Omega-3 Fatty Acids and Cardiovascular Disease Risk: Has the Story Ended or Only Just Begun?

The skeptical cardiologist recently gave a virtual presentation for the Saint Louis University School of Medicine Grand Rounds which was an update on recent studies examining the therapeutic benefit of omega-3 fatty acids and fish oil supplements.

The talk is about 45 minutes and is absolutely mesmerizing. Just kidding. Actually, I’m always amazed at how oddly and slowly I speak even when I’m totally at ease and know the topic backwards and forwards.

I start with reminiscing on my training at SLU: “It’s a great pleasure to be back here at SLU where I did all my medical and cardiology training in the clinical crucibles of fire known as City Hospital, the John Cochran VA Hospital and Fermin Desloge.”

City Hospital has long been gone and the building and area, both of which were quite scary in the 1980s have long been gentrified. Fermin Desloge hospital, per Wikipedia, was opened in 1932 by the Jesuits of Saint Louis University and the Sisters of Saint Mary and was established to serve the poor and needy.

Fermin Desloge Hospital on left where I did my training. The brand new SLU/SSM on the right. Inpatient SLU operations shifted to the new hospital in late 2020.

I began by indicating that I would be talking on “a weirdly interesting topic which spans the disciplines of nutrition, business, the nutraceutical-industrial complex, quackery and preventive cardiology and yields fascinating insights into the glaring weaknesses of nutritional epidemiology, the hidden weaknesses of randomized clinical trials, and the many sources of bias in scientific research.”

Here’s the video of my talk which was followed by about 30 minutes of questions and comments, including a discussion on cooking oils.

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I wrote out the beginning of the talk and that transcript is below:

What I’ll address in the next 40 minutes can be boiled down to a question most of us over the age of 40 have asked ourselves: Should I take fish oil supplements to prevent cardiovascular disease.?

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Although almost all my academic research and publications have been in the field of echocardography, for the last dozen years I have evolved into a clinical cardiologist with major interests in preventive cardiology and enlightened medical management of atrial fibrillation

Over the years I’ve cultivated a healthy skepticism for medical and scientific information that has potential bias.

To educate my patients, myself and the public at large I started writing a blog in 2013 which began by looking at the scientific underpinning (or lack thereof) of current dietary guidelines relating to cardioprotection

One of the first topics I tackled was fish oil supplements which seemed to have a solid scientific and guideline support. Before I looked deeply into the topic I was advising patients with CAD or at high risk for CAD to take fish oil supplements but after I began taking patients off them.

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The fish oil story begins with observations that Eskimos in Greenland who consumed an extremely high fat diet rarely had evidence of coronary heart disease

In the 70s, two Danish doctors, Hans Olaf Bang and Jørn Dyerberg, went to Greenland because they’d read there were very low levels of cardiovascular disease among the Inuit eating seals and whales and fish. 

When they did blood lipid analyses of Inuit samples, they found very high amounts of omega-3 fatty acids and formed a hypothesis that omega-3s might be responsible for the lower levels of coronary heart disease among Greenland Inuit.

These observations have triggered tens of thousands of studies which have attempted to determine if omega-3 fatty acids (OMFAs) are the key to cardio protection. 

In the last 40 years there has been a pronounced movement to proclaim all saturated fats as bad and all PUFAs as good. Simplifying nutritional advice in this way makes for simple public health messaging but blurs the truth. For example, there is no solid evidence that dairy fat which is predominantly saturated has any negative cardiac effects.

Likewise, with PUFAs, many researchers have concluded that humans are consuming far too many omega-6 PUFAs which are predominantly obtained from corn, safflower and soybean oil. Canola oil, a product of factory ultra processing and genetic manipulation is widely promoted as very good for the heart.

The Omega-3 fatty acid family consists of long-chain (18 to 22 carbons) PUFA with a double bond at the third carbon from the omega end. The marine OMFAs of interest are EPA and DHA which are predominantly derived from seafood consumption

DPA levels aren’t associated with fish consumption and have minimal relevant physiologic or clinical effects. DHA is a primary structural component of the human brain, cerebral cortex, skin, and retina. For organisms that do not eat algae containing DHA nor animal products containing DHA, DHA is instead produced internally from α-linolenic acid. Alpha-linolenic acid is an 18-carbon essential n-3 polyunsaturated fatty acid (PUFA) derived from plant sources.

In addition to long-chain-3 PUFA, fish provide specific proteins, vitamin D, selenium, and other minerals and elements.

