Omega-3 fatty acids boast demonstrable preclinical and epidemiologic benefit. The consumption of omega-3 fatty acids has been demonstrated to favorably alter lipoprotein fractions, particularly via the reduction of hypertriglyceridemia, reduce markers of inflammation, and fortify endogenous anti-oxidant capacity.
Yet, secondary analyses of the large-scale trials of omega-3 containing formulations as carboxylic acids or ethyl esters have offered null conclusions, which may cast doubt on the utility of its approved indication for the prevention of composite reduction of major adverse cardiovascular events (MACE) in statin-treated patients with fasting hypertriglyceridemia (Ridker et al. Citation2022; Nissen et al. Citation2021).
Specific critiques of the STRENGTH and REDUCE-IT trials have come chiefly in two forms, those addressing the question of mineral oil as an ‘inert’ agent in the REDUCE-IT trial and others demonstrating null MACE risk in either trial or, more pointedly, the incidence of atrial fibrillation (AF), relating to omega-3 serum concentrations in either (Kastelein and Stroes Citation2019; Curfman Citation2021).
A post hoc analysis of the STRENGTH trial conducted by Nissen et al. (Citation2021) noted that neither omega-3 serum levels nor the presence of DHA alone significantly related to the benefit or harm of therapy with a carboxylic acid-based omega-3 therapy. Related, Ridker et al. (Citation2022) found that serum inflammatory markers, aside from hsCRP, did not significantly improve with omega-3 ethyl ester therapy. Other authors have focused on the arrhythmogenic potential of omega-3 fatty acid therapy, finding that serum omega-3 likely correlates with arrhythmic risk (Curfman Citation2021).
While several authors have argued against the purported benefit of omega-3 therapy owing to the mitigated success of STRENGTH and REDUCE-IT trials, it should be noted that the VITAL trial, which tested omega-3 ethyl esters Lovaza (Omacor, 1 gram/per day), detected no significant (p=0.06) AF signal and was associated in a pre-specified secondary analysis with a 28% statistically significant reduction in fatal plus non-fatal myocardial infarction (MI) as well as a significant reduction in total coronary heart disease (CHD). It should be remarked, however, that the dose of omega-3 ethyl ester in VITAL was less than 1/4 of that used in STRENGTH and REDUCE-IT and was combined with the immunomodulatory hormone vitamin D3, which can reduce inflammation (Manson et al. Citation2019; Zhou and Hyppönen Citation2023).
We ask if the results of the heterogeneity in response to ethyl esters and carboxylic acid omega-3 therapy, and the signals pertaining to its arrhythmogenic risk, are better explained by the ethyl ester and carboxylic acid vehicles and their dose, as opposed to a triglyceride (TG) or phospholipid (PL) vehicle.
Fish oils are naturally present as TG and PL. Indeed, the production of omega-3 fatty acids involves primary esterification of the natural TG to ethyl ester during manufacturing. Ethyl ester absorption is reduced in comparison with TG and PL (Chevalier et al. Citation2021; Minton et al. Citation2023). Moreover, ethyl esters necessarily must be re-esterified as TG in the gut from available glycerol stores and subsequently acted upon by digestive enzymes to be emulsified and finally taken up by enterocytes in the small intestine and excreted as ApoB48 containing chylomicrons (Minton et al. Citation2023). The net effect is that omega-3 ethyl esters necessarily spend more time in the acidic gastrointestinal (GI) environment and thus may be subjected to greater oxidation prior to eventual incorporation than TG or PL. Similarly, while carboxylic acid absorption is superior to that of ethyl esters formulations, it is perhaps the most susceptible to endogenous oxidation prior to incorporation. In fact, prior authors have reported that free fatty acids may actually inhibit tocopherol mediated suppression of oxidation, thus increasing oxidative conditions (Musakhanian et al. Citation2022; Hamam and Shahidi, Citation2006).
