Something Smells Fishy: A Review of Omega-3 and the REDUCE-IT Results Controversy


As evidence for omega-3 continues to develop, pharmacists remain poised to guide patients toward the most indicated, safe, effective, and convenient options available.

Historical use and dosing of omega-3 fatty acids

Omega-3 fatty acids (omega-3s, n-3s) have a storied history of use for heart health. Initially recognized in the diets of Greenland natives through epidemiological studies,1 eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) have since been proposed to benefit cardiovascular health through several pathways.

Most well established are the effects of omega-3s on triglyceride levels, which is the only indication for which FDA-approved therapies have been introduced.2,3 Omega-3s may also have a small impact on blood pressure and platelet aggregation, both of which have been theorized to contribute to the overall cardiovascular benefit.2

Although it is difficult to say with confidence which mechanisms truly present the most benefit, a perhaps more relevant problem exists in what to recommend for omega-3 intake. Setting aside the FDA indication for hypertriglyceridemia, it can be difficult to recommend a specific dose or source of omega-3s based on available evidence.

Although the Food and Nutrition Board of the National Academy of Medicine has established recommendations for Adequate Intake, evidence was deemed insufficient to develop a Recommended Dietary Allowance.4 The American Heart Association (AHA) has previously recommended omega-3 intake preferentially through regular consumption of fish, aiming for around 1 gram of EPA and DHA combined in patients with documented coronary heart disease (CHD).5

Although evidence for use of pharmaceutical-grade doses of omega-3 (2 to 4 grams/day) in cardiovascular disease and secondary prevention was bolstered by data from the REDUCE-IT trial, critics have voiced concern about the validity of the trial results.

Criticism for REDUCE-IT trial design and implications for the findings

A recently released biomarker substudy of REDUCE-IT explored the potentially confounding nature of using mineral oil as the comparator. Although median levels of each measured biomarker were similar across the 2 treatment groups, atherosclerotic biomarker levels increased in those allocated to the mineral oil placebo at both 12 and 24 months of therapy, while there were only minimal changes in the icosapent ethyl group.6

Examples of this provided by the study includes that at REDUCE-IT study completion, median percent differences in the mineral oil group were 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized LDL, 19.8% for interleukin-6, and 38.5% for high sensitivity C-reactive protein. All these values were statistically significant (p ≤0.007). This is notable because other large-scale trials did not have substantial biomarker changes in their placebo arms, including the STRENGTH trial, which used a corn oil placebo.6

Considering this information when interpreting these trial results makes it difficult to detangle the potential benefit of icosapent ethyl and the adverse effects (AEs) from the mineral oil. When the comparator arm is not inert and contributes any significant effect—positive or negative—estimating the clinical effect of the intervention becomes muddy at best. As the difficulty with interpretation arises from an issue with the core design of the study, resolution of the controversy will most likely require additional research studies.6

Recommendations moving forward

As with any pharmaceutical intervention, pharmacists and providers must weigh the potential benefits against the risk of harm. The same is true with OTC and prescription-strength omega-3s.

Upon review, there may be less evidence to support high doses (4 grams/day) of icosapent ethyl for reduction of cardiovascular events. Additionally, the risks of harm—including clinical bleeding and worsened glucose control in those with impaired glucose tolerance—may be increased in these higher doses.2

However, many formulations of fish oil and omega-3s exist OTC in strengths more in line with recommendations for intake from the AHA and Food and Nutrition Board. Hearing about these recommendations, patients may seek to supplement their intake with oral formulations of fish oil, especially those averse to dietary intake. For these patients, the risk versus benefit equation is a bit clearer.

The major AEs from OTC doses of omega-3 may be generally tolerable, and include GI disturbances such as upset stomach, fishy burps, and fishy aftertaste.2-4 The risks of clinical bleeding and worsening glycemia is much lower at these doses, and the FDA has ruled marine omega-3s up to 3 grams/day as “Generally Recognized as Safe.”2

Evidence for cardiovascular benefit exists, and the AHA encourages patients with CHD to consume around 1 gram/day of omega-3s.2-3 Additional considerations include patient preferences and availability of reputable formulations. As evidence for omega-3 continues to develop, pharmacists remain poised to guide patients toward the most indicated, safe, effective, and convenient options available.

About the Author

Marvin Buckland, PharmD Candidate, University of Minnesota, Class of 2023.


1. Dyerberg J, Bang HO, Stoffersen E, Moncada S, Vane JR. Eicosapentaenoic acid and prevention of thrombosis and atherosclerosis?. Lancet. 1978;2(8081):117-119. doi:10.1016/s0140-6736(78)91505-2

2. Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease [published correction appears in Circulation. 2003 Jan 28;107(3):512.]. Circulation. 2002;106(21):2747-2757. doi:10.1161/01.cir.0000038493.65177.94

3. Krupa K, Fritz K, Parmar M. Omega-3 Fatty Acids. [Updated 2022 Sep 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:

4. Office of Dietary Supplements. Omega-3 fatty acids - fact sheet for health professionals. Accessed December 13, 2022.

5. Kris-Etherton PM, Harris WS, Appel LJ; AHA Nutrition Committee. American Heart Association. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler

6. Ridker PM, Rifai N, MacFadyen J, et al. 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(5):372-379. doi:10.1161/CIRCULATIONAHA.122.059410.

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