Higher circulating levels of EPA, but not DHA, associated with lower MACE risk

Higher docosahexaenoic acid levels lower the protective impact of eicosapentaenoic acid on long-term major cardiovascular events

Literature - Le VT, Knight S, Watrous JD, et al - Front Cardiovasc Med. 2023 Aug 23;10:1229130. doi: 10.3389/fcvm.2023.1229130

Introduction and methods


Several meta-analyses have shown that omega-3 fatty acid supplements do not reduce the risk of MACE [1-5]. More recent meta-analyses have demonstrated inverse relationships of both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) circulating levels and supplementation dose with mortality and CV events [6,7]. Remarkably, 5 contemporary RCTs indicated that supplementation with only EPA reduces the occurrence of MACE, while the combination of EPA and DHA does not [8-12].

Aim of the study

The authors evaluated the associations between EPA and DHA levels and long-term MACE, and the potential interaction between EPA and DHA in these associations.



For this prospective observational cohort study, data were collected from 987 randomly selected individuals enrolled in the INSPIRE Biobank Registry who underwent their first coronary angiography at a center affiliated with Intermountain Healthcare, an American not-for-profit healthcare system, from January 1994 through December 2012. EPA and DHA plasma levels were assessed in blood samples taken at the time of the coronary angiography. Mean ± SD follow-up time was 12 ± 5 years. The significance level was set at 0.01.


The primary endpoint was the occurrence of MACE, defined as all-cause mortality, MI, stroke, or HF hospitalization, after 10 years.

Main results

  • The 10-year MACE rate was associated with lower levels of EPA (unadjusted P=0.0002, adjusted P=0.0005) but not DHA (unadjusted P=0.43; adjusted P=0.52).
  • Of the individual components of the primary endpoint, only all-cause mortality was associated with EPA (unadjusted P<0.0001; adjusted P=0.0003).
  • Subjects in the highest quartile of EPA level showed a reduced 10-year MACE rate compared with those in the lowest EPA quartile (22.8% vs. 40.5%; unadjusted HR: 0.48; 95%CI: 0.35–0.67). Adjustment for both DHA level and significant baseline differences lowered the HR to 0.36 (95%CI: 0.22–0.58).
  • For DHA, the unadjusted HR for 10-year MACE risk for the highest versus lowest quartile was not significantly different (27.6% vs. 33.6%; HR: 0.78; 95%CI: 0.56–1.01). Adjustment for EPA level resulted in a significantly higher risk of 10-year MACE (HR: 1.81; 95%CI: 1.14–2.90), but after additional adjustment for significant baseline differences, there was no difference between the highest and lowest DHA quartiles (HR: 1.37; 95%CI: 0.85–2.20).
  • Subgroup analyses showed that higher levels of EPA are associated with lower 10-year MACE risk in patients with severe coronary artery disease at baseline (adjusted HR: 0.35; 95%CI: 0.18-0.68) and in patients with no, mild, or moderate coronary artery disease at baseline (adjusted HR: 0.42; 95%CI: 0.20-0.85). There were no significant associations when stratifying for prior HF, age ≥75 years, or triglycerides ≥200 mg/dL.
  • Subjects with an EPA/DHA ratio >1 had a lower 10-year MACE risk compared with those who had an EPA/DHA ratio ≤1 (27.3% vs. 36.7%; adjusted HR: 0.75; 95%CI: 0.60–0.94).


This prospective observational cohort study of individuals undergoing coronary angiography showed that higher plasma levels of EPA, but not DHA, were associated with a lower 10-year risk of MACE. Adjustment for DHA level increased the estimated protective effect of higher EPA levels. In addition, an EPA/DHA ratio >1 was associated with a lower 10-year MACE risk compared with an EPA/DHA ratio ≤1. According to the authors, “these observations are consistent with a proposed anti-inflammatory/membrane-stabilizing effect of EPA, which, in part, is neutralized by increasing levels of DHA.”


1. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA. (2012) 308(10):1024–33. doi: 10.1001/2012.jama.11374

2. Kwak SM, Myung SK, Lee YJ, Seo HG, Korean G. Meta-analysis Study, Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. (2012) 172(9):686–94. doi: 10.1001/archinternmed.2012.262

3. Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 Fatty acids and cardiovascular outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. (2012) 5(6):808–18. doi: 10.1161/CIRCOUTCOMES.112.966168

4. Jump DB, Depner CM, Tripathy S. Omega-3 fatty acid supplementation and cardiovascular disease. J Lipid Res. (2012) 53(12):2525–45. doi: 10.1194/jlr.R027904

5. Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J Clin Lipidol. (2012) 6(1):5–18. doi: 10.1016/j.jacl.2011.10.018

6. Harris WS, Tintle NL, Imamura F, Qian F, Korat AVA, Marklund M, et al. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nat Commun. (2021) 12(1):2329. doi: 10.1038/s41467-021-22370-2

7. Hu Y, Hu FB, Manson JE. Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants. J Am Heart Assoc. (2019) 8(19):e013543. doi: 10.1161/JAHA.119.013543

8. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. (2019) 380(1):11–22. doi: 10.1056/NEJMoa1812792

9. Group ASC, Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, et al. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med. (2018) 379(16):1540–1550. doi: 10.1056/NEJMoa1804989

10. Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med. (2019) 380(1):23–32. doi: 10.1056/NEJMoa1811403

11. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ, et al. Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial. JAMA. (2020) 324(22):2268–2280. doi: 10.1001/jama.2020.22258

12. Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, et al. Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial. Circulation. (2021) 143(6):528–539. doi: 10.1161/CIRCULATIONAHA.120.052209

Find this article online at Front Cardiovasc Med.

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free