Curmudgeon's Corner 
A Cochrane Review of Fish Oil: A Whopper of a Disappointment
Jacob Schor, ND, FABNO

The earliest reference I have found to fish oil having a protective effect against cardiovascular disease is Bang and Dyerberg’s 1971 paper.(1) This perturbs me as I clearly recall my tenth grade biology teacher mentioning this Eskimo and fish business a few years earlier.  Suffice to say the idea that fish oil offers protection against heart disease has been around for about half a century.  Recall in the late 1960s, heart disease was supposedly linked to high animal fat diets.  Yet Eskimos didn’t seem to have the predicted risk.  The explanation was that the high fish oil in their diet was somehow protective. 

We’ve swallowed this idea, hook, line and sinker, if you can tolerate the fishing expression.  It’s only recently that this common assumption is being questioned.  Most of us have strenuously made excuses and rationalized why these contrary studies didn’t find cardiovascular benefit to supplementing with fish oil or consuming more fish.

The strongest argument against our fish oil belief was published in mid-July on the Cochrane Database and at this point we’re left with a pretty kettle of fish.(2) Abdelhamid and colleagues performed the most comprehensive meta-analysis we’ve seen to date.

Being a Cochrane Review they did a meticulous job.  The authors searched CENTRAL, MEDLINE, and Embase up until April 2017.  Studies were compiled for meta-analysis.  The authors included randomized controlled trials (RCTs) that lasted at least 12 months and compared supplementation and/or advice to increase omega-3 polyunsaturated fatty acids from oily fish [long-chain omega-3 (LCn3) or alpha-linolenic acid (ALA)] intake versus usual or lower intake.

Their literature search yielded 79 randomized controlled trials (RCTs) with a total of 112,059 participants.

Two review authors independently assessed studies for inclusion, extracted data and assessed validity. The authors performed separate random-effects meta-analysis for ALA and LCn3 interventions and assessed dose-response relationships through meta-regression.

Trials were of 12 to 72 months' duration and included adults at varying cardiovascular risk, mainly in high-income countries. Most studies assessed LCn3 supplementation with capsules, but some used LCn3- or ALA-rich or enriched foods or dietary advice compared to placebo or usual diet.

The authors did everything right.  We will have a hard time finding fault with their methodology.  They didn’t bother looking at blood markers associated with CVD, instead they looked at bottom line measures that included all-cause mortality, cardiovascular mortality, cardiovascular events, arrhythmia, stroke, bleeding, and coronary heart disease.  These are what we really care about when it comes right down to it.

The conclusion of this large meta-analysis was that increasing fish oil consumption either as oil supplements or by eating more fish had no effect on all-cause mortality, cardiovascular mortality, cardiovascular events, coronary heart disease (CHD) mortality, stroke or arrhythmia.

Increasing ALA didn’t have much more benefit. It was not associated with any significant change in all-cause mortality or congestive heart disease events.  Increasing ALA did, however, was associated with a non-significant reduction in cardiovascular events from 4.8% to 4.7%[RR 0.95, 95% CI 0.83 to 1.07, 19,327 participants; 884 CVD events, 5 RCTs, low-quality evidence), and probably reduces risk of CHD mortality (1.1% to 1.0%, RR 0.95, 95% CI 0.72 to 1.26, 18,353 participants].  Mind you these benefits were not statistically significant.  Not even close, but I’m trying to lessen the shock of these outcomes.

The only statistically significant benefit to show up in the data was for congestive heart disease.  Fish oil was associated with a 7% drop in risk.  Well, it was until the researchers performed a sensitivity analysis and the benefit disappeared.  Still it’s better than nothing.

These data suggest some potential risks of morbidity from things we had assumed fish oil would lower risk of.  One of those conditions is stroke, that there was a slight uptick in stroke in the fish oil groups. This uptick in strokes was not statistically significant and it was super small.  Still that should give us pause as we were considering multiple numbers that were not statistically significant. It kind of works both ways. This does go contrary to the common belief that fish oil is an anticoagulant and so decreases the risk of ischemic strokes. Bleeding also is a potential risk of fish oil, and we saw that there was no difference in either group with increased risk of bleeding We aren't very certain of this, but this again argues that fish oil probably isn't an adequate anticoagulant to prevent strokes and this is further evidenced by the fact that it doesn't increase bleeds. If something is going to prevent strokes because it's an anticoagulant, it should also increase bleeds because that's one of the downsides of anticoagulant therapy.

