Recent studies confirm the utility of the omega-3 index

Abstract

Purpose of review

The Omega-3 Index (O3I) was proposed 20 years ago as not only a marker of body omega-3 fatty acid status, but more importantly, as a risk factor for fatal coronary heart disease. The purpose of this review is to document the continued and growing use of this metric in nutrition research.

Recent findings

Of the 456 citations to the O3I in PubMed, 58 have appeared in the last 18 months. Several of these articles are reviewed, and they underscore the widespread use of the metric.

Summary

Although the O3I was originally developed in the cardiovascular field, it has since been used in the study of a remarkably large number of health conditions, all of which appear to be favorably impacted by higher levels of tissue omega-3 fatty acids as reflected by the O3I.

INTRODUCTION

The Omega-3 Index (O3I) is the EPA+DHA content of red blood cells (RBCs) expressed as a percentage of total fatty acids. It was first proposed as a risk factor for death from cardiovascular disease (CVD) by Harris and von Schacky in 2004 [1], and the extent to which it fulfilled the criteria of a risk factor was evaluated in 2009 [2]. The O3I can serve as a biomarker, a risk marker and a risk factor, and the differences among these are important. In this context, a biomarker simply reflects body levels or status of a substance without being necessarily linked to any health significance. A risk marker implies that levels of the metric do have health implications, but they may not be causally related to the disease and/or may not be modifiable (e.g., age, sex, genetic variants). A risk factor, in its strongest sense, is both causally involved with the pathophysiology and modifiable, such that changing the levels results in altered risk (e.g., for CVD, LDL-Cholesterol and high blood pressure). The O3I fulfills the criteria for all three [2]. It is, in many ways, analogous to hemoglobin A1c: both are measured in RBCs, both are expressed as a percentage, and both are stable and long-term measures of status (omega-3 or glucose). As originally proposed, the low (undesirable, high risk) cut-point was less than 4%, intermediate was 4–8%, and the target value (high, desirable, low risk) was more than 8%. Average values for the O3I in the US and Europe are around 5% [3], and data from individuals from these regions constituted 92% of all the data available for the construction of a new (2024) Omega-3 Index world map [4^▪▪]. The purpose of this update is to discuss the continuing relevance of the O3I in biomedical research 20 years after it first appeared in the literature. 

Box 1.

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CITATIONS IN THE LITERATURE

The original 2004 article has been cited 383 times as of July 10, 2024 (Fig. 1), and a Google Scholar search returned 5790 references to this phrase. There have been 456 articles referring to the O3I in the title or abstract not authored by Harris or von Schacky, and in the last 18 months, a PubMed search found 58 articles with the O3I in the title or abstract. Based on these numbers, it appears that this metric continues to gain traction.

FIGURE 1.

Citations to the original Omega-3 Index report. The number of citations to the 2004 publication of the original article proposing the Omega-3 Index as a risk factor for fatal coronary heart disease.

What follows is a sampling of recent research articles that have used the O3I. These reports were selected to illustrate the utility of the O3I in establishing plausible associations between omega-3 status and risk for a range of human diseases and to demonstrate how this metric has been used to evaluate the bioavailability of new omega-3 products.

HEART HEALTH

As noted, the O3I was originally proposed in the CVD context, and it continues to be employed there. Perhaps the clearest example of the utility of the O3I in recent literature is a study from Bernhard et al.[5^▪▪] in which the investigators studied the effects of high doses of a prescription omega-3 product (Lovaza, GSK) on myocardial remodeling in the immediate postmyocardial infarction (MI) setting. Post-MI patients were randomized to omega-3 or placebo for six months, and their effects on cardiac architecture were assessed by MRI. In the 2016 primary report from the study, omega-3 treatment significantly slowed the rate of adverse myocardial remodeling. Six years later, these researchers followed up on the patients in this trial and examined the long-term effects on major adverse cardiovascular events (MACE), not of the original randomization (which were null), but of achieving at least 5% increase in the O3I or not. Of the 254 patients in the trial available, 43 experienced at least an O3I increase of 5% or greater. Baseline and end O3I values [mean (SD)] in these patients were 5.1% (1.4) and 11.6% (1.5) compared with 5.8% (1.7) and 7.0% (2.4) in the 211 controls. Over the next 6 years, those whose O3I increased by at least 5% during the 6 months of active treatment experienced a MACE rate of 2.9% compared with 7.1% in the controls; a more than 50% reduction in risk (Fig. 2). This article illustrates the potential importance of increasing the O3I [regardless of how it was accomplished, by initiating supplementation, increasing the intake of oily fish, or simply being (perhaps genetically) more responsive to an increased supply of omega-3] vs. simply being told to consume more omega-3. Although needing replication, this finding has potential implications for patient management, at least in the post-MI setting.

