some specific recommendations are emerging for pregnancy/lactation.
• Prospective studies indicate that ~250g fish per week may significantly reduce risk of coronary heart disease and myocardial infarction.

Omega-3 Status

Omega-3 Index (O3I): a measure of the proportion of EPA and DHA in the blood, specifically the red blood cell membranes. Results are expressed in percentages, i.e., <4% is typically deemed inadequate and >8% seen as “optimal”, but cut-offs vary depending on the health outcomes.

• First characterised in 2004, as the sum of DHA + EPA in RBCs, expressed as a percentage of the total fatty acids in the RBC measure.
• Because DHA is the predominant omega-3 fatty acid in membrane phospholipids, DHA makes up the majority of the Index (not to suggest that EPA does not have important roles, however, it may mean that looking at EPA alone would not yield any meaningful findings).
• An attractive feature of the Omega-3 Index is that the analytical laboratory procedure has been standardised, which means the measure should be reproducible across populations: the standardised method is known as the “HS-Omega-3 Index”.
• Populations with an O3I less than 4% appear to have worse outcomes vs. those with an O3I greater than 8%.
  • A seminal global survey by Stark et al., 2016 suggested that optimum O3I for health could be > 8%, as seen in Japan and Scandinavia, with at least a clear increased chronic disease risk at levels < 4%, which is common in many other parts of the world.
• O3I was found to be a more robust predictor of cardiovascular disease. For CVD risk, a target range of 8% to 12% was proposed in 2004 for reduced risk of primary cardiac death, and subsequent research has confirmed this target as clinically relevant.
• As Dr. Harris emphasised in this episode, the O3I appears to be stable and not easily altered by short-term or modest changes to diet or n-3 supplementation.
• Over the longer term, Dr. Harris mentioned that there is large inter-individual variability in the response to food intake and/or supplementation. In other words, for the same intake of omega-3 from foods or supplements, the Omega-3 Index of two individuals may change to a very different degree.
• However, targeted higher dose supplementation may increase O3I in a dose-response manner.
• Of note, higher EPA content in a mixed EPA/DHA formulation does not increase O3I to same magnitude as one with a higher DHA content (i.e., a balanced EPA:DHA), reflecting the slower turnover time of DHA in membranes.
• In terms of ‘vegan-friendly’ omega-3 sources and O3I, high dose flaxseed or echium seed oil supplements, provided no increases to O3I and some studies showed reductions. However, microalgal oil supplementation increased O3I levels for all studies.
• Revelevant review paper: Harris, 2007 – Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor

Mechanisms: How Might Omega-3 Help Reduce CVD Risk?

Omega-3 fatty acids affect interrelated risk pathways including arrhythmia, coagulation, vascular health, blood pressure, plaque stability, and inflammation.

High dose omega-3 supplementation seems to reliably decrease blood triglceride (TG) levels in those with elevated levels (although doses less than 1 g/d don’t seem to do this). In patients with significant TG elevation, a 20% to 30% reduction in fasting values is typical and often accompanied by small reductions in non–HDL cholesterol and apolipoprotein B.

Omega-3 Supplement Trials – CVD

VITAL (Vitamin D and Omega-3 Trial)

