Are Omega-3 Fatty Acids A Magic Potion?

See article vol. 31: 122-134

Omega-3 polyunsaturated fatty acids have been recognized to exert favorable effects on the risk reduction of atherosclerotic cardiovascular disease (ASCVD) in many clinical trials. The mechanism is mainly attributable to their triglyceride-lowering and anti-inflammatory functions. In the JELIS trial, ASCVD risks were reduced by additionally administering eicosapentaenoic acid (EPA, 1.8 g/day) to the patients taking statins¹⁾. As a result, the administration of EPA to high-risk patients is now recommended to reduce ASCVD risks, such as heart attacks and strokes, in a variety of guidelines. Furthermore, recent results of the REDUCE-IT trial, which showed that additional administration of 4 g/day EPA to statin-treated patients with high ASCVD risks reduced major cardiovascular events by 25%, were shocking worldwide²⁾. In contrast, the STRENGTH trial, which verified the effects of 4 g/day of EPA (75%), and docosahexaenoic acid (DHA, 25%) administration in patients with moderate-high ASCVD risks, did not prove any significant beneficial effect on ASCVD risks³⁾. Thus, the effects of omega-3 fatty acids remain controversial. The reasons for these discrepancies are often explained by factors such as the difference in cardiovascular risks in the study population, active oils (EPA alone vs. EPA/DHA), doses and blood concentrations of fatty acids, type of control oil or comparator oils, and the presence or absence of concomitant use of statins⁴⁾.

In this issue of the Journal of Atherosclerosis and Thrombosis, Nakao et al. provided clues for solving some of the issues mentioned above. They investigated the dose-dependent atheroprotective effect of EPA/DHA in statin-treated patients with coronary artery disease (CAD) whose serum low-density lipoprotein cholesterol level is ＜100 mg/dL⁵⁾. They evaluated changes in plaque size and morphology using noncontrast T1-weighted magnetic resonance (MR) imaging and computed tomography angiography. In their study, there was no difference in plaque size and morphology among the groups treated with 4 g/day-, 2 g/day-, or no EPA/DHA. The atheroprotective effect of EPA/DHA was evaluated based on the serum concentration of EPA or the EPA/AA ratio⁶⁾. In this context, it should be noted that in the study by Nakao and colleagues, the EPA/AA ratio was significantly increased over 0.80 by the EPA/DHA treatment. Thus, the negative result was not likely to be explained by an insufficient dose or serum concentration of omega-3 fatty acids.

As is the case with the STRENGTH study³⁾, the findings by Nakao et al. do not seem to support the use of EPA/DHA in the secondary prevention of CAD. However, it would be premature to conclude that EPA is more effective than EPA/DHA based on the results of this study for the following reasons: The patients in this study were Japanese. The general cardiovascular risk in them is low, and the serum concentration of high-sensitive C-reactive protein (hs-CRP) was quite low. In addition, serum LDL-C levels were well controlled by statin treatment⁵⁾. In such a population with low risk, effective detection is often difficult. Omega-3 fatty acids are usually used in patients with high triglyceride levels, and their atheroprotective effects are especially evident in cases with hypertriglyceridemia and low levels of high-density lipoprotein cholesterol (HDL-C)^{1, 7)}. The effect of EPA/DHA on plaque size and morphology in patients with high triglyceride and low HDL-C levels would be of interest and needs to be determined elsewhere. To compensate for the short observation period (12 months), in the study of Nakao and colleagues, the morphological changes in coronary plaque were evaluated by MR imaging (plaque-to-myocardial ratio; PMR) as primary endpoints instead of being time-consuming for major adverse cardiovascular events. Their unique and quantitative method for plaque volume evaluation needs to be validated further with a longer observation period.

It is widely known that intake of fish or omega-3 fatty acids is inversely related to ASCVD prevalence⁸⁾. It is also true that administration of omega-3 fatty acids can prevent ASCVD in many studies^1-3). Further consideration is needed to determine the types and amounts of omega-3 fatty acids administered to what kinds of patients in order to reduce major adverse cardiovascular events.

Conflict of Interest

TI received honoraria from Kowa Pharmaceutical Co Ltd, Bayer Yakuhin Ltd, and Novartis Ltd.

References

• 1)  Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; Japan EPA lipid intervention study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet, 2007; 369: 1090-1098
• 2)  Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med, 2019; 380: 11-22
• 3)  Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, Davidson MH, Kastelein JJP, Koenig W, McGuire DK, Mozaffarian D, Ridker PM, Ray KK, Katona BG, Himmelmann A, Loss LE, Rensfeldt M, Lundström T, Agrawal R, Menon V, Wolski K, Nissen SE. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTHRandomized Clinical Trial. JAMA, 2020; 324: 2268-2280
• 4)  Doi T, Langsted A, Nordestgaard BG. A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Eur Heart J, 2021; 42: 4807-4817
• 5)  Nakao K, Noguchi T, Miura H, Asaumi Y, Morita Y, Takeuchi S, Matama H, Sawada K, Doi T, Hosoda H, Nakashima T, Honda S, Fujino M, Yoneda S, Kawakami S, Nagai T, Nishihira K, Kanaya T, Otsuka F, Nakanishi M, Kataoka Y, Tahara Y, Goto Y, Kusano K, Yamamoto H, Omae K, Ogawa H, and Yasuda S. Effect of Eicosapentaenoic acid/Docosahexaenoic acid on Coronary High-intensity Plaques Detected Using Non-Contrast T1-Weighted Imaging: The AQUAMARINE EPA/DHA Randomized Study. J Atheroscler Thromb, 2024; 31: 122-134
• 6)  H Robert Superko, Scott M Superko, Khurram Nasir, Arthur Agatston, Brenda C Garrett. Omega-3 fatty acid blood levels: clinical significance and controversy. Circulation, 2013; 128: 2154-2161
• 7)  Saito Y, Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; JELIS Investigators, Japan. Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis, 2008; 200: 135-140
• 8)  Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y, Kokubo Y, Tsugane S; JPHC Study Group. Intake of fish and n3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation, 2006; 113: 195-202