There are many of us who will be unhappy with these results.  We have been advising patients to take fish oil for so long it will be hard to change our thinking.

This isn’t the first large study that has called the fish ‘myth’ into question. In September 2012, JAMA published as systematic review by Rizos et al that also assessed the effect of fish oil supplementation on cardiovascular events.(3)  Data from twenty studies that included 68,680 patients were analyzed. Their conclusions were similar to what we see in the current Cochrane Review: “Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.”

A Korean meta-analysis also published in 2012 failed to find any benefit of fish oil supplementation in people with a history of heart disease.  This study analyzed data from 14 randomized, double-blind, placebo-controlled trials involving 20,485 patients with a CVD history.(4)

In 2013, NEJM published the results of a clinical trial giving fish oil to patients with multiple CVD risk factors.  Patients had multiple CVD risk factors but had not had a myocardial infarct yet. 12,513 patients enrolled, 6244 were assigned to n-3 fatty acids and 6269 to placebo, which we should mention was olive oil. After a median time of five years, 11.7% of those taking fish oil and 11.9% of those receiving placebo had died or had a non-fatal MI or stroke.  There is no significant difference between these two rates.(5)

It feels like these data snuck up on us in a way.  A 2004 meta-analysis did suggest fish oil was doing what we thought it should.  Yzebe and Lievre searched the medical literature published from 1966 to 2003 and selected ten randomized controlled trials looking at omega-3 fatty acids use by adults with recent acute myocardial infarction (MI) or angina. A total of 14,727 patients were included.  Daily intake of omega-3 supplements for a mean of 37 months decreased all causes of mortality by 16% and death due to MI by 24%.(6)  The new Cochrane Review with 112,059 patients had data from seven times as many patients. It’s more believable.  It makes me wonder, though, whether fish oil did more good years ago when the only fish we ate was an occasional whopper or canned tuna? Per capita fish consumption was 16.6 pounds in 2004 down to 14.9 pounds in 2016.(7)

 

Another possible explanation might be that there is a sweet spot for omega-3 oils, a little bit helps but more than that and fish oil benefits decrease?  If so, fish oil wouldn’t be the first ‘supplement’ to display a hormetic effect.  Past research has suggested that fish oil’s effects on mood might display this sort of u-shaped curve.(8)

A 2014 paper published in the Canadian Journal of Cardiology took a second look at the original Bang and Dyerberg paper that started this whole fish thing off. They reviewed the literature and reported that risk of cardiac arterial diseases among both the Greenland Eskimo and Alaskan Inuit never did differ from other populations and that the original basis for the “Eskimo diet” never existed. Bang and Dyerberg never studied native populations directly; they used death reports and hospital admission figures to make their calculations.  It turns out that CVD is common in the Inuit and curiously rates may decrease as people are ‘Westernized.” (9,10,11)

There is a new trial scheduled to be published at the end of this year. The trial ended last year. This trial is a large trial with 25,000 participants, and it has examined the effect of vitamin D and omega-3s on the primary prevention of cardiovascular disease over a five-year period. This is the largest study to ever be done on this topic. It looks at long-term supplementation of fish oil and is robustly designed.(12)  It may overturn other things we thought we know about fish oil and cardiovascular disease. It will have the statistical power to question these current Cochrane Review findings, that is if they disagree.

Another interesting study will have been published by the time this issue of the Townsend Letter is printed and be generating media coverage.  Results of a five-year clinical trial using Vascepa will be presented at the American Heart Association’s November 10 meeting in Chicago. Vascepa is one of four prescription forms of fish oil that have been approved by the FDA for treating high triglycerides.  The FDA approved Lovaza in 2004, Vascepa in 2012, and Epanova and Omtryg in 2014.  Vascepa stands out as being pure EPA with no DHA in the product; the other three are combinations of EPA and DHA.  While all of these products lower triglyceride levels, all but Vascepa raise LDL levels at the same time.(13)