Manson et al., N Engl J Med 2019; 380:23-32

• Largest, most ethnically diverse omega-3 randomized controlled trial (RCT) focused on primary prevention
• VITAL assigned more than 25,000 people to either:
  • 1 g/d of omega-3 acid ethyl esters (providing 840 mg EPA and DHA)
    • This is an FDA-approved omega-3 drug, O3AEE
  • 2,000 IU of vitamin D3 (generic cholecalciferol)
  • both O3AEE and vitamin D3
  • dual placebo for approximately 5 years
• In VITAL, O3AEE did not significantly reduce major CV events, which was the trial’s primary outcome.
• Several statistically significant effects on pre-specified secondary outcomes worth noting:
  • 28% reduced risk for heart attacks
  • 50% reduced risk for fatal heart attacks
  • 17% reduced risk for total coronary heart disease events
• These effects were most pronounced in people with low fish intake (below the median of 1.5 servings per week) and African Americans.
• VITAL was considered a “null” study because the primary end point of composite major CV events was not significantly reduced (8% reduction, 95% CI, −20% to 6%).
  • Composite outcomes are when multiple end points are combined. This may create issues.
• Of the 3 end-points that made up the composite, two were not reduced: total stroke and CVD mortality, and one was: total myocardial infarction. So pooling them together produced an overall null effect.
• But a valid question to ask would be should a failure to reduce the risk for stroke and death from CVD nullify the success in reducing rates of myocardial infarction?
• Some other note-worthy points include:
  • Use of a relatively low dose of EPA + DHA (< 1 g/d)
  • Relatively short follow-up period
  • The focus on primary prevention.

While VITAL was reported as having null findings, the results need to be viewed in appropriate context. When looking at individual outcomes, there was significant reduction in myocardial infarction. Additionally, there are some important limitations to note when extrapolating these results.

ASCEND Trial (A Study of Cardiovascular Events in Diabetes)

The ASCEND Study Collaborative Group, N Engl J Med 2018; 379:1540-1550

• 7-year RCT in the United Kingdom; 15,480 patients with diabetes and no diagnosis of CVD
• Omega-3 product and dose were the same as in VITAL
• ASCEND was also reported as a null trial because there was no statistically significant differnce between the groups in the primary endpoint.
• However, again, the primary endpoint was a composite outcome; namely a combination of risk for nonfatal MI, nonfatal stroke, transient ischemic attacks, and CVD death.
• If we look at individual endpoints, indeed there was no effect of EPA and DHA on three of them; nonfatal MI, nonfatal stroke, and ischemic attacks. However, there was a 19% reduction in risk of CVD death.

REDUCE-IT (the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial)

Bhatt et al., N Engl J Med 2019; 380:11-22

• The REDUCE-IT trial used EPA-only in an ethyl ester form.
• Specifically, the form was icosapent ethyl (brand name Vascepa)
  • Vascepa was the second FDA-approved omega-3 drug indicated for TG lowering (O3AEE was first)
• REDUCE-IT investigated whether 4 g/d EPA combined with statin therapy was superior to statin therapy alone in preventing CV events in over 8,000 high-risk patients (followed for ~ 5 years).
  • “High risk” in this context was:
    1. TG levels of 135 to 499 mg/dL
    2. Known CVD or diabetes
    3. At least one other CV risk factor
• EPA significantly reduced total CV events by 25%.
• Also significant reductions in:
  • CV death, heart attack, or stroke in the secondary prevention population: 28%
  • CV death or nonfatal heart attack: 26%
  • Fatal or nonfatal heart attack: 31%
  • Urgent or emergent revascularization: 35%
  • CV death: 20%
  • Hospitalization or unstable angina: 32%
  • Fatal or nonfatal stroke: 28%
  • Total mortality, nonfatal heart attack, or nonfatal stroke: 23%
• Dr. Harris importantly pointed out a potential shortcoming of this study relative to others; the use of a mineral oil placebo. This has been suggested to be problematic as, compared to stardard use of a vegetable oil placebo or similar, using a mineral oil placebo may account for some of the worsening in outcomes for the placebo group.

The magnitude of the results in REDUCE-IT is incredible when viewed in context; these results would suggest pharmaceutical-grade EPA (specifically Vascepa) to be a more effective add-on agent to statins for reducing adverse CVD outcomes than virtually every other lipid-lowering drug tested in the last 12 years, including ezetimibe.

It’s important to bear in mind the very specific context of REDUCE-IT; i.e. it was in a specific population of patients who had already achieved low LDL-cholesterol levels via taking statins, but who had a residual risk from still elevated triglycerides. And of course it was a high-dose EPA-only prescription-only product used to reduce triglyceride levels.

