By William S. Harris, PhD, FASN

Fatty Acid Research Institute (FARI); OmegaQuant Analytics; and the Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD

 

Based on a new study from Chen et al. (1) published in May 2024 in the British Medical Journal, headlines around the world are blaring, “Fish oil supplements cause heart disease!” This is a serious misrepresentation of, not only this specific study, but of the field at large. In this blog we are going to discuss some serious issues with this study that were overlooked by not only the authors and the BMJ editors but also the medical media at large.

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First, this new study used self-reported data from the UK Biobank (UKBB) on “regular fish oil supplement (FOS) use” and prospectively linked FOS use vs. non-use to clinical outcomes. This is not the only study to have done this. Table 1 summarizes 10 previous reports on the relationships between FOS use and conditions ranging from death to liver cancer to fractures. Summarizing these data, there have been 18 relationships that were both statistically significant and favorable for FOS users; three relationships that were not significant, and one unfavorable, atrial fibrillation (AF).

Table 1. Summary of previous studies from the UKBB linking the reported use of fish oil supplements with clinical outcomes

*All participants free of the outcome of interest at baseline

Thus, the larger story (that naively one would hope the press would have covered) is solidly in favor of the use of FOS. So, it is difficult to criticize Chen et al. simply for using self-reported FOS data in the UKBB since so many others have done the same, but these authors arrived at different conclusions.

Why this is the case is not clear to me since Chen et al. adjusted their analyses for most of the same factors that the other studies in Table 1 adjusted for, including age; sex; ethnic group; Townsend deprivation index; consumption of oily fish, non-oily fish and alcohol; smoking status; obesity; hypertension; diabetes mellitus; chronic obstructive pulmonary disease; chronic renal failure; and use of statins, antidiabetic, and antihypertensive drugs. So, the relationships uncovered should be independent of any of these other factors.

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Second, Chen et al. examined cardiovascular disease (CVD)-related “pathways” and how risk was different between FOS users and non-users going (for example) from healthy to AF and then from AF to myocardial infarction, or to stroke, or to heart failure and/or to death. There were four different “transition patterns” labeled I-IV and six sets of transitions labeled A-F. In all, there were 15 separate “pathway” outcomes, with hazard ratios (HRs) for each (see their Table 2), and 9 of these were non-significant (p≥0.05); one was adversely associated with FOS use; and five were favorably associated with FOS use (Figure 1).

The authors did not present the raw event rates in this paper, but if one calculates the absolute risk (as opposed to the relative risks reported), the actual incidence of AF in the non-FOS users was 4.2% and 4.8% in the FOS users. In other words, the actual risk for AF increase was only 0.6% (personal communication, A. Bernsaconi). This perspective was missing from the Chen et al. discussion.

Figure 1. Associations (p<0.05) between CVD outcome paths and reported fish oil supplement use in the UK Biobank (1). The red column indicate increased risk and the green columns decreased risk.

The authors concluded their abstract with, “Regular use of FOS might be a risk factor for atrial fibrillation and stroke [not significant] among the general population, but [it] could be beneficial for progression of CVD from AF to major adverse cardiovascular events, and from AF to death.” In other words, although the risk for AF was somewhat higher, those who transitioned from healthy to AF were protected against further development of more debilitating outcomes if they were taking FOS.

Unfortunately, the media not only focused on the single adverse outcome – risk for AF (the stroke relationship was only a trend, but the authors – and the press – acted like it was statistically significant), and most reporters dropped the word “might.” In addition, the headlines screamed “FOS increases risk for heart disease” when the only real finding was for AF, not for “heart disease” writ large. And of course, as noted, the five favorable outcomes were completely ignored.

VIDEO: Does Fish Oil Help with Atrial Fibrillation?

Third, as mentioned, Chen et al. not only failed to discuss any of the previous studies outlined in Table 1, but they also ignored the most relevant study of all, that of Li et al. (12) which also focused on CVD outcomes and FOS use in the UKBB.

In Li et al., every CVD outcome (except death from stroke), including total mortality, was statistically significantly and beneficially associated with FOS use. Despite coming from the same subjects and using the same exposures and outcomes, Chen et al. said nothing about why their results directly contradicted those of Li et al.

