Some Inconvenient Facts About Omega-3 Fatty Acids in Heart Disease and Prostate Cancer

Two recent meta-analysis studies published by the same lead author have stated the conclusion that omega-3 fatty acids have little, if any, benefit in treating cardiovascular disease and may promote prostate cancer (1,2).

Does the actual recent clinical research not reported in these meta-analysis support such broad statements?  I believe the answer is resounding no.

Let’s start with cardiovascular disease and with the basic premise that you need a therapeutic dose of omega-3 fatty acids  to  get a therapeutic  effect.  In the published meta-analysis (1), the vast majority (78%) of the studies complied for the meta-analysis used low-dose omega-3 fatty acids (less than 3 grams of EPA and DHA per day).  Therefore, if there is good reason to believe that a minimum dose would be 3 grams of  EPA and DHA per day for efficacy, then 78% of the studies used in this meta-analysis would have to be thrown out.  This is reinforced by the emission of the recent REDUCE-IT study which was not included in this meta-analysis.  The REDUCE-IT study used 4 grams of EPA per day with extraordinary clinical results (3).  In  the REDUCE-IT  trial virtually  all the patients were taking statins as it was a secondary prevention trial meaning the subjects already had a heart attack.  One would expect since  everyone was  taking statins, then the addition of omega-3 fatty  acids should have no benefit.  Just the opposite occurred.  Those who were taking the 4 grams of omega-3 fatty acids for nearly five years had a further 25 percent reduction in the primary  clinical endpoint compared to the placebo group  taking the statins  alone.  Furthermore, these effects begin to appear within the first 18 months of the study.  In a sub-group analysis consisting of only the patients from the U.S., their cardiovascular benefits were even greater (4).   

Harvard Medical School has done their own meta-analysis of the 13 largest cardiovascular trials, they found that omega-3 supplementation lowers the risk for heart attack and that the risk reduction was “linearly related” to the omega-3 fatty acid dose (5).  This means the higher the dose, the greater the clinical benefits. 

A major problem in doing meta-analysis studies is not having a consistent marker of omega-3 fatty acid intake for comparing various studies.  The most validated marker of omega-3 fatty acid intake is the AA/EPA ratio in the blood.  The average AA/EPA ratio in Americans is about 18 and their dietary intake of EPA and DHA is approximately 0.150 grams per day.  Supplementing with 4 grams of EPA per day as the REDUCE-IT trial reduces the AA/EPA ratio to approximately 2.  This strongly suggests that instead of looking at amount of omega-3 fatty acids being given, it may be better to look at trials in which the AA/EPA ratio was reduced to less than 2.  Under those conditions, the combination of omega-3 fatty acid supplementation with statins is strikingly superior to statin use alone in reducing cardiovascular events (3,6).   

This leads to the second meta-analysis  published on use of omega-3 fatty  acid increasing prostate cancer (2).   Much of this comes from a published  study looking at retained blood samples from a totally different study (7).  My analysis of the fatty acid data in that study indicated that the AA/EPA ratio was virtually identical to that of the average American population regardless of their degree of severity of prostate cancer of the subjects in the trial. A recent paper that was not included in the published meta-analysis has demonstrated that blood levels of omega-3 fatty acids had no impact on the progression of prostate cancer.  However, the higher the levels of omega-3  fatty  acids in the prostate tissue there was an associated significant reduction of severity of the cancer in the prostate tissue (8).  This is in line with epidemiological studies that indicate the incidence and  mortality from prostate cancer are inversely proportional  to  omega-3 fatty acid dietary intake (9,10).  This would help explain why  prostate cancer incidence is 10 times lower in Japan than the United States and that the mortality from  prostate cancer is also 5 times lower in Japan than the United States (10).  

The reason that high-dose omega-3 fatty acids are critical for cancer treatment is that you need adequate levels to make a group of hormones known as resolvins (11).  The resolvins are essential to mobilize the immune  system to clear up the cellular debris for cancer treatments to prevent the formation of increased inflammation that will accelerate the development of metastasis (12–14).  This can only happen when the AA/EPA ratio in the blood is less than 3.  This is because  omega-6 fatty acids such AA accelerate  cancer (15), whereas omega-3 fatty  acids such as EPA will reduce the spread of metastasis (12–14).  The higher the AA/EPA ratio, the more likely that any cancer will spread.

The bottom line is that publishing meta-analysis studies is like making sausage.  It all depends on the quality of the studies used (or ignored).  The high-quality clinical studies using therapeutic levels of omega-3 fatty acids support their role in reduction of cardiovascular mortality and epidemiological studies strongly suggest the same is true in prostate cancer.  However, you need a therapeutic dose and ideally reducing the AA/EPA ratio in the blood to less than 3.  Using  the AA/EPA ratio level in the blood as marker of omega-3 intake removes much of the selection bias of published clinical studies used for meta-analysis.  The end result is a more meaningful studies instead of conflicting results of the role of omega-3 fatty acids generating more confusion by the general public. 

References

1. Abdelhamid AS et al.  “Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease.”  Cochran Database Syst Rev 3: 3:CD003177 (2020)
2. Hanson S et al.  “Omega-3, omega-6 and total dietary polyunsaturated fat on cancer incidence: systematic review and meta-analysis of randomized trials.”  Br J Cancer doi: 1038/sd4146—020-0761-6 (2020)
3. Bhatt DL et al.  “Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.”  N Engl J Med 380:11-22 (2019)
4. Bhatt DL et al. “REDUCE-IT USA: Results from the 3146 patients randomized in the United States.”  Circulation 141(5):367-375 (2020)
5. Hu Y et al.  “Marine omega-3 supplementation and cardiovascular disease:  An updated meta-analysis of 13 randomized controlled trials involving 127 477 participants.”  J Am Heart Assoc 8:e013543 (2019)
6. Yokoyama M et al. “Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): A randomized open-label, blinded endpoint analysis.”  Lancet  367: 1090-1098 (2007)
7. Brasky TM et al.  “Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial.”  J Natl Cancer Inst 105:1132-1141 (2013)
8. Moussa H et al.  “Omega-3 fatty acids survey in men under active surveillance for prostate cancer: From intake to prostate tissue level.”  Nutrients  11: 1616 (2019)
9. Haas GP  et al.  “The worldwide epidemiology of prostate cancer: perspectives from autopsy studies.”  Can J  Urol 15: 3866-3871 (2008)
10. Marugame T and Mizuno S.  “Comparison of prostate cancer mortality in five countries: France, Italy, Japan, UK and USA from the WHO mortality database (1960-2000).”   Jpn J Clin Oncol 35: 690-691 (2005)
11. Serhan CN.  “Pro-resolving lipid mediators are leads for resolution physiology.” Nature 510:  92-101 (2014)
12. Sulciner ML et al.  “Targeting lipid mediators in cancer biology.”  Cancer Metastasis Rev 37:557-572 (2018)
13. Sulciner ML et al.  “Resolvins suppress tumor growth and enhance cancer therapy.”  J Exp Med 215: 115-140 (2018)
14. Panigrahy D et al. “Preoperative stimulation of resolution and inflammation blockade eradicates micrometastases.”  J Clin Invest 129: 2964-2979 (2019)
15. Greene ER et al.  “Regulation of inflammation in cancer by eicosanoids.”  Prostaglandins Other Lipid Mediat 96: 27-36 (2011)