STRENGTH Trial (Statin Residual Risk Reduction with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia)

Nicholls et al., JAMA. 2020;324(22):2268-2280

• Larger study but similar design as REDUCE-IT
• 4 g/day of EPA and DHA (as free fatty acids) – brand name Epanova (omega-3 carboxylic acids)
• No significant difference in composite of CV events

Meta-analysis by Hu et al., 2019

Hu et al., J Am Heart Assoc. 2019 Oct;8(19):e013543

• Meta-analysis of randomised controlled clinical trials
• Omega-3 supplementation compared to placebo
• Minimum sample size of >500 participants
• Follow-up duration of >1yr
• As REDUCE-IT had used a dose of 4g/d purified EPA, meta-analysis was conducted with and without this trial included.

Results:

• Total CHD: 7% reduction in risk [HR 0.93, 95% CI 0.89-0.96]
• CHD Death: 8% reduction in risk [HR 0.92, 95% CI 0.86-0.98]
• Total CVD: 5% reduction in risk [HR 0.95, 95% CI 0.92-0.98]
• CVD Death: 8% reduction in risk [HR 0.92, 95% CI 0.88-0.97]
• Myocardial Infarction: 12% reduction in risk [HR 0.88, 95% CI 0.83-0.94]
• Major vascular events: 5% reduction in risk [HR 0.95, 95% CI 0.93-0.98]

Conducting the analysis both with and without REDUCE-IT allowed for the significant effects of this particular trial on the overall results to be fully examined.

• The overall analysis showed a 12% reduction in risk of myocardial infarction.
• But REDUCE-IT alone resulted in an 30% reduction in risk.
• In the analysis excluding REDUCE-IT, there was still an 8% reduction in risk.

Trials showing null effect vs. benefit: Issues to consider

• Type of EPA used
  • Some trials use EPA-only, some use a combination of EPA + DHA
  • Even in EPA + DHA trials, there may be differences in the specific type (e.g. n-3 carboxylic acids vs. n-3 acid ethyl esters)
  • [Side note: note the difference in prescription n-3 products used in research vs. typical consumer products]
  • Some trials use a low omega-3 dose (or at least potentially lower than what might be needed to exert pharmocological effects)
• Intervention duration
  • CVD is a disease with a long time-course of progression – are trials of a couple of years sufficient to detect benefits?
• Lengthy event-to-enrollment interval in secondary prevention
• The better treatment interventions in CVD now (compared to the past), mean that data sets will likely see less events and deaths. While morally this is great, it impacts the effect sizes in studies.
• Background fish intake
  • There is no zero nutrient exposure in nutrition – i.e. controls groups still have omega-3 fatty acids
  • Omega-3 intake may have gone up over time – important when comparing older and newer trials
  • Certain populations have a higher baseline fish intake, therefore omega-3 supplementation would be expected to not confer much additional benefit

Omega-3 Supplementation & Atrial Fibrillation

Some of the data in the already mentioned trials suggest that supplementation could possibly increase the risk of atrial fibrillation.

• Atrial fibrillation (or A-fib) is an irregular and often very rapid heart rhythm (arrhythmia) that can lead to blood clots in the heart. A-fib increases the risk of stroke, heart failure and other heart-related complications

Meta-analysis in 2021 by Lombardi et al., (that included REDUCE-IT, ASCEND, STRENGTH and other big trials) suggested there was a meaningful increase in risk.

This is an interesting and potentially important finding, with more evidence directly looking at this issue being needed. Consideration of the absolute change in risk, as well as the net impact on CVD risk overall, is warranted.

DHA

DHA has been linked to many health benefits but its most established role is in brain health, specifically, during pregnancy and early life. However, the body can’t produce it in adequate amounts, so humans need to obtain it through their diet (e.g., seafood, fish oils and some microalgae).

Those who don’t consume these dietary sources are vulnerable to low levels of DHA (i.e., vegetarians, vegans, non-fish eaters). Some plant-based omega-3 from a-linolenic acid (ALA) (precursor of the n-3 series of fatty acids) can be converted to EPA, and ultimately DHA, but not in large quantities.

