Last update: 24 August 2021
Omega-3 fatty acids are a biomarker strongly negatively associated with cardiovascular disease1. However, when systematically reviewed, the RCT evidence shows at best little benefit2. This may or may not be due to failure of the intervention (usually – taking pills) to affect body lipids3. To my knowledge, nobody has done an analysis of trials that did measure effectiveness of the intervention by how it affected n-3 biomarkers.
Methods
I went through the Cochrane systematic review’s references section2 and selected the trials that, according to the reviewers, collected biomarker information (as per the trial summaries, mainly the “compliance” sections).
Where there were multiple markers available, I focused on those better reflecting recent intake of n-3 PUFA (f.ex. plasma over adipose). Where I had no access to the article, I used whatever information was provided in the abstract or in the Cochrane review.
I skipped studies, labelling them irrelevant, that did not report cardiovascular outcomes. I focused on major outcomes (ACM, CVM, CVE, CHDM, CHDE, Stroke, MI, Arrythmia, SCD – as reported in the review) and remarked where the trial only employed risk factors (or other metrics) for outcomes.
Results
46 trials were identified, of which 30 were relevant to cardiovascular disease.
| Trial | Markers | Outcomes |
| AFFORD 2013 | n-3 index baseline: ~4.6% at 6mo: ~7.7% | ACM: null CVE: null Stroke: null Arrythmia: null |
| AlphaOmega 2010 ALA | serum CE at 40mo: ALA +68.8% EPA +41.6% | ACM: null CVM: null CVE: null CHDM: null CHDE: null Stroke: null MI: null |
| AlphaOmega 2010 EPA+DHA | serum CE at 40mo: EPA +61.6% DHA +30.0% | ACM: null CVM: null CVE: null CHDM: null CHDE: null Stroke: null Arrythmia: null MI: null |
| Baldassarre 2006 | plasma FA baseline: EPA 0.65% DHA 1.55% at 24mo: EPA 3.58% DHA 4.06% | CVE: null CHDE: null MI: null |
| Bates 1989 | irrelevant | irrelevant |
| Berson 2004 | irrelevant | irrelevant |
| Brox 2001 | serum FA (sum n-3) cod liver oil: baseline: 1.04% 14mo: 2.05% seal oil: baseline: 1.01% 14mo: 2.38% | ACM: null CVM: null CVE: null CHDM: null CHDE: null MI: null SCD: unestimable |
| Caldwell 2011 | irrelevant | irrelevant |
| Deslypere 1992 | RBC lipid EPA baseline: 0.7-0.78% 12mo: 3g: 2.82% 6g: 4.31% 9g: 5.86% | biomarkers only |
| DIPP 2015 | irrelevant | irrelevant |
| DISAF 2003 | RBC FA increased n-3 | ACM: null Arrythmia: null |
| DO IT 2010 | plasma EPA and DHA increased | ACM: null CVE: null CVM: null CHDE: null CHDM: null Stroke: null MI: null SCD: null |
| DREAM Asbell 2018 | irrelevant | irrelevant |
| EPE-A 2014 | irrelevant | irrelevant |
| EPOCH 2014 | irrelevant | irrelevant |
| FAAT 2005 | RBC PL EPA+DHA baseline: 3.4% 12mo: 7.6% | ACM: null CVM: null Arrythmia: null CVE: null CHDM: null Arrythmia: null |
| FLAX-PAD 2013 | plasma ALA baseline: 0.024 mg/ml 6mo: 0.067 mg/ml | ACM: null CVM: null CVE: null CHDM: null CHDE: null Stroke: null MI: null |
| FOSTAR 2016 | serum PL n-3 (high dose) baseline: 6.3% 24mo: 14.5% | Arrythmia: null SCD: null |
| Franzen 1993 | serum lipid FA baseline: 3.6 mg/dl 4mo: 16.2 mg/dl | ACM: no deaths CVE: no events otherwise biomarkers only |
| HARP 1995 | adipose FA (EPA, DPA, DHA) intervention: 2.37% control: 0.76% | ACM: null CVM: null CVE: null CHDM: null CHDE: null Stroke: null MI: null |
| HERO 2009 | RBC FA (ALA) baseline: control: 0.10% intervention: 0.12% 12mo: control: 0.17% intervention: 0.18% | ACM: no deaths otherwise metrics and biomarkers only |
| JELIS 2007 | plasma FA baseline: EPA/AA: 0.6 treatment: EPA/AA: 1.3 | ACM: null CVE: benefit CHDM: null CHDE: null Stroke: null MI: null SCD: null |