Observational studies have demonstrated an inverse association between dietary consumption of either fatty fish or omega-3 fatty acids and incident cardiovascular events and that circulating concentrations of eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) inversely correlate with cardiovascular risk.

Of course all these studies did not prove that eating fish or taking OMFA supplements reduces your risk of CVD.

 This doesn’t stop press releases and news stories related to these observational studies from promoting them as showing causality and implying an important role for supplementation in reducing heart disease. Nutrition guidelines from the AHA in 2005 co-authored by Bill Harris, arguably the world’s foremost expert on OMFA concluded that Everyone in the population should eat “a variety of (preferably oily) fish at least twice a week” and that their diet should include “oils and food rich in ALA (flaxseed, canola and soybean oils” flaxseed and walnuts.”

What are the “oily fish” all Americans should be consuming twice per week. The amount of EPA+DHA in the recommended portion size of 3.5 oz of fish varies wildly

To make things more complicated with fish consumption, one has to consider mercury content and the sustainability of the species one is consuming. The EDF has a seafood selector that rates each type of fish on these 3 items. But even within something you might think would be incredibly healthy, the mackerel, depending on the specific kind the levels of mercury vary wildly

As a result, most Americans through up their arms in frustration and confusion and prodded on by a burgeoning fish oil supplement industry which was freed from any constraints of the FDA by legislation in 1994, they began buying millions of fish oil supplements

Thus began the era of fish oil as snake oil, promoted widely by quacks like Dr. Oz who recommended “FISH OIL FOR ALL!”

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Thus ends the “transcript.”

For the remainder of the presentation I spoke without script, analyzing in detail recent large randomized controlled trials of large dosage omega-3 fish oil supplementation. Spoiler alert, the STRENGTH trial found no cardiovascular benefits.

Along the way I touch on the weaknesses of observational epidemiology and the sneaky ways the fish oil supplement industry biases scientific publications.

My conclusion is that there is no compelling evidence for you to take over the counter fish oil supplements for primary or secondary prevention of cardiovascular disease.

I also discuss the reasons behind questioning the benefits of icosapent ethyl (Vascepa) which were demonstrated in the REDUCE-IT trial and why there needs to be another trial that compares icosapent ethyl to a neutral oil like corn oil rather than mineral oil.

Just prior to giving my talk I came across a study published in late 2020 which is the first prospective study in Inuit on the cardiovascular effects of long-chain n-3 polyunsaturated fatty acids. No effect was found, as summarized in this cute graphic, which I believe brings us full circle in our OMFA journey.

Pescatorially Yours,

-ACP

Feature image Evidently Cochrane

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36 thoughts on “Omega-3 Fatty Acids and Cardiovascular Disease Risk: Has the Story Ended or Only Just Begun?”

  1. Thank you for navigating the conflicting reports and claims for Omega-3 supplementation and CVD.

    This whole fish oil for the treatment of xyz also seems big with the ophthalmologists to treat dry eyes. A handful of studies over the last 10-20 years report improvement with high Omega-3 supplementation, and multiple ophthalmologists recommending one particular company’s “re-esterified TriGlyceride Omega-3” formulation at over $60/month.

    At the moment, I need “The skeptical ophthalmologist”

    Reply
    • Evidence is conflicting on OMFA for dry eye disease. But that doesn’t stop doctors from promoting a specific brand that only they sell for that indication.
      Your comment prompted me to quickly look at the topic as I am a dry eye sufferer and found no benefit of oral fish oils supplements
      This article has a reasonable summary in the context of How NZ ophthalmologists make recommendations
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230711/

      Reply
  2. Dr.Pearson, I am a 57 yo female with a routine of many years that include a healthy diet and regular work out routine With weight lifting walking and crossfit. I don’t drink often maybe 5 times a year and don’t smoke. I am within normal weight range and have no signs of diabetes or high blood pressure but…
    I have both high LDL 186 and high HDL 111, LDL P 1993 HDL P 33.9 small LDL-P <90 LDL size 22 and normal range triglycerides 68. My Dr recommends statins but i am trying to avoid them due to side effects. Are there any other options available? Thank you so much!

    Reply
    • Erika,
      Sorry for the delayed response.
      Your cholesterole numbers suggested an inherited or familial hypercholesterolemia, something that likely puts you at high risk of atherosclerotic cardiac complications
      Read my article entitled “are you on the fence about statin drugs” or something like that. it is very relevant to your case. Bottom line is, consider getting a coronary artery calcium scan (read about that in my article entitled “the ultimated guide to coronary artery calcium scans”
      There are lots of treatment options available in addition to statins.
      Dr P

      Reply
  3. Dr Pearson: Thank you very much for taking your personal (and unpaid) time to share your knowledge via your blogs, emails and now this excellent video. Much appreciated by average citizens like myself who are interested in their health.

