Fish Oil Supplements are Widely Promoted for Heart Health, But is it Justified?

Pharmacists are often consulted by patients on the potential benefits of different omega-3 fatty acid (n3-FA) products, especially among those at risk for cardiovascular disease (CVD). Fish oil supplements appear to be a convenient approach to meet the need for dietary or even therapeutic levels of n3-FAs.

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But there remains significant confusion surrounding the contents, quality, and regulatory oversight of these products compared to prescription or OTC formulations. Several lines of scientific investigation into the quality and content of fish oil supplements have produced disconcerting results that pharmacists should consider alongside patients and their primary physicians.

During the past eight years, my colleagues and I have been investigating the chemical composition and biological activity of fish oil dietary supplements and prescription n3-FA formulations. I recently published a review article on this topic that evaluates both the basic and clinical evidence for various n3-FA formulations and their comparative benefits for CVD treatment, and I refer interested readers to this for a deeper exploration of the topic.¹

Are Fish Oil Supplements Interchangeable with OTC or Prescription Products?

The n3-FAs are considered essential fatty acids and, as such, must be consumed from dietary sources, such as oily marine fish. As a popular source of n3-FAs, fish oil supplements are often recommended as OTC products for this purpose.

Unfortunately, this implies a level of regulation that does not apply to these products.² An OTC medication undergoes rigorous FDA oversight prior to marketing, whereas dietary supplements are considered a “food product,” for which there is no requirement for clinical testing for safety and efficacy.

Given their popularity with annual sales expected to exceed $10 billion by 2028,³ it begs the question: what are actually in fish oil supplements? Do they support heart health as they widely claim in their promotions? A review of the literature has identified at least 3 areas of concern with these widely used products:

1. The commonly purchased, 1-gram capsules of fish oil typically have one-third or even less of the essential n3-FAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These levels have been found to deviate from advertised amounts, are far lower than therapeutic doses provided by prescription formulations, and can vary widely from product to product.^2,4-6 As a result, patients needing to achieve the recommended therapeutic dose (4 g/d) would need to consume at least 10-20 supplement capsules, depending on the formulation.
2. The composition of most of the oils (i.e., non-n3-FAs) in dietary supplements are not disclosed in packaging and vary widely among these products. A chemical analysis showed that popular US supplements (based on sales) contained dozens of fatty acids that include medium and long chain saturated fats.⁷ In addition to their high caloric content, such saturated fats are considered atherogenic and not recommended for high-risk CVD patients.
3. Finally, most widely used fish oil supplements are produced in large quantities by an industrial process that renders the n3-FAs vulnerable to unregulated heat and oxygen exposure.⁵ This results in oxidation of their highly unsaturated fatty acids with a consequent loss of biological benefit.^6,7 Such “rancidity” has been precisely measured by multiple laboratories using dozens of products. In addition to losing their health benefits, consumption of oxidized oils leads to vascular inflammation and dyslipidemia, key causes of CVD.⁸

What About FDA Approved n3-FA Formulations and their Outcome Trials?

Along with common fish oil supplements, the quality of prescription n3-FAs were investigated. Due to FDA regulation and manufacturing oversight, the prescription n3-FA formulations contained precise levels of n3-FAs and were not contaminated with oxidized lipids or saturated fats as compared to supplements.⁷

Among prescription formulations, the highly purified ethyl form of EPA (icosapent ethyl or IPE) demonstrated CVD risk reduction among statin-treated patients at high risk of CV disease in a large outcomes trial (REDUCE-IT). It is currently indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of serious CVD events in patients with elevated TGs and established CVD or diabetes mellitus along with additional risk factors.⁹

By contrast, the STRENGTH trial, which used a mixed combination of EPA/DHA in a similar high CVD risk population was terminated early due to futility.¹⁰ Similar negative results have been observed in other randomized trials using mixed n3-FA preparations in contrast to IPE.^11-13

Does Placebo Choice Matter in n3-FA Trials?

There has been some debate surrounding the role of placebo choice in different n3-FA trials. Some have argued that despite their distinct formulations, the pronounced differences in clinical outcomes may be attributed to the placebo choice: pharmaceutical grade mineral oil (REDUCE-IT) or corn oil (STRENGTH)¹⁴ as suggested by a recent biomarker post hoc analysis.¹⁵

A closer examination of these biomarker changes showed that levels only increased over 12 months and then plateaued, whereas CVD event reduction in REDUCE-IT with IPE began after approximately 2 years and then continued uninterrupted throughout the remainder of the trial. If mineral oil was inducing systemic inflammation that led to CVD events and masked the benefit of IPE, one would expect these levels to only increase with continued exposure.¹⁶

Additionally, the levels of these biomarkers were well-below other large randomized clinical trials and close to minimum detection levels. For further details on this topic, I refer the reader to a recent commentary I wrote in Circulation.¹⁶

Placebo oils differ in composition: mineral oil contains saturated, aliphatic hydrocarbons ranging from approximately C15-C26, while corn oil is primarily composed of the omega-6, linoleic acid.¹⁷ We recently demonstrated that human lipoproteins or membranes containing these placebo oils did not affect atherosclerotic processes, including lipid oxidation, while EPA had pronounced antioxidant benefits.¹⁸ Analyses of REDUCE-IT by the FDA found that changes in these biomarkers in the placebo arm had little effect, if any, on the favorable CVD benefits of IPE.¹⁷

What is the Safety Profile for Prescription n3-FAs?