| Kumar 2012 | serum FA EPA: 2.1x vs control DHA: 1.8x vs control | Arrythmia: benefit |
| Kumar 2013 | plasma PL baseline: EPA: 1.5% DHA: 4.2% 6mo: EPA: 4.3% DHA: 7.7% | ACM: null CVM: null CVE: null |
| MAPT 2017 | RBC lipids EPA +3.52pp DHA +3.29pp | ACM: null CVE: null Stroke: null |
| MARGARIN 2002 | serum ALA baseline: 0.52% intervention 1: +0.36pp intervention 2: +0.47pp | ACM: null CVM: null CVE: null Stroke null |
| MARINA 2011 | RBC lipids (1.8g group) baseline: EPA: 1.3% DHA: 6.5% 12mo: EPA: ~+2.5pp DHA: ~+2.3pp | biomarkers only |
| MENU 2016 | RBC ALA baseline: 0.12% 6mo: 0.17% | biomarkers only |
| NAT2 2013 | irrelevant | irrelevant |
| Nodari 2011 HF | circulating EPA + DHA baseline: 1.76% 12mo: 4.31% | CVE: benefit Stroke: null Arrythmia: null |
| OPAL 2010 | irrelevant | irrelevant |
| Raitt 2005 | n-3 index baseline: 4.7% 24mo: 8.3% | ACM: null CVM: null CVE: null CHDM: null CHDE: null Arrythmia: null MI: null SCD: null |
| Ramirez-Ramirez 2013 | irrelevant | irrelevant |
| REDUCE-IT 2019 | median serum EPA baseline: 26.1 ug/ml 12mo: 144 ug/ml | ACM: null CVM: benefit CVE: benefit CHDE: benefit Stroke: benefit Arrythmia: null MI: benefit SCD: benefit |
| Rossing 1996 | PLT lipids baseline: EPA: 0.42% DHA: 1.66% 12mo: EPA: 2.72% DHA: 3.59% | ACM: no deaths otherwise biomarkers only |
| Sandhu 2016 | irrelevant | irrelevant |
| SCIMO 1999 | RBC PL EPA +2.89pp DHA +6pp | ACM: null CVM: null CVE: null CHDM: null CHDE: null Stroke: null MI: null |
| seAFOod Hull 2018 | irrelevant | irrelevant |
| Shinto 2014 | irrelevant | irrelevant |
| SHOT 1996 | serum EPA + DHA baseline: 177.1 mg/L 6mo: 256.8 mg/L | ACM: null CVM: null CVE: null CHDM: null CHDE: null Stroke: null MI: null |
| SMART 2013 | n-3 index baseline: fish: 3.5% fish + supplement: 3.6% 12mo: fish: 3.4% fish + supplement: 4.4% | ACM: no deaths CVE: no events otherwise metrics and biomarkers only |
| SOFA 2006 | serum CE EPA baseline: 1.1% 12mo: 2.3% | ACM: null CVM: null CVE: null CHDM: null CHDE: null Arrythmia: null MI: null |
| SU.FOL.OM3 2010 | plasma n-3 +37% vs placebo | ACM: null CVM: null CVE: null CHDM: null CHDE: null Stroke: null Arrythmia: null MI: null SCD: null |
| WAHA 2016 | irrelevant | irrelevant |
| Weinstock-Guttman 2005 | irrelevant | irrelevant |
| WELCOME 2015 | irrelevant | irrelevant |
| Zhang 2017 | irrelevant | irrelevant |
Conclusion
I substantially concur with the Cochrane review that any benefits of n-3 supplementation are likely small. This does not seem to be driven by failure to induce body lipid recomposition, but it is still possible that targeting fivefold improvements (such as in the REDUCE-IT trial) is the level at which you can more reliably detect hard outcome benefits. In any case, such high-dose supplementation isn’t harmful, so it’s a definite avenue for further studies.
Note: I have noticed some inconsistencies in some writeups of the studies in the review (regarding the n-3 biomarkers), compared what the studies reported, but it’s unclear to me if I’m in error or if the Cochrane authors made typos or thinkos sometimes.
References
- William S Harris, The omega-3 index as a risk factor for coronary heart disease, The American Journal of Clinical Nutrition, Volume 87, Issue 6, June 2008, Pages 1997S–2002S, https://doi.org/10.1093/ajcn/87.6.1997S
- Abdelhamid AS, Brown TJ, Brainard JS, Biswas P, Thorpe GC, Moore HJ, Deane KHO, Summerbell CD, Worthington HV, Song F, Hooper L. Omega‐3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2020, Issue 3. Art. No.: CD003177. DOI: 10.1002/14651858.CD003177.pub5. Accessed 22 August 2021.
- von Schacky C. Omega-3 index in 2018/19. Proc Nutr Soc. 2020 May 11:1-7. doi: 10.1017/S0029665120006989. Epub ahead of print. PMID: 32389149.