FIGURE 2.

Six-year MACE rates by O3I response. Annualized rate of major adverse cardiac events (MACE) in patient whose O3I increased by more or less than 5% during 6 months of treatment with omega-3 fatty acids after a myocardial infarction. Adapted with permission from [5^▪▪].

The O3I has enjoyed widespread use well beyond the CVD world. Below is a summary of several recent studies from across the disease spectrum where the O3I was used, either to track compliance with treatments (supplementation, increased fish consumption), to correlate with risk for a given disease, or to explore the O3I as a diagnostic or prognostic test metric. Since the O3I can be raised by increased omega-3 intake, if favorable relationships with these outcomes can be discerned, then the probability that a greater EPA+DHA intake would prove beneficial increases.

The potential role of omega-3 FAs in risk for atrial fibrillation, and more specifically postoperative atrial fibrillation (POAF), was explored by Rubanenko et al.[6] in a study with 158 patients undergoing coronary artery bypass surgery. POAF developed in 47 patients by postop day 5. A low O3I (<1.59%) was, along with several inflammatory and oxidative stress biomarkers, a significant predictor of who did and did not develop POAF. Linking a low omega-3 status with increased risk for POAF can, again, help risk stratify patients, and suggests opportunities for further research to explain why tissue omega-3 levels may influence the susceptibility to POAF.

BRAIN HEALTH

In a meta-analysis of randomized trials testing the effects of omega-3 supplementation on cognitive function in older people, He et al.[7^▪] reported that although there was no overall effect of omega-3 on global cognitive function, a higher baseline O3I and a higher O3I increment during supplementation were associated with an improvement in cognitive function. Elderly healthy, cognitively normal Seventh-day Adventists (n = 40) were tested for the O3I, for cognitive ability and had MRI brain scans completed. The O3I was directly associated with better memory, faster processing speed, and larger structural brain volumes. [8]

Antao et al.[9^▪] undertook a narrative review of the link between the O3I and mental illness with the goal of identifying clinically relevant O3I risk thresholds. They reviewed 30 studies and found either significant differences in the O3I between patients and controls or inverse relationships between O3I and disease severity. They concluded that the evidence was compelling enough to suggest that the O3I could be viewed as a risk factor for major depression and dementia (O3I <4--%), postpartum depression (O3I <5%), and psychosis (O3I <4%). These authors clearly believed that the O3I has at least potential relevance in the diagnosis of these diseases.

Cardiorespiratory fitness (CRF) and its associations with cognitive function were explored by investigators from the Cooper Center Longitudinal Study associated with the Cooper Clinic in Dallas, Texas, USA [10]. In addition to data on CRF, data on the O3I were also available for the 5464 individuals between 55 and 85 years of age. Based on scores from the Montreal Cognitive Assessment test, an O3I of less than 4% was associated with greater cognitive impairment compared with those whose O3I was more than 8%. Although this finding was attenuated when CRF was included in the model, in joint association analysis, risk of cognitive impairment was elevated with lower O3I or CRF or both. Again, the point is that this research team deemed the O3I a valid and meaningful measure of omega-3 fatty acid status with possible clinically relevant relationships with mental health.

COVID-19

SARS-CoV-2 infection can cause multisystem inflammatory syndrome in children, and since omega-3 fatty acids have well known anti-inflammatory properties, a group in Italy examined the relationship between the O3I and risk for hospitalization of children (mean age 8 years) with this syndrome [11]. They found that lengths of stay for children in the highest quartile of the O3I (≥ 2.51%) was 11.2 days compared with 14.8 days (P = 0.03) for those with lower O3I levels. The implications of this finding are two: that measuring the O3I at admission may help risk stratify children into higher vs. lower risk groups, and that increasing the O3I (probably via supplementation or by i.v. delivery) may help children recover more quickly.

