Health effects of omega-3 fish oil supplements: is there cause for concern?

Patients take omega-3 fish oil supplements in the belief that these oils are heart healthy. But emerging evidence suggests a possible downside and that the benefits are dependent on an individual’s current state of health.

The boom in fish oil supplements: a brief history

In the 1970s, Danish researchers first observed how Greenland Eskimos had a fatty acid plasma profile with a higher concentration of long-chain polyunsaturated fatty acids – known as omega-3 fatty acids.¹ At the time, the indigenous Eskimos had a lower incidence of cardiovascular disease mortality compared to the wider Danish population. The reasons for these were unclear but researchers speculated that it might have something to do with the higher intake of these omega-3 fatty acids.

Over the following years, it became clear that there were two fatty acids in particular – docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – which conferred a cardiovascular benefit. In fact, as early as 1985, it was shown that men who were initially free of coronary heart disease had a 50% lower cardiovascular mortality if they consumed at least 30g of fish per day.² Furthermore, in a later randomised post-myocardial infarction dietary trial in men, those eating more fatty fish, such as salmon, sardines and herring, had a 29% reduction in two-year all-cause mortality.³

In summarising the available evidence, a 2021 meta-analysis of 38 randomised controlled trials with nearly 150,000 participants, clearly demonstrated that there were cardiovascular benefits from consumption of both EPA and DHA.⁴ As well as being available for purchase, fish oil supplements can also be prescribed and are licensed as an adjunct to diet and statin use in those with hypertriglyceridaemia and for secondary prevention following a myocardial infarction in the preceding three months.⁵ But while there appeared to be clear cardiovascular benefits from fish and fish oil supplements, emerging evidence pointed to a potential downside.

Fish oils and the risk of arrhythmias

Some of the earlier fish oil supplement studies had detected that consumption of fish oils also increased the risk of arrythmias, particularly atrial fibrillation (AF). Taking a closer look, in a 2021 meta-analysis, researchers showed that there was a 37% higher risk of incident AF compared with placebo in randomised trials of fish oil supplementation in patients with cardiovascular disease.⁶

But was this elevated risk due to EPA, DHA or both? Unfortunately, the available data has been unable to pinpoint which of the two oils was responsible. Some evidence suggested that DHA was the likely culprit because those with the highest levels of EPA had a 45% lower risk of AF.⁷ Nevertheless, other work simply muddied the waters, showing no effect of either type of oil on incident AF.⁸

Fish vs fish oil supplements

But were these risks still present for those eating oily fish? Fortunately, eating fish seems less risky. For instance, a prospective analysis published in 2023 assessed the risk of marine omega-3 fatty acid intake with the risk of AF.⁹

The analysis involved over 300,000 individuals and the authors stated that ‘consumption of marine omega-3 fatty acids was not associated with a higher incidence of AF.’ This finding was also confirmed in another recent analysis, where it was shown that blood levels of both EPA and DHA from eating fish were not associated with increased risk of incident AF.¹⁰

Benefits of fish oils are health dependent

To what extent is the risk:benefit ratio of taking fish oil supplements dependent on health status? In other words, which patients gain the most benefit from taking these oils? The answer is that it depends.

In a recent meta-analysis in people without cardiovascular disease, taking fish oil supplements increased the risk of developing atrial fibrillation by 13%.¹¹ In contrast, for those with existing cardiovascular disease and atrial fibrillation, the risk of progression to a major adverse cardiovascular event was reduced by 8%.

What about plant-based sources of EPA and DHA?

Intake of the plant-based omega-3 fatty acid alpha-linolenic acid (ALA) for example, in flaxseed and rapeseed oils (for those who don’t like fish), is associated with cardiovascular benefits.¹² Other data derived from the Cardiovascular Health Study,¹³ which was a community-based longitudinal cohort of adults aged 65 or older, also confirmed that there was no association between plasma phospholipid or dietary ALA and incident AF.

What advice should be given to patients?

