Omega-3 Fatty Acid Formulations in Cardiovascular Disease: Dietary Supplements are Not Substitutes for Prescription Products

Abstract

Omega-3 fatty acid products are available as prescription formulations (icosapent ethyl, omega-3-acid ethyl esters, omega-3-acid ethyl esters A, omega-3-carboxylic acids) and dietary supplements (predominantly fish oils). Most dietary supplements and all but one prescription formulation contain mixtures of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Products containing both EPA and DHA may raise low-density lipoprotein cholesterol (LDL-C). In clinical trials, the EPA-only prescription product, icosapent ethyl, did not raise LDL-C compared with placebo. To correct a common misconception, it is important to note that omega-3 fatty acid dietary supplements are not US FDA-approved over-the-counter drugs and are not required to demonstrate safety and efficacy prior to marketing. Conversely, prescription products are supported by extensive clinical safety and efficacy investigations required for FDA approval and have active and ongoing safety monitoring programs. While omega-3 fatty acid dietary supplements may have a place in the supplementation of diet, they generally contain lower levels of EPA and DHA than prescription products and are not approved or intended to treat disease. Perhaps due to the lack of regulation of dietary supplements, EPA and DHA levels may vary widely within and between brands, and products may also contain unwanted cholesterol or fats or potentially harmful components, including toxins and oxidized fatty acids. Accordingly, omega-3 fatty acid dietary supplements should not be substituted for prescription products. Similarly, prescription products containing DHA and EPA should not be substituted for the EPA-only prescription product, as DHA may raise LDL-C and thereby complicate the management of patients with dyslipidemia.

Fig. 1

Structures of omega-3 fatty acids. Both omega-6 and omega-3 fatty acids are polyunsaturated fatty acids, meaning that the hydrocarbon chain contains multiple double bonds. The naming convention is [number of carbon atoms]:[number of double bonds], n- (or ω)-[position of first double bond starting from the methyl end of the chain, shown in red]. Omega-3 fatty acids generally have anti-inflammatory and anti-thrombotic properties, whereas omega-6 fatty acids generally have pro-inflammatory and pro-thrombotic properties

Fig. 2

Omega-3 fatty acids are components of triglycerides and phospholipids, and may also be found as free fatty acids. Star indicates sn-2 position; phospholipase A₂ releases fatty acids from the sn-2 position of membrane phospholipids

Fig. 3

Percentage change from baseline versus placebo in key lipid parameters from clinical trials of prescription omega-3 fatty acid products (4 g/day) in patients with very high triglycerides (≥500 mg/dl) [–50, 54]. Upper limit for triglycerides was 2000 mg/dl in studies of omega-3-acid ethyl esters, omega-3-carboxylic acids, and icosapent ethyl and 1500 mg in the omega-3-acid ethyl esters A study. Omega-3-acid ethyl esters values are based on pooled data from two studies [10, 11] (6 and 16 weeks’ duration) as reported in the omega-3-acid ethyl esters prescribing information [48]. Icosapent ethyl data are from the MARINE (Multi-Center, Placebo-Controlled, Randomized, Double-Blind, 12-Week Study with an Open-Label Extension) study (12 weeks) [12]. Omega-3-acid ethyl esters A data (12 weeks) have only been published in the product’s prescribing information [49]. Omega-3-carboxylic acids data are from the EVOLVE (Epanova for Lowering Very High Triglycerides) study (12 weeks) [13]. Difference versus placebo: omega-3-acid ethyl esters = omega-3-acid ethyl esters median % change—placebo median % change; icosapent ethyl = median of [icosapent ethyl % change—placebo % change] (Hodges–Lehmann estimate); omega-3-acid ethyl esters A = Hodges–Lehmann median of all pairwise differences from placebo; omega-3-carboxylic acids = median of [omega-3-carboxylic acids % change—placebo % change] (Hodges–Lehmann estimate). HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, TC total cholesterol, TG triglycerides