BIOMARKER OF OMEGA-3 STATUS

As noted, one of the uses of the O3I is to objectively compare the effects of various omega-3 FA products on the body's omega-3 status. A recent example is that of Vosskötter et al.[12] who compared a relatively new omega-3 preparation from Canalus oil with both fish oil and krill oil using the O3I as the outcome metric. Canalus oil is extracted from a zoo plankton from north Atlantic waters (Calanus finmarchicus), in which EPA and DHA are present largely as wax esters (i.e., FAs bound to fatty alcohols). After 12 weeks of supplementing 62 volunteers with similar doses of each of these three sources of omega-3, the changes in the O3I were compared and did not differ significantly. Hence, Canalus oil could join the growing list of nonfish options as sources of EPA and DHA. The O3I was used in a similar way in a study of a fish oil rich in cetoleic (C22 : 1n11) and gondoic (C20 : 1 n-9) acids in which the change in the O3I was reportedly greater than expected for the dose of EPA+DHA fed [13].

The O3I is also being used to assess population omega-3 status. In another study by Schuchardt et al.[14], the O3I was measured in a previously untested population, that is young (mean age 20) Palestinian men and women (n = 149). With a mean O3I of 2.56% this cohort has one of the lowest levels of any population ever tested [4^▪▪]. Another cohort that has been chronically low in omega-3 FA intake is members of the US military. Rittenhouse et al.[15] undertook a study in 197 cadets at three service academies to determine the extent to which simply being offered a choice to select fish (twice a week) and/or omega-3 enriched foods (daily; smoothies or toppings to be added to milk, yogurt, etc.) would impact the overall O3I. They found that fish intake did not change, but the omega-3 enriched foods were well received, and that the greatest increase in the O3I was seen in those reporting the most frequent use of these novel food products. The O3I was used as the omega-3 biomarker of choice in a study of pregnant Australian Aboriginal women, seeking to link omega-3 status with risk for premature birth [16], and in a study of German young people with severe forms of acne [17]. The O3I served as the target metric for researchers seeking to find urinary metabolites that could possibly serve as less invasive markers of omega-3 status [18].

LIMITATIONS

As the O3I is defined by the sum of EPA and DHA in RBC membranes, it can obviously be affected differently by supplementation with either of these FAs separately. Indeed, gram for gram, DHA increases the O3I more than EPA, but whether this is reflected in different degrees of disease risk is not known. From a research perspective, it is important to store RBC samples at -80°C instead of -20°C where peroxidation of the PUFAs occurs at variable and unpredictable rates. Cross sectional studies have repeatedly confirmed that the O3I appears to rise with age, and thus in long-term observational studies seeking to link baseline O3I status with risk for a given disease it is critical to adjust for age (as a continuous variable) to avoid serious confounding. Finally, the focus on EPA and DHA alone, to the exclusion of alpha-linolenic acid and especially docosapentaenoic acid n-3, in the O3I has been questioned. This has been justified by demonstrating that the predictive power of the O3I as originally defined is not improved upon by including these other omega-3 PUFAs [19–22].

FUTURE DIRECTIONS

There is a continuing need to assess the predictive value of the O3I in unique populations. For example, the question of whether the upper end of the target range (8–11%) is properly set, that is, is there additional risk reduction (vs. 8%) in individuals with O3I values of say, 12–14%? Such a question would best be addressed in observational studies in countries like Japan where many more individuals with ‘very high’ levels are available, or in high-dose RCTs. It is also of interest to know the extent to which the O3I would predict risk for CVD, dementia, metabolic disease, etc. in vegetarian/vegan populations (e.g., certain South Asian or the Seventh Day Adventist groups) whose diets are largely devoid of fish and yet their (presumed) risk for adverse health outcomes is low owing to their habitual diet pattern.

CONCLUSION

This brief overview of recent studies utilizing the O3I provides strong confirmation that this metric continues to be viewed as a valid, reproducible, sensitive, and clinically relevant marker of omega-3 fatty acid status by the wider nutrition research community. In a 2024 review of the importance of testing omega-3 status and a comparison of the different tests available to clinicians, researchers, and the public, Dicklin et al.[23^▪▪] concluded that the Omega-3 Index is ‘the most widely used [omega-3 status] test with the largest evidence base’.

Acknowledgements

The author wishes to thank the co-developer of the Omega-3 Index, Dr Clemens von Schacky for his work, not only strengthening the scientific basis for the O3I but also for his many contributions over the last 40 years to the omega-3 research field.

Financial support and sponsorship

None.

Conflicts of interest

The author holds stock in OmegaQuant Analytics, LLC; a laboratory that offers fatty acid testing, including the O3I, to researchers, clinicians, and consumers.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

• ▪ of special interest

• ▪▪ of outstanding interest