No consideration of a prescription product is complete without discussing potential adverse effects. Early in the development of prescription n3-FA formulations, some argued that higher therapeutic doses of n3-FAs (4 g/d) could lead to worsened glucose control in those with impaired glucose tolerance.¹⁹

Since that time, several studies and meta-analyses have determined to be an unsubstantiated concern. None of the regulatory trials using 2-4 g/d IPE (ANCHOR, MARINE) nor REDUCE-IT, which included patients with diabetes, showed worsening in glucose control. Further, a meta-analysis of more than 80 randomized controlled trials failed to show any association between glucose changes and n3-FA treatment.²⁰

Although there was a small but significant increase in bleeding with IPE treatment compared to placebo in REDUCE-IT (2.7% vs 2.1%, P = 0.06), there were no bleeding deaths. Instead, there was a 31% reduction in the composite of serious CVD events that include myocardial infarction, stroke, and death that support anti-thrombotic benefits for IPE.

Final Thoughts for Pharmacists About n3-FA Products

Despite their popularity, fish oil supplements are not OTC products that have been rigorously tested for quality or evaluated in large, randomized trials for efficacy and safety. They often contain relatively low amounts of the desired n3-FAs, and such levels vary widely among products.

Popular dietary supplements also contain significant amounts of other oils, such as saturated fat and oxidized lipids, which would not be recommended for consumers, much less CVD patients. It is important for pharmacists to educate patients, especially those with CVD or at high-risk, about the differences between fish oil supplements and prescription n3-FAs products when it comes to therapeutic options advised by their physicians.

About the Author

Samuel C.R. Sherratt is a PhD candidate in the Department of Molecular, Cellular, and Biomedical Sciences at the University of New Hampshire. He has published more than 100 original articles, reviews and abstracts related to research on omega-3 fatty acids. He has presented and received awards for this research at international scientific meetings. Mr. Sherratt also has an employment relationship with Elucida Research that has received research support from manufacturers of omega-3 fatty acid products, including Amarin Corp.

References

1. Sherratt SCR, Libby P, Budoff MJ, Bhatt DL, Mason RP: Role of Omega-3 Fatty Acids in Cardiovascular Disease: the Debate Continues. Current Atherosclerosis Reports 2023, 25:1-17.

2. Hilleman DE, Wiggins B, S., Bottorff MB: Critical differences between dietary supplement and prescription omega-3 fatty acids: a narrative review. Advances in Therapy 2020, 37:656-670.

3. Omega 3 Supplements Market Share, Size, Trends, Industry Analysis Report, By Form (Tablets, Capsules, Soft Gels), By Functionality (Cardiovascular Health, Brain, Nervous System & Mental Health, Eye Diseases, Diabetes), By End-Use; By Source; By Regions; Segment Forecast, 2021 - 2028 [https://www.polarismarketresearch.com/industry-analysis/omega-3-supplement-market]

4. Albert BB, Derraik JGB, Cameron-Smith D, et al: Fish oil supplements in New Zealand are highly oxidised and do not meet label content of n-3 PUFA. Scientific Reports 2015, 5.

5. Sherratt SCR, Lero M, Mason RP: Are dietary fish oil supplements appropriate for dyslipidemia management? A review of the evidence. Current Opinion in Lipidology 2020, 31(2):94-100.

6. Sullivan Ritter JC, Budge SM, Jovica F: Quality analysis of commerical fish oil preparations. Journal of the Science of Food and Agriculture 2013, 93:1935-1939.

7. Mason RP, Sherratt SC: Omega-3 fatty acid fish oil dietary supplements contain saturated fats and oxidized lipids that may interfere with their intended biological benefits. Biochemical and Biophysical Research Communications 2017, 483:425-429.

8. García-Hernández VM, Gallar M, Sánchez-Soriano J, Micol V, Roche E, García-García E: Effect of omega-3 dietary supplements with different oxidation levels in the lipidic profile of women: a randomized controlled trial. International Journal of Food Sciences and Nutrition 2013, 64(8):993-1000.

9. Bhatt D, L., Steg PG, Miller M, et al: Cardiovascular risk reduction with Icosapent Ethyl for hypertriglyceridemia. New England Journal of Medicine 2019, 380:11-22.

10. Nicholls SJ, Lincoff AM, Garcia M, et al: Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA 2020, 324(22):2268-2280.

11. Kalstad AA, Myhre PL, Laake K, et al: Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial. Circulation 2021, 143(6):528-539.

12. Manson JE, Cook NR, Lee I-M, et al: Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. New England Journal of Medicine 2018, 380(1):23-32.

13. Group TASC: Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus. New England Journal of Medicine 2018, 379(16):1540-1550.

14. Nissen SE: When Is a Placebo Not a Placebo. JAMA Cardiology 2022.

15. Ridker PM, Rifai N, MacFadyen J, et al: Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1b, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy. Circulation 2022, 146(5):372-379.

16. Sherratt SCR: Letter by Sherratt Regarding Article, “Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy”. Circulation 2022, 146(20):e282-e283.

17. Olshansky B, Chung MK, Budoff MJ, et al: Mineral oil: safety and use as placebo in REDUCE-IT and other clinical studies. European Heart Journal Supplements 2020, 22(Supplement_J):J34-J48.

18. Sherratt SCR, Libby P, Bhatt DL, Mason RP: Comparative Effects of Mineral Oil, Corn Oil, Eicosapentaenoic Acid, and Docosahexaenoic Acid in an In Vitro Atherosclerosis Model. Journal of the American Heart Association 2023, 12:e029109.

19. Kris-Etherton PM, Harris WS, Appel LJ: Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease. Circulation 2002, 106(21):2747-2757.

20. Brown TJ, Brainard J, Song F, Wang X, Abdelhamid A, Hooper L: Omega-3, omega-6, and total dietary polyunsaturated fat for prevention and treatment of type 2 diabetes mellitus: systematic review and meta-analysis of randomised controlled trials. BMJ 2019, 366:l4697.