    I also live in St. Louis and hope I never have to meet you professionally (hah !!) but you seem like a wonderful doctor who cares about his patients and I point friends / acquaintances to your site all of the time.

    Keep up the great work !!

    Reply
  4. Hi Dr.P,

    Thank you for your amazing lecture and article. What do you make of the subgroup analysis of STRENGTH in which there’s a significant MACE reduction in both Asian ethnicity and Asian region. I know the limitation of subgroup analysis, but Is it just coincidental or does it mean anything? Looking forward to your reply. Thank you!

    Siyao

    Reply
    • It’s interesting and hypothesis-generating but could be a red herring.
      There are known differences between some Asian populations and American/Western European populations in terms of baseline fish consumption and therefore omega-3 index levels. To me , intuitively, the benefits of fish oil supplementation should be less, not more in , say, the Japanese who have high omega-3 levels to begin with.

      Reply
  5. Thank you for posting this, it was very interesting. I would be really curious what the results would be with a different placebo for an identical setup trial as REDUCE-IT. That’s really cool you spoke with Bill Harris,I think his statement is telling about DHA, but I would like to see it confirmed with another trial. I thought it was very interesting that HSCRP and LDL-C increased w/ placebo with the REDUCE IT trial, as well as your slide on how MO effects the efficacy of statins, I was not aware of that.

    Two other points, one point you greatly illustrated is how observational data has been utilized for years in advocating benefits for health. When tested under the rigors of RCTs these medical dogmas have often times come to be unfounded or actually detrimental to outcomes. I think FO is considered a benign home remedy, but REDUCE-IT and STRENGTH both showed that FO might cause episodes of AF. In looking at both trials I think this revelation should give anyone pause that sees FO as benign or looking to lower TGs. As you mentioned TGs are a biomarker that have little upside in artificially lowering, with the exception of patients that have hypertriglyceridemia and what Vascepa was originally FDA approved to do. To me the AF in some individuals might be the big story in this whole FO debate.

    Another point worth mentioning is the phenomenon of artificial vs natural remedies for the treatment of any disease, obviously in this case heart disease from your lecture. Fish oil I think resonates with people because it “comes from nature”, even though this oil (Vascepa) is highly processed and only particular compounds (EPA) are isolated and put into the drug, making it hardly anything resembling a “natural fish”. On the other hand you have statins, which are seemingly made in an artificial lab environment and are “synthetic”. Interestingly the earliest statins had the same chemical composition as another natural material (Red yeast rice) that contains the compound mevinolin, a less potent inhibitor of HMGCOA. If you asked the average person, I would venture that most consider FO natural and statins as a drug, when both are heavily processed to get them to where they are efficacious in the clinical setting. I also wonder if that influences patients in the past and now between taking an OTC FO which they might consider a natural remedy for CVD prevention vs a statin drug that is artificial.

    Reply
    • Christian,
      Great points. The natural versus drug dichotomy is often a false one which I touched on briefly in my first Vascepa piece. I’ve also discussed it with respect to foxglove treatment of heart failure which has become the drug digoxin.
      It was so dangerous in its natural form but proved very useful once the dosing and manufacture was standardized.
      Dr P

      Reply
    • I found it. it’s part of my post entitled three more nails in the fish oil coffin.
      Nothing to suggest Krill oil superior to fish oil and I pointed out downsides.
      A technical paper from Greenpeace review the importance of krill to to the marine ecosystem in the Antarctic and this paper, entitled “License to Krill” details the problem.
      Do you want to be responsible for starving penguins, whales and seals??!

      Reply
  6. Also vascepa now has a warning about heart palpitations which I started suffering from in abundance after taking it. The palpitations set off an entire diagnostic roller coaster with insurance not wanting to approve a heart cath that I needed for an abnormal coronary calcium score and a blockage of 70% or greater which actually ended up being a 90 % bifurcation blockage in my mid lad . So I guess I should feel grateful towards vascepa !

    Reply
    • So this is a common logical mistake that doctors/patients/scientists have made over the years
      If biomarker A is associated with a higher risk of outcome B and drug/supplement/intervention C lowers biomarker A then shouldn’t outcome B also be lowered ?
      With HDL which is clearly associated with better outcomes multiple drug trials utilizing different mechanisms for increasing HDL failed to show any benefit and some showed worsening outcomes.
      Frequent PVCs were clearly associated with increase risk of sudden death in patients post MI. Flecainide lowered the frequency of PVCs. Therefore, we assumed it would lower sudden death risk. CAST trial showed it raised risk.
      With triglycerides we don’t have any RCTs showing lowering them improves outcomes. This includes REDUCE-IT. Outcomes. The triglyceride reduction with Vascepa was minimal and not related to outcomes.

