For our last blog of the year, we decided to look back at a few important developments that impacted omega-3 fatty acids and vitamin D in 2020. First, it would be foolish to put together a review of 2020 without mentioning COVID-19. We will talk about the potential role of omega-3s and vitamin D in this deadly disease, as well as some of the clinical trials that have recently been initiated.
Second, STRENGTH, a study of a pharmaceutical preparation of omega-3 EPA and DHA (i.e., EPANOVA), was a surprising failure this year. It will take some time to truly understand what happened, but we’ll share some of our current perspectives.
And third, there were several studies published this year not only on the importance of omega-3s in sports, but also how differences in the Omega-3 Index can affect athletic performance. We’ll recap the highlights.
#1 – The COVID Connection: Omega-3 & Vitamin D
The global coronavirus pandemic continues to tighten its grip on people worldwide. But perhaps one silver lining to take from this public health crisis is the renewed focus people have when it comes to health and nutrition.
A recent survey showed a major acceleration of consumer interest in the role of nutrition in immunity. In fact, this data indicated 50% of consumers worldwide have begun eating foods more frequently that boost their immune health since the pandemic started. The survey also found that 84% of consumers now plan to make greater attempts to stay healthier in the future.
Earlier this year when COVID-19 creeped into our lives and locked some of us down, we at OmegaQuant wanted to explore how omega-3s impact immune function. And there was plenty to talk about, even in the context of a surging global pandemic.
The first blog we wrote reviewed the ways in which omega-3s exert their anti-inflammatory effects in the face of infection. But inflammation is only the first step in a highly complex, overall immune response to viral infections.
The blog described omega-3s’ role as “flattening the curve,” which is precisely what they do within the body as it responds to infections. With enough omega-3 on board, the infection does not cause an over-stimulation of the inflammatory response — it allows for what some call a “Goldilocks” response: not too much and not too little, but just right.
The mechanistic data clearly shows that omega-3s in cell membranes play an important role in taming the more toxic aspects of the immune response.
With regard to the immune system, an omega-3 deficiency (low Omega-3 Index) could result in excessive and damaging inflammation, while an excessive omega-3 blood level could result in a lackluster immune response to an infection.
Having an Omega-3 Index >12%, on the other hand, is relatively rare and not well studied, and thus there is not enough data to know what level is too high and what that looks like, which is why testing is important. OmegaQuant’s Dr. Bill Harris recommends consuming enough EPA and DHA to reach and maintain an Omega-3 Index of between 8-12%.
Another blog we wrote in April discussed earlier research suggesting how omega-3s might lend a helping hand in fighting some of the symptoms of COVID-19.
One of the most serious symptoms of COVID-19 is Acute Respiratory Distress Syndrome (ARDS), which is what requires people to be put on ventilators or oxygen to survive. Adding omega-3s to a “tube-feeding” diet have been tested in ARDS patients with mixed, but potentially positive, results.
For example, a 2014 meta-analysis that included data from seven randomized controlled trials (RCTs) concluded, “Among patients with ARDS, enteral supplementation of omega-3 fatty acids seemed ineffective regarding all-cause 28-day mortality, ventilator-free days, and ICU-free days. Routine use of enteral omega-3 fatty acids cannot be recommended based on the available evidence.”
However, a more recent meta-analysis of 12 RCTs on omega-3 and ARDS was more encouraging. The authors concluded that, in critically ill patients with ARDS, giving omega-3 in enteral formulas appeared to be associated with an improvement in blood oxygen levels, with trends toward shorter ICU stays and less need for mechanical ventilation. “Considering these results, administering omega-3 fatty acids appears a reasonable strategy in ARDS,” they said.
On the back of this evidence, several clinical trials exploring omega-3 in COVID-19 patients have been initiated this year, according to the Global Organization of EPA and DHA Omega-3s (GOED).
“Since the World Health Organization declared the novel coronavirus (COVID-19) outbreak a global pandemic nine months ago,” GOED said in a recent newsletter, “we have been tracking the clinical trials and scientific publications related to omega-3s and COVID-19.”
