Has REDUCE-IT Resurrected Fish OIl Supplements (And Saved Amarin)?

The answers are no and yes.
There is still no reason to take over the counter fish oil supplements.
In fact, a study published Saturday found that fish oil supplementation (1 g per day as a fish-oil capsule containing 840 mg of n−3 fatty acids, including 460 mg of eicosapentaenoic acid [EPA] and 380 mg of docosahexaenoic acid [DHA]

did not result in a lower incidence than placebo of the primary end points of major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type.

However, another study  published Saturday (REDUCE-IT) and presented at the annual American Heart Association Scientific Sessions to great fanfare found that an ethyl-ester formulation (icosapent ethyl) of eicosapentanoic acid (EPA, one of the two main marine n-3 fish oils)  reduced major cardiovascular events by 25% in comparison to placebo.
When I wrote about