      Reply
      • So would you say the best way to reduce CVD risk is lifestyle, health monitoring eg. Blood pressure, lipid profiles to include oxidised ldl measurements plus calcium scoring and statins if necessary? But why do the AHA recommend fish oil, recommend lowering trigs? And don’t high trigs contribute to hardening of the arteries and/or thickening of the artery walls? ( Source:Mayo clinic)

        Reply
  7. Well that was fascinating. I would love to get bigger views of your slides. I’ve never been able to take fish oil. Regardless of the brand that I’ve tried, it all makes me sick. So I try to eat fish at least twice a week even though the mercury levels are a concern. I bought a product called Good Fish recently. It’s salmon skin fried in palm oil and heavily salted. They taste horrible. I was thinking since I couldn’t take the fish oil, this would give me a source for fish oil. Now that I feel certain I don’t need the fish oil, the skins can go into the compost heap. My integrative physician recently did a CT scan of my carotid arteries and informed me that there were no major blockages but that I had some plaque buildup – both hard plaque and soft plaque. He said the hard plaque was not a concern and nothing would remove it but that there was a promising new product that could remove the soft plaque which he said was the more dangerous plaque. The product was called Arterosil. It is a pricey supplement. Through his office it’s about $80 for a month’s supply. He claimed that studies have shown statins can reduce plaque about 25% over a five year period. This product is supposed to reduce it by 50% over a six month period. He thought if I was game and wanted to try it, we would see where I was on the CT scan at the end of the year and see if any of the plaque was actually reduced. The product does have a website – http://www.arterosil.com. I was wondering if you’ve heard of the product. Your experience with statins and plaque reduction and whether you could confirm the 25% over 5 years claim.

    Reply
    • Cheryl,
      I looked at the arterosil website and it has numerous red flags of quackery. The alleged scientific papers or studies on the site appear made up. There is no reference link. If there were such a miracle drug with proven efficacy it would have been approved by the FDA very swiftly.
      I’m also concerned that your doc is performing CT scans to look at your carotids. That is not a good way to follow plaque given the radiation.
      Statins have proven safety and efficacy in reducing risk of stroke and heart attack related to soft plaque in over 500,000 patients over the last 20 years. Very sophisticated research studies using imaging modalities (not available in your local doctor’s office) such as intravascular ultrasound or 3D vascular ultrasound or CT angiography having shown plaque reduction with statin therapy lowering LDLC to <70.

      Reply
  8. Fish oil reduced my LDL by 30 points. Nevertheless, my cardiologist kept pushing statins. When I saw on ProPublica that he earns over $100,000 yearly from statin manufacturers I understood why ;).

    Reply
    • That is interesting because in large randomized controlled trials it has little effect on LDL-C
      Also, it is hard to imagine drug manufacturers paying doctors any more for prescribing statins. 95% of the statins I prescribe are generic and cheap. The one brand name drug Livalo has an important niche role but I usually end up providing patients with samples due to cost and insurance reluctance to cover it.

      Reply
  9. The JELIS trial had no mineral oil problem and demonstrated the efficacy of pure EPA. The REDUCE-IT trial data is producing more data as time goes on. Its the actual EPA blood serum level along with the EPA/DHA blood serum level ratio that is more critical. Only using pure EPA by a solid lab is useful. The Japanese consistently have the lowest rate of heart disease in the world. Although their are many factors (see Ogato), their average blood EPA serum level is over 10 vs. 2.5 in the U.S. Just like calling “HDL” good cholesterol is inaccurate at this point and very complicated, so will be the story of the EPA/DHA relationship five years from now.

    Reply
    • TJ,
      Thanks for your comments. JELIS has definitely been discussed as further confirmation of the CV benefits of pure EPA, however, it was not compelling enough for Vascepa to get an FDA indication for CV risk reduction. There are issues with the trial, including that LDLC was not controlled well with most patients on lower dosage statin therapy. Statin therapy was more intense in REDUCE-IT but still the average LDL was >70 and rose significantly in the mineral oil placebo group thus not at goal for secondary prevention.
      To fully prove Vascepa/icosapent ethyl or pure EPA is the key to CV risk reduction I’d like to see a trial of secondary prevention with patients at goal LDLC of icosapent ethyl high dosage versus a neutral comparator as placebo.
      Agree that calling HDL the good cholesterol outdated and with this change has come recognition that high trigs confer residual risk.
      Dr P

      Reply
      • Can you comment more on HDL not being the good cholesterol?