At last count, the organization said 18 clinical studies have been announced, with the majority investigating the potential anti-inflammatory benefits of omega-3s for prevention of COVID-19 through alleviation of symptoms in seriously ill patients. While GOED has heard about some of the investigations running into recruitment and data collection issues, the first results were scheduled to be reported during the National Lipid Association Scientific Sessions in mid-December.
One of these studies, using Amarin’s Vascepa drug, which contains purified omega-3 EPA, showed that the drug reportedly cut patient-reported COVID-19 symptoms by 52%.
Thus far, GOED says 32 articles have been published on the topic of omega-3 and COVID-19. Most are speculative hypotheses about the potential benefit(s) (e.g. anti-inflammatory) of omega-3s for COVID-19 treatment.
In early December, unpublished and yet to be peer-reviewed results from a longitudinal app-based community survey on dietary supplement usage since the beginning of the pandemic were released, demonstrating a significant association between use of omega-3s and lower risk of testing positive for COVID-19, particularly in women. While this is exciting news for omega-3s, GOED says the results from randomized clinical trials are necessary to confirm the findings before any recommendations can be made.
Dr. Bill Harris, through his new non-profit entity — the Fatty Acid Research Institute (FARI) — has also made a move to initiate a study that explores more deeply the connection between the Omega-3 Index and COVID-19. With this new study, which is currently in the funding stage, FARI has a rare opportunity to partner with a major medical center in Los Angeles.
“We have just completed a pilot study in 100 patients, and we observed a trend in which a higher Omega-3 Index at admission was associated with a 4-fold lower risk for death from COVID-19,” Dr. Harris explains. “However, given the small sample size it was not publishable (not statistically significant). We need more samples to do this study properly, to ensure the results hold in a larger sample size and get the results peer-reviewed and published as soon as possible.”
In a fundraising letter, Dr. Harris expressed the urgency of getting this study funded: “There is no time to submit an NIH-style grant to do this study, so we are reaching out to those of you who have a deep interest in documenting the health benefits of EPA and DHA to help. We estimate that the study will cost $100,000 to get the 1000 patients needed for this study. The faster we get the support, the quicker the study will be done.”
The budget for this study includes fees 1) for the hospital system to identify and pull the banked blood samples, to spot them on filter paper for Omega-3 Index analysis, and to find and download the clinical data for each patient; 2) for OmegaQuant Analytics to perform the lab assays (at a steeply discounted rate they have agreed to for this important study); and 3) for FARI to analyze the data, write up the paper for publication and disseminate the results widely.
FARI’s important work relies on the donations and grants. To donate to the COVID study, click here.
While the evidence behind omega-3s and COVID-19 looks promising, it is even stronger for vitamin D. So much so that it prompted 120 health experts to send an open letter to all world governments this week, urging them to respect the scientific and medical evidence behind this humble vitamin. “Research shows low vitamin D levels almost certainly promote COVID-19 infections, hospitalizations, and deaths. Given its safety, we call for immediate widespread increased vitamin D intakes,” the letter said.
It has been shown that 3875 IU (97mcg) daily is required for 97.5% of people to reach 20 ng/ml, and 6200 IU (155mcg) for 30ng/ml, intakes far above all national guidelines. Unfortunately, the report that set the US RDA included an admitted statistical error in which required intake was calculated to be ~10x too low, the vitamin D experts claim.
Decades of safety data show that vitamin D has very low risk: Toxicity would be extremely rare with the recommendations here. The risk of insufficient levels far outweighs any risk from levels that seem to provide most of the protection against COVID-19, and this is notably different from drugs and vaccines.
“Vitamin D is much safer than steroids, such as dexamethasone, the most widely accepted treatment to have also demonstrated a large COVID-19 benefit,” they said. “Vitamin D’s safety is more like that of face masks. There is no need to wait for further clinical trials to increase use of something so safe, especially when remedying high rates of deficiency/insufficiency should already be a priority.”
Omega-3s Staying Strong in the Face of STRENGTH
A major hint that the STRENGTH study wasn’t going to pan out as experts hoped was when the trial was halted in early 2020 because of a lack of showing any benefits for those who have cardiovascular disease (CVD).
