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.2023.1229130Introduction and methods
Background
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.
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Methods
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.
Outcome
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).
Conclusion
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.”
References
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
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