This Vascepa study is getting attention from investors who are hoping widespread adoption will lead to profits.  Stock prices tripled in the days after early results were released.(14) According to Amarin, the manufacturer, “Vascepa lowered the risk of heart attacks and strokes in patients with very high levels of triglycerides… and whose cholesterol levels were already held in check by drugs called statins. Patients on Vascepa had a 25% reduction in the relative risk of a heart attack, stroke, cardiovascular death, or hospitalization for unstable angina or bypass surgery after a median of 4.9 years of treatment, compared to those on statins and a placebo.”(15) Patients received 4 grams of EPA per day. The patients were type-2 diabetics with high triglyceride levels (>500 mg/dL).  We should delay further interpretation until the full details are made public.  Yet we must admit that prescription fish oils may be a different story from eating more fish. 

How could we be so far off with this?  Science isn’t perfect and the idea that dietary interventions might have a large impact on disease prevention is attractive to practitioners, manufacturers and consumers alike. The idea took on a life of its own.   Let’s return to Greenland for a moment.  A paper published in 1992 offered an alternative explanation for why Eskimos have such good lipid profiles.  Eskimos have significantly lower lipoprotein(a) [Lp(a)] and this is apparently due to their genetics rather than diet.(16)  We were too caught up with the fish business to notice this and other early reports.

 

Note parts of this article are from an online lecture given by Drs. Andrew Day and Joshua Goldenberg as part of their Doctors Journal Club.

References

1. Bang HO, Dyerberg J, Nielsen AB. Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet. 1971 Jun 5;1(7710):1143-5.

2. Abdelhamid AS, et al. Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease.  Cochrane Database Syst Rev. 2018 Jul 18;7:CD003177.

3. Rizos EC, et al.  Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events A Systematic Review and Meta-analysis.  JAMA. 2012;308(10):1024-1033.

4. Kwak SM1, et al. 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 May 14;172(9):686-94.

5. Risk and Prevention Study Collaborative Group, Roncaglioni MC, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors.  N Engl J Med. 2013 May 9;368(19):1800-8.

6. Yzebe D1, Lievre M. Fish oils in the care of coronary heart disease patients: a meta-analysis of randomized controlled trials. Fundam Clin Pharmacol. 2004 Oct;18(5):581-92.

7. https://www.seafoodhealthfacts.org/seafood-choices/overview-us-seafood-supply

8. Arnold LE, et al.  Omega-3 Fatty Acid Plasma Levels Before and After Supplementation: Correlations with Mood and Clinical Outcomes in the Omega-3 and Therapy Studies. J Child Adolesc Psychopharmacol. 2017 Apr;27(3):223-233.

9. Howard BV, Comuzzie A, Devereux RB. Cardiovascular disease prevalence and its relation to risk factors in Alaska Eskimos.  Nutr Metab Cardiovasc Dis. 2010 Jun;20(5):350-8.

10. Bjerregaard P1, Young TK, Hegele RA. Low incidence of cardiovascular disease among the Inuit--what is the evidence?  Atherosclerosis. 2003 Feb;166(2):351-7.

11. Fodor JG, et al. "Fishing" for the origins of the "Eskimos and heart disease" story: facts or wishful thinking? Can J Cardiol. 2014 Aug;30(8):864-8.

12.  Vitamin D and Omega-3 Trial (VITAL) ClinicalTrials.gov Identifier: NCT01169259

13. Ito MK.  A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P.T. 2015 Dec; 40(12): 826-836, 857.

14. The Motley Fool Staff. How Big Could Amarin’s Vascepa Be? September 30, 2018.

15. Amarin Corp. INVESTOR RELATIONS / REDUCE-IT™ CARDIOVASCULAR OUTCOMES STUDY OF VASCEPA® (ICOSAPENT ETHYL) CAPSULES MET PRIMARY ENDPOINT. Sep 24, 2018. https://investor.amarincorp.com/news-releases/news-release-details/reduce-ittm-cardiovascular-outcomes-study-vascepar-icosapent. [accessed 10-11-2018]

16. Klausen IC, et al. Differences in apolipoprotein (a) polymorphism in west Greenland Eskimos and Caucasian Danes. Hum Genet. 1992 Jun;89(4):384-8.