The oxidation of omega-3 fatty acids, and their metabolites, have significant effects on their biologic potential and function with many authors demonstrating adverse effects associated with oxidized omega-3 ingestion, such as the generation of oxidative stress and elevations in associated markers. (Albert et al. Citation2013) Oxidative stress, broadly, has been linked to the pathogenesis of AF, and there have been reports of its reduction in the setting of peri-operative antioxidant therapy (Korantzopoulos et al. Citation2007).
Prior to the incorporation of agents combating oxidation of omega-3 fatty acids, such as mixed tocopherols and rosemary extract, elevations in serum malondialdheyde (MDA), the final product of omega-3 fatty acid membrane peroxidation associated with free-radical-induced damage, were reported. Intriguingly, in vitro analysis has demonstrated that endogenous antioxidants contained in certain species, such as astaxanthin in king salmon, can also dramatically reduce the formation of malondialdehyde and various radical species (Larsson et al. Citation2016).
Indeed, it is noteworthy that clinical evidence has demonstrated significant anti-arrhythmic potential associated with fish oil, specifically when paired with antioxidant therapy in the operative setting, and, further, that no such association between AF and omega-3 has been revealed among those that consume fish with many authors, in fact, reporting the opposite in retrospective studies (Mozaffarian et al. Citation2004; OMEMI Investigators, 2021, Guo et al. Citation2014). Fish consumption is conversely linked to replicated and uncontested reductions in CHD, MACE, and a panoply of other outcomes. Intriguingly, depending on the species, fish store most omega-3 fatty acids as TG or PL in ratios approaching 60:40 (Burri et al. Citation2012). The predominance of TG and relative abundance of PL in natural omega-3 containing products is a significant variable that merits exploration.
The implication is that refined fish oils presented in non-natural vehicles, such as carboxylic acid and ethyl esters, might be acting, in-part and especially with higher doses, to either prolong the residence time of omega-3 fatty acid in the GI system or promote the oxidation of omega-3 fatty acid; thereby setting the stage for the incorporation of oxidized and, thus, potentially diminished or adverse omega-3 fatty acids into various tissues. Notable questions persist, however, including the relatively increased incidence of AF and micro-episodic fibrillation, likely related to plasma EPA, in the OMEMI trial in which 1.8 grams/per day of a highly purified TG based supplement was selected (Myhre et al. Citation2022). While OMEMI did test a TG dominant formulation, this trial was conducted in subjects recently post-MI, a decidedly pro-arrhythmic and electrically vulnerable period. Importantly, this cohort also boasted highly sufficient omega-3 fatty acid serum levels such that the inclusion of supplemental omega-3 fatty acid as TG was unlikely to provide additional benefit.
Of note, in no trial was the oxidative status of the omega-3 fatty acid documented as assessed by the total peroxide or para-anisidine values, thus we cannot formally comment on the baseline quality of the omega-3 fatty acid therapy.
In the absence of formal evidence, this question remains hypothetical, but demands consideration due to strong mechanistic plausibility coupled with differing results from supplemental versus dietary omega-3 fatty acids. Future authors wishing to test this hypothesis may do so by (1) supplying omega-3 formulation as TG or PL, (2) reporting oxidation parameters of the supplement tested, (3) dosing < = 2 g/day, (4) supplementing with antioxidant adjunctive therapy.
The George Washington University School of Medicine & Health Sciences, Washington, District of Columbia, USA
[email protected]
Leigh A. Frame
The George Washington University School of Medicine & Health Sciences, Washington, District of Columbia, USA
© 2024 Taylor & Francis Group, LLC
https://doi.org/10.1080/19390211.2024.2336212
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Authors declare no conflicts of interest.
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Notes on contributors
Jacob M. Hands
Jacob M. Hands is a M2 at the George Washington University School of Medicine and Health Sciences. His research interests include Omega-3 Fatty Acids, glucose, contaminants in vitamins and supplements, and the pathology of aging.
Leigh A. Frame
Leigh A. Frame is an Associate Professor of Clinical Research and Leadership, the Program Director for Integrative Medicine, and and Associate Director of the Resiliency and Well-being Center at George Washington University School of Medicine and Health Sciences.
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