Are vegetarians/vegans lower in DHA? Yes, based on data in the UK, the US, and Austria.

This has generated debate as to whether a direct source of DHA should be encouraged in these at-risk groups. And if they truly are at risk – given there is no recommended daily amount or criteria for adverse effects with deficiency. In addition, there is no consistent evidence that DHA supplementation offers extra health benefits.

Proposed Health Benefits of DHA

• Brain Health – DHA is the most abundant omega-3 in the brain and plays a critical role in its development and function. As such, low levels are believed to disrupt brain function and are linked to an increased risk of memory complaints, dementia, and Alzheimer’s disease. Vegans who consume a DHA supplement may experience beneficial brain effects.
• Early life development – It is well established that DHA intake is critical for brain and eye function during the final trimester of pregnancy and early life development. Some studies show that babies of mothers who consumed 220 mg per day from the 20th week of pregnancy until delivery had improvements in vision and problem solving. The European Food Safety Authority mandated the inclusion of DHA in infant formula, recommending 20-50 mg/100 kcal.
• Heart health – DHA may reduce risk of heart disease by lowering blood triglycerides and blood pressure, among other effects. However, its role in heart disease prevention is controversial and lack strong evidence.
• Other health benefits – DHA has been investigated in many other conditions such as arthritis, inflammatory bowel disease and cancer but findings are inconsistent.

ALA

ALA is an omega-3 fatty acid found in a number of plant foods, including walnuts, flax, chia, beans.

Is ALA beneficial?

• An interesting question to ponder is: if we have enough EPA & DHA, do we still benefit from ALA intake? i.e. are there unique benefits of ALA?
• ALA has associations with health benefits prospectively in dietary assessments, but the recent FORCE consortium analysis of blood omega-3 levels found inverse associations with EPA/DHA, but not ALA.
• ALA likely has direct health benefit, and dietary patterns rich in ALA-containing foods are typically health-promoting.

Can ALA alone meet our omega-3 needs?

• The average conversion from ALA is minimal, around 8-12% conversion to EPA and ~1% to DHA.
• Intake of flax oil (rich in ALA) appears to significantly increase levels of ALA and EPA, but not DHA.
• Review from Philip Calder’s group (Baker et al., 2016): Almost all (47 out of 54) studies which increased ALA consumption report increased content of EPA in blood lipids and blood cells, while most report either little or no change, or even a decrease, in DHA content.
• The overwhelming majority of the research indicates that neither low or high ALA intakes of a range of 2-15g/d have any effect on DHA.
• Dr. Harris is of the opinion, based on current evidence, that a direct source of EPA/DHA would confer a health benefit to those who currently do not consume a dietary source of EPA/DHA.

DHA levels in the body appear to be only responsive to direct preformed DHA sources.

Direct DHA intake in pregnancy and lactation seems to be important. In other stages of life, DHA may confer health benefits, and ALA seems unable to meaningfully increase levels, thus it seems prudent for those on a vegan/vegetarian diet to consume a supplemental direct source of DHA.

For a more detailed discussed of this specific issue, please see episode 418: Should We Consume a Direct Source of DHA?

Pragmatic Conclusions

1. Guidelines typically recommend 1-2 servings of oily fish per week, with the goal of supplying adequate dietary EPA + DHA.
2. Intakes of combined EPA + DHA of around ~ 500 mg/d is commonly suggested as sufficient for reducing CVD risk in primary prevention.
3. However, the average intake in many Western countries (US, UK, Australia, Belgium, Germany and Canada) falls short of such a target, with intake being reported as 100 – 290 mg/d or less.
4. Conversely, in other populations such as the Japanese, intake is much higher, with some estimates putting average intake at 1.3 – 2.5 g/d.
5. Data from the Framingham Study cohort suggests that, for cognitive health, having an O3I < 4% seems problematic.
6. This O3I level of < 4% also seems to reliably relate to increased risk of various chronic diseases.

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