Unfortunately, the reasons for the failure of STRENGTH to find a benefit in subjects taking 4 grams/day of omega-3 carboxylic acids (at least 3.1 g EPA+DHA, with most as EPA) are not clear, GOED said recently. “While our science team has been talking to other experts on the topic, at this point, we have no additional information to share. It’s also worth mentioning that we are incorporating the results of STRENGTH into our recently-published dosage paper to understand how it changes the estimated effect for each of the cardiovascular outcomes.”
So does this mean omega-3s don’t work for heart disease? It depends what you mean by “work.” According to Dr. Bill Harris, the truth may very well be that even with 3 grams of omega-3 fatty acids per day (amount provided in 4 capsules of Epanova), you can’t — in just 3 years — change the course of CVD events in 65-year-old people, on statins, at high risk for CVD.
He also points out that the placebos used in the STRENGTH study vs. the REDUCE-IT study could have been an issue. He says the STRENGTH researchers claim that corn oil is a true placebo, and at 4 g per day (which provides 2 g of linoleic acid; about 1/8th of the normal daily intake) it is benign.
“Furthermore, some have argued that the only reason REDUCE-IT ‘appeared’ to show benefit with EPA alone was the use of mineral oil as a placebo may have INCREASED CVD events, and EPA didn’t actually lower risk,” Dr. Harris said. “Without an untreated control group, we cannot know if that’s true or not.”
Meanwhile, Dr. Harris points out that part of the reason STRENGTH was neutral could be related to possible benefits of the corn oil “placebo” used as the control. Corn oil provided about 2 g/day of linoleic acid, the essential omega-6 fatty acid, and although controversial, higher blood levels of linoleic acid have been associated with lower risk for CVD.
“I wonder if the truth is somewhere in the middle,” Dr. Harris said. “That is, mineral oil might have had a small adverse effect in REDUCE-IT, and corn oil might have had some small beneficial effect in STRENGTH. What I can’t believe is that DHA was harmful or neutralizing of EPA.”
How could we ever know the real story? Well, for starters, Dr. Harris suggests a head-to-head comparison of 4 g of corn oil vs 4 g of mineral oil would be interesting, but would probably never be financed. Can the FDA mandate that Amarin pay for a redo of REDUCE-IT using corn oil? “I suppose, but it seems very unlikely especially with the patent troubles Amarin has in the US. Would AstraZeneca redo STRENGTH vs mineral oil? Never,” Dr. Harris said.
“I’m not sure how the world’s cardiology (and diabetes) societies that have all rushed to embrace REDUCE-IT and set new recommendations for the use of EPA will view all of this. The foundation for REDUCE-IT is quite shaky,” Dr. Harris asserted.
Dr. Harris added: “Hopefully we (at OmegaQuant since we generated the fatty acid data) can do some more nuanced studies in the STRENGTH dataset. The paper in JAMA did not ask if those who got to >8% actually did better than those who ended <4%, or whether any such cut-points could be identified from an analysis of achieved EPA, DHA or Omega-3 Index levels vs outcomes. We are working to get access to the clinical outcomes data.”
Using omega-3s as drugs is still uncharted territory. The good news is, the omega-3 story in the health and nutrition world is still as solid as ever.
Omega-3s for Athletes – The Breakout Category in 2020
This year more than any other those who live active lifestyles or compete on an elite athletic level received great news on the many ways omega-3s support various levels of fitness. This was also a pivotal year for the Omega-3 Index as several experts and high profile journal publications noted the need to establish omega-3 status in athletes, who appear to be chronically low in these important nutrients.
It started in April with a paper published PLOS One. Researchers interested in the omega-3 fatty acid status of athletes conducted a study in NCAA Division 1 athletes who play a wide range of sports, from football to golf to swimming — in all, students from a total of 35 sports were included in this research. First, they conducted a survey to learn more about their diet, and then tested their blood levels of the omega-3s EPA and DHA via an Omega-3 Index test.
The researchers found that most athletes they studied fell short of the recommended 500 mg/day intake of omega-3s, according to the Academy of Nutrition and Dietetics. In addition, all of those who submitted blood samples had subpar Omega-3 Index levels — below 8%.
In total, 1528 male and female student athletes completed a food frequency questionnaire, which asked about their dietary intake of omega-3s in addition to their supplementation habits. Roughly 300 of these participants also took an Omega-3 Index test. Of those, the average Omega-3 Index was 4.3%, with no athletes reaching the ideal target of 8%.