        I have a metabolic profile that is almost entirely like that of my father (almost 70 and I almost 40).

        Both of us have had pre-diabetic glucose our adult lives that has never progressed into the diabetic territory (A1C at my peak was 6.4 right now is 5.5 with no medication for it). Both of us carry abdominal weight, though are not extremely obese (I am 190 lbs and 6’2″ but all of my weight is in my gut). We both have low HDL (mine is 34) and normal LDL (can’t recall off the top of my head what the number is but it’s in the normal range–however, I did have a more specific test that I don’t have in front of me that showed a very high small particle LDL count–not sure the exact name of it). Normal CRP.

        I have normal triglycerides.

        In addition, I have unexplained extremely low total testosterone (varies from total testosterone of 80 to highest measured of 240). I have normal to low LH and FSH. It’s a secondary issue, but the insurance wouldn’t pay for an MRI of the sella. I have chosen not to treat with exogenous testosterone.

        Anyhow, I know I am not metabolically healthy—I have always assumed so mostly from the pre-diabetic sugar levels and also the low HDL, for which there didn’t seem to be any particularly good treatment. I am curious if you can expand on it not being as simple as it being the good cholesterol.

        Reply
        • Absolutely no medical training here, just curiosity. I tend to document and quantify everything in my life. I’ve been tracking my cholesterol for decades. I take a Vitamin D supplement. A rather large one actually. Even though I live in Southern California I find my Vitamin D levels drop too low without the supplement. I’ve found a correlation between my Vitamin D levels and my HDL levels. Do you know what your Vitamin D levels are? Are they also as low as your HDL. I’m just curious as to whether the correlation holds true for everyone or it’s just something peculiar to me.

          Reply
          • Cheryl,
            Here’s a thought. Exercise and alcohol are the only 2 lifestyle factors known to increase HDL. Could the Vitamin D levels and HDL be influenced by one of those?
            dr P

            Reply
            • Well Southern California and an outdoor lifestyle is kinda common here. I don’t drink. So I don’t see alcohol as a factor. The exercise is basically walking, yoga and Pilates. The knees are shot so anything more strenuous is out and I’ve been at the same level for years. So I don’t see that as a factor. I only recently started looking at my Vitamin D levels and tracking them (last two years maybe). So I don’t know if it would track further back. I’ve always had pretty high HDL levels.

              Reply
          • Actually, I’ve increased my HDL from 37 or less to the mid to high 50s…by eating a low carb/ketogenic diet for the last 7.5 years. Exercise is the same, alcohol intake dropped over that time. (It took a lot less than 7.5 years to get to the mid 50s, but that’s how long I’ve been keto now.)

            I was never able to see any change in HDL for exercise. And I drank waaaaaaay more when I had my 37 HDL tests. Carbs for me seemed to reduce HDL.

            And there’s quite a bit of evidence this occurs for most people on a low carb diet. Easy to find studies where keto dieters raise HDL.

            HOWEVER, I have been taking vitamin D, whereas I did not before keto. So, I can’t rule that out.

            Reply
  10. I wasn’t able to control my triglycerides until I started on vascepa. My levels were as high as 1800 in my lifetime . I have familial hyper triglyceridemia. My number is currently 153 with no other changes to diet or lifestyle . Total cholesterol is lower also at 130 however my total cholesterol has always been well below 200. I am 55 with a horrific family history of cvd and a stent in my mid LAD.

    Reply
    • Laurence,
      Vascepa is indicated for very high triglycerides as in your case and provides about 20-30% reduction.
      Based on the REDUCE-IT trial it is indicated for patients with established CV disease, on statins with triglycerides>135. As I mention in the talk, however, some of the benefits of Vascepa may be overstated as the mineral oil comparator raised LDL and inflammatory markers and wasn’t entirely neutral.

      Reply
      • I have CAD and high triglycerides (300’ish). Untreated, 35 years ago at the age of 30, I tested trigs at 4,000. Can you comment on Lovaza instead of Vascepa. The price difference is very substantial.

        Reply
        • Both lovaza and vascepa are indicated for triglycerides >500 and reduce them by on average 20-30% .
          Over the counter fish oil dosages also lower the trigs when they are >500 but not as reliably.

          Reply

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