A problem may also have occurred with the data extraction from the UKBB (Table 2). These data were taken from the Table 1 data from both Li et al. and Chen et al. Note that although the n’s differed by about 3% (Chen et al. apparently excluded patients with AF or HF at baseline that Li et al. included), for several measures the two cohorts looked virtually identical (age, sex, smoking), but for other variables (in red), the differences were stark. It’s not clear if one is correct and the other not, or both are incorrect, but these differences raise concerns about data extraction (in both studies).

Table 2. Comparison of UKBB study population characteristics between Li et al. and Chen et al.

Fourth, self-reported FOS use is a far less objective measure of omega-3 intake and status than are actual blood levels of omega-3 fatty acids. A recent report from O’Keefe et al. (13) in the UKBB looked at the association between plasma omega-3 levels (in particular, DHA) and risk for death from all causes and from CVD, cancer and remaining other causes. They found significant inverse (beneficial) associations between DHA levels and risk for all four mortality outcomes (Figure 2). Why did this report receive virtually no attention by either Chen et al. or the press?

Figure 2. Associations between plasma DHA levels by quintile and risk for all-cause and cause-specific mortality in the UK Biobank. (The y-axis is truncated at 50%). From O’Keefe et al. (11)

 

Finally, beyond the UKBB and CVD, there have been six high quality meta-analyses of omega-3 fatty acid status (blood and tissue levels) and multiple disease outcomes produced by the Fatty Acids and Outcomes Research Consortium (FORCE) (Table 3). FORCE performs meta-analyses on de novo (i.e., previously unpublished) data from between 15 and 30 individual cohort studies (depending on the outcome) from around the world. All six of these studies have reported favorable associations between omega-3 fatty acid levels and clinically-relevant outcomes — the only exception being for hemorrhagic stroke where there was no statistically significant association (which, since omega-3 fatty acids do, like aspirin, “thin the blood,” was a re-assuring finding). None of these studies has reported adverse relationships with omega-3 levels, and of course, none of these studies were considered by Chen et al.

Table 3. Associations between in vivo omega-3 fatty acid levels and clinical outcomes from FORCE

Leaving observational studies and looking at the randomized clinical trial (RCT) data also supports the CV benefits of omega-3 fatty acids. Meta-analyses by both Laukkanen et al. (19) and Rizos et al. (20) have reported statistically significant risk reductions for multiple CVD outcomes, especially (as shown in Rizos et al.) with higher doses of omega-3 fatty acids. Thus, even “gold standard” RCT data support the cardioprotective effects of omega-3 fatty acids.

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There appears to be a bias towards reporting adverse effects of FOS on CVD and ignoring the far more compelling story that has confirmed, ever since the groundbreaking studies of Dyerberg and Bang among Greenland Inuits in the 1970s (21), that omega-3 fatty acids are heart healthy.

 