In an effort to recruit a geographically diverse subject pool, the research team solicited volunteer research collaborators such as Registered Dietitians (RDs) or other sports performance staff from the NCAA Division 1 “Power 5” — Atlantic Coast Conference (ACC), Big Ten Conference (Big 10), Big Twelve Conference (Big 12), Pacific-12 Conference (PAC 12), and Southeastern Conference (SEC).
In their paper, the study authors discussed why they decided to use the Omega-3 Index vs. other methods. “The Omega-3 Index requires a minimum amount of blood (i.e., finger stick blood sample), has a low biological variability, is less affected by acute feedings to better reflect long-term omega-3 fatty acid status, and has been shown to correspond with omega-3 fatty acid concentrations in the heart, brain, and a variety of other tissues,” they said.
Each additional serving of seafood was associated with an Omega-3 Index increase of 0.27% Additionally, those who reported taking omega-3 supplements had a significantly higher Omega-3 Index compared with those not taking supplements (4.7 vs. 3.7%, respectively). Participants who met the Academy of Nutrition and Dietetics’ recommendation of 500 mg EPA + DHA per day had a higher Omega-3 Index compared to those who consumed less than the daily 500 mg EPA + DHA recommendation (5.4% vs. 4.3%).
According to the study authors, these findings may inform interventions aimed at improving the omega-3 fatty acid status of collegiate athletes. However, they said further research on athlete-specific omega-3 fatty acid requirements is needed.
In May, a systematic review published in Advances in Nutrition looked 32 randomized placebo-controlled trials (RCTs) that met the authors inclusion criteria and revealed benefits for omega-3 fish oil for athletes in the areas of cognition, heart health, muscle recovery and immunity.
This benefit was seen across a wide range of sports for male and female recreational, well-trained, elite or professional athletes. This is promising news for omega-3 and sports performance—an area that is relatively young compared to the well-established benefits of omega-3 supplements in areas such as heart, brain and prenatal health, despite the 25 years of research.
Yet another study published in July supported the role of fish oil on several parameters of performance and recovery. The researchers pointed out that while previous studies have hinted at the benefit of taking fish oil omega-3s to help reduce muscle soreness and improve recovery time, this latest study is the first study to show that you likely need pretty high doses to make that happen.
According to the study authors, while certain recovery strategies have been shown to be successful in alleviating some of the symptoms of skeletal muscle damage, nutritional strategies have also been proposed to mitigate the negative effects that one may experience following a damaging/rigorous bout of exercise.
“One dietary strategy that has garnered interest is consumption of omega-3 fatty acids. The discovery of omega-3s pleiotropic effects on human health (e.g., cardioprotective, triglyceride lowering, and anti-inflammatory) have driven significant medical and public interest, but of late, omega-3s have caught the exercise community’s attention,” they said. “Omega-3s are commonly obtained via the diet by consuming oily fish, such as tuna and salmon, and may also be obtained via oral supplementation, such as fish oil soft-gel supplements.”
Specifically, the purpose of this investigation was to examine the effect of fish oil supplementation dosing on the recovery of measures of muscular performance, perceived soreness, and markers of muscle damage following a rigorous bout of eccentric exercise.
To that end, 32 college-aged resistance-trained males were supplemented with 2, 4, 6 g/day fish oil or placebo for ~7.5 weeks. Following the supplementation period, pre-exercise performance assessments of vertical jump, knee extensor strength, 40-yard sprint, T-test agility, and perceived soreness were completed prior to a bout of muscle-damaging exercise and were repeated immediately post, 1-, 2-, 4-, 24-, 48-, and 72-hours post-exercise.
In the end, they found that 6 grams of fish oil was the magic dosage that optimized the recovery of jump performance and muscle soreness following a damaging bout of exercise.
What’s to Come?
With a year like we’ve had with COVID-19 running in the background of everyone’s lives, you almost hate to tempt fate and ask that question. Let’s just hope for the continued emergence of new research supporting not only omega-3s and vitamin D, but also the importance of testing blood levels of these important nutrients to make sure we’re all getting enough to protect our health. There’s a lot more to come. Stay safe and healthy out there. See you in 2021.