In September 2023, the European Medicines Agency agreed to add atrial fibrillation as a common side-effect to the product information for medicines containing omega-3 fatty acids.¹⁴ This was an explicit recognition that omega-3 fish oil supplements at a dose of 4g/day, led to a dose dependent increased risk of AF when taken by those with established cardiovascular disease or with cardiovascular risk factors.

Overall, while there are risks and benefits from taking fish oil supplements, eating oily fish or plant-based alternatives does not appear to be associated with these risks. But if patients do choose to take fish oil supplements, they need to be advised on the potential risk of atrial fibrillation which might ultimately erode any recognised cardiovascular benefits.

References

1. Bang HO, Dyerberg J, Hjøorne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand. 1976;200(1-2):69-73. doi: 10.1111/j.0954-6820.1976.tb08198.x.
2. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med. 1985 May 9;312(19):1205-9. doi: 10.1056/NEJM198505093121901.
3. Burr ML, Fehily AM, Gilbert JF et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet. 1989 Sep 30;2(8666):757-61. doi: 10.1016/s0140-6736(89)90828-3.
4. Khan SU, Lone AN, Khan MS et al. Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis. 2021 Jul 8;38:100997. doi: 10.1016/j.eclinm.2021.100997. PMID: 34505026.
5. Omega-3-acid ethyl esters. BNF Available online at: https://bnf.nice.org.uk/drugs/omega-3-acid-ethyl-esters/ [Accessed May 2024]
6. Lombardi M, Carbone S, Del Buono MG et al. Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials. Eur Heart J Cardiovasc Pharmacother. 2021 Jul 23;7(4):e69-e70. doi: 10.1093/ehjcvp/pvab008.
7. Rix TA, Dinesen P, Lundbye-Christensen S et al. Omega-3 fatty acids in adipose tissue and risk of atrial fibrillation. Eur J Clin Invest. 2022 Jan;52(1):e13649. doi: 10.1111/eci.13649.
8. Albert CM, Cook NR, Pester J et al. Effect of Marine Omega-3 Fatty Acid and Vitamin D Supplementation on Incident Atrial Fibrillation: A Randomized Clinical Trial. JAMA. 2021 Mar 16;325(11):1061-1073. doi: 10.1001/jama.2021.1489.
9. Guardino ET, Li Y, Nguyen XM et al. Dietary ω-3 fatty acids and the incidence of atrial fibrillation in the Million Veteran Program. Am J Clin Nutr. 2023 Aug;118(2):406-411. doi: 10.1016/j.ajcnut.2023.06.001.
10. Qian F, Tintle N, Jensen PN et al. Fatty Acids and Outcomes Research Consortium (FORCE). Omega-3 Fatty Acid Biomarkers and Incident Atrial Fibrillation. J Am Coll Cardiol. 2023 Jul 25;82(4):336-349. doi: 10.1016/j.jacc.2023.05.024. PMID: 37468189.
11. Chen G, Qian ZM, Zhang J et al. Regular use of fish oil supplements and course of cardiovascular diseases: prospective cohort study. BMJ Med. 2024 May 21;3(1):e000451. doi: 10.1136/bmjmed-2022-000451.
12. Sala-Vila A, Fleming J, Kris-Etherton P et al. Impact of α-Linolenic Acid, the Vegetable ω-3 Fatty Acid, on Cardiovascular Disease and Cognition. Adv Nutr. 2022 Oct 2;13(5):1584-1602. doi: 10.1093/advances/nmac016.
13. Fretts AM, Mozaffarian D, Siscovick DS et al. Associations of plasma phospholipid and dietary alpha linolenic acid with incident atrial fibrillation in older adults: the Cardiovascular Health Study. J Am Heart Assoc. 2013 Jan 31;2(1):e003814. doi: 10.1161/JAHA.112.003814.
14. European Medicines Agency. New safety information for Omega-3-acid ethyl esters. Available online at: https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-25-28-september-2023 [Accessed May 2024]

Rod Tucker

See Full Bio