Cardiovascular Impact of Nutritional Supplementation With Omega-3 Fatty Acids

JACC Focus Seminar

Richard L. Weinberg, MD, PHD; Robert D. Brook, MD; Melvyn Rubenfire, MD; Kim A. Eagle, MD


J Am Coll Cardiol. 2021;77(5):593-608. 

In This Article


Nomenclature and Types of Polyunsaturated Fatty Acids

PUFAs exist in 2 major classes: omega-3 (n-3 or ω-3) and omega-6 (n-6 or ω-6). PUFAs differ from saturated and monounsaturated fatty acids by containing 2 or more double bonds between carbon atoms in the fatty acid chain. The 3 major omega-3 PUFAs which have been studied with respect to the heart are alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Common omega-6 PUFAs are linoleic acid and arachidonic acid (Table 1).[1]

Dietary Sources of Omega-3 and Omega-6 PUFAs

Major sources of omega-6 PUFAs (predominantly linoleic acid) include nuts, crop seeds, and vegetable oils. Plant oils including flaxseed, soybean, and canola oil, and chia seeds, walnuts, and flax also contain omega-3 PUFAs (as alpha-linolenic acid). EPA and DHA are found in fish, although the content of DHA and EPA varies widely (Table 2).[2,3] The omega-3 PUFA content of fishes depends on their diet and environment. Compared with warm-water fishes, cold-water fishes accumulate higher levels of omega-3 PUFAs, which help adaptation to lower temperatures. Levels of DHA and EPA in fish can vary among wild-caught and farm-raised fish as a function of their diet.[4] Higher-fat fishes such as mackerel, salmon, herring, sardines, and albacore tuna are sources of DHA and EPA.[5] The U.S. Department of Agriculture's FoodData Central website[2] provides the content of PUFAs in many foods.

Recommended adequate intakes for omega-3 PUFAs were developed by the Food and Nutrition Board of the Institute of Medicine and are 1.6 g/day for men and 1.1 g/day for women older than 19 years of age (as alpha-linolenic acid).[6] No specific intake recommendations were made for EPA or DHA. The 2015 to 2020 Dietary Guidelines Advisory Committee and most recent American Heart Association Science Advisory recommend ≥2 servings per week of fish (preferably oily fish) to provide approximately 250 mg/day of EPA plus DHA in place of other animal sources of protein.[7–9]

Dietary Supplements

Fish oil dietary supplements are the most commonly consumed nonvitamin, nonmineral natural products by adults. It is estimated that 19 million people take fish oil dietary supplements in the United States.[10,11] The U.S. Food and Drug Administration classifies fish oil dietary supplements as food; therefore, these products are not subject to U.S. Food and Drug Administration oversight. The content of fish oil dietary supplements varies widely, with some containing saturated fatty acids, oxidized fatty acids, persistent organic pollutants, and mercury, which may counteract the beneficial effects of omega-3 PUFAs.[12–15] Cardiac patients frequently consume fish oil dietary supplements without medical oversight and without knowledge of the ingredients in the supplement.[16]

Fish oil dietary supplements have been studied in 2 distinct but overlapping roles. First, at lower doses (typically 1 g/day) fish oil dietary supplements have been evaluated in preventing CVD events in patients with known ASCVD or at high CVD risk. Based on the latest meta-analysis[17] and American Heart Association Scientific Statement,[18] there is modest support for their use. Second, at higher doses (2 to 4 g/day), fish oil dietary supplements have been used to lower triglycerides, although there are now prescription omega-3 PUFAs, which have been approved by the U.S. Food and Drug Administration for this indication.[19] Neither fish oil dietary supplements nor prescription omega-3 PUFAs have been proven to lower the risk of chylomicron syndrome or pancreatitis, owing to lack of trial data.

Prescription Omega-3 PUFAs

There are 4 U.S. Food and Drug Administration–approved prescription omega-3 PUFA formulations. They are indicated as adjunctive therapy (2 to 4 g/day) to diet to reduce triglyceride levels in adults with severe hypertriglyceridemia (≥500 mg/dl) (Table 3). Although they typically lower triglycerides by 25% to 40%, approximately 10% per 1 g of EPA or DHA, none have proven to prevent the consequences of severe hypertriglyceridemia (i.e., chylomicronemia syndrome or pancreatitis) owing to the lack of RCTs.[19] Icosapent ethyl (IPE), the ethyl ester of EPA, has an additional indication as an adjunct to maximally tolerated statin therapy to reduce the risk of ASCVD events in select populations based on the results of the REDUCE-IT (Reduction of Cardiovascular Events with EPA-Intervention Trial).[20]