References

  1. Chen G, Qian ZM, Zhang J, Zhang S, Zhang Z, Vaughn MG, et al. Regular use of fish oil supplements and course of cardiovascular diseases: prospective cohort study. BMJ Med 2024;3(1):e000451.
  1. Liu X, Li Y, Wan X, Zhuang P, Wu Y, Zhang L, et al. Association of Fish Oil Supplementation with Risk of Coronary Heart Disease in Individuals with Diabetes and Prediabetes: A Prospective Study in the UK Biobank. Nutrients 2023;15(14).
  1. Gan X, Liu M, He P, Ye Z, Xiang H, Zhou C, et al. Habitual fish oil supplementation, genetic susceptibility of kidney stones and the risk of new-onset kidney stones. J Clin Lipidol 2024;18(1):e116-e24.
  1. Zhang J, Cai A, Chen G, Wang X, Cai M, Li H, et al. Habitual fish oil supplementation and the risk of incident atrial fibrillation: findings from a large prospective longitudinal cohort study. European journal of preventive cardiology 2022;29(14):1911-20.
  1. Jiang W, Li FR, Yang HH, Chen GC, Hua YF. Relationship Between Fish Oil Use and Incidence of Primary Liver Cancer: Findings From a Population-Based Prospective Cohort Study. Front Nutr 2021;8:771984.
  1. Ma T, He L, Luo Y, Li J, Zhang G, Cheng X, et al. Associations of baseline use of fish oil with progression of cardiometabolic multimorbidity and mortality among patients with hypertension: a prospective study of UK Biobank. European journal of nutrition 2022:1-10.
  1. Ma H, Zhou T, Li X, Heianza Y, Qi L. Use of fish oil supplements is differently related to incidence of all-cause and vascular dementia among people with the distinct APOE ε4 dosage. Clinical nutrition (Edinburgh, Scotland) 2022;41(3):731-6.
  1. Liu X, Zhuang P, Li Y, Wu F, Wan X, Zhang Y, et al. Association of fish oil supplementation with risk of incident dementia: A prospective study of 215,083 older adults. Clinical nutrition (Edinburgh, Scotland) 2022;41(3):589-98.
  1. Huang X, Li Y, Zhuang P, Liu X, Zhang Y, Zhang P, et al. Habitual Fish Oil Supplementation and Risk of Incident Inflammatory Bowel Diseases: A Prospective Population-Based Study. Front Nutr 2022;9:905162.
  1. Mei Z, Chen GC, Hu J, Lin C, Sun Z, Liu C, et al. Habitual use of fish oil supplements, genetic predisposition, and risk of fractures: a large population-based study. Am J Clin Nutr 2021;114(3):945-54.
  1. O’Keefe EL, O’Keefe JH, Tintle NL, Westra J, Albuisson L, Harris WS. Circulating Docosahexaenoic Acid and Risk of All-Cause and Cause-Specific Mortality. Mayo Clinic proceedings 2024.12. Li Z-H, Zhong W-F, Liu S, Kraus VB, Zhang Y-J, Gao X, et al. Associations of habitual fish oil supplementation with cardiovascular outcomes and all-cause mortality: evidence from a large population based cohort study. BMJ (Clinical research ed) 2020;368:m456.
  1. O’Keefe JH, Tintle NL, Harris WS, O’Keefe EL, Sala-Vila A, Attia J, et al. Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies. Stroke 2024;55(1):50-8.
  1. Del Gobbo LC, Imamura F, Aslibekyan S, Marklund M, Virtanen JK, Wennberg M, et al. Omega-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease: Pooling Project of 19 Cohort Studies. JAMA internal medicine 2016;176(8):1155-66.
  1. Qian F, Ardisson Korat AV, Imamura F, Marklund M, Tintle N, Virtanen JK, et al. n-3 Fatty Acid Biomarkers and Incident Type 2 Diabetes: An Individual Participant-Level Pooling Project of 20 Prospective Cohort Studies. Diabetes Care 2021;44(5):1133-42.
  1. Harris WS, Tintle NL, Imamura F, Qian F, Korat AVA, Marklund M, et al. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nat Commun 2021;12(1):2329.
  1. Qian F, Tintle N, Jensen PN, Lemaitre RN, Imamura F, Feldreich TR, et al. Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation. J Am Coll Cardiol 2023;82(4):336-49.
  1. Ong KL, Marklund M, Huang L, Rye KA, Hui N, Pan XF, et al. Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. BMJ (Clinical research ed) 2023;380:e072909.
  1. Laukkanen JA, Bernasconi AA, Lavie CJ. Bringing the Potential Benefits of Omega-3 to a Higher Level. Mayo Clinic proceedings 2024;99(4):520-3.
  1. Rizos EC, Markozannes G, Tsapas A, Mantzoros CS, Ntzani EE. Omega-3 supplementation and cardiovascular disease: formulation-based systematic review and meta-analysis with trial sequential analysis. Heart 2021;107(2):150-8.
  1. Harris WS, Calder PC, Mozaffarian D, Serhan CN. Bang and Dyerberg’s omega-3 discovery turns fifty. Nat Food 2021;2(5):303-5.

These statements have not been evaluated by the Food and Drug Administration. This test is not intended to diagnose, treat, cure, prevent or mitigate any disease. This site does not offer medical advice, and nothing contained herein is intended to establish a doctor/patient relationship. OmegaQuant, LLC is regulated under the Clinical Laboratory improvement Amendments of 1988 (CLIA) and is qualified to perform high complexity clinical testing. The performance characteristics of this test were determined by OmegaQuant, LLC. It has not been cleared or approved by the U.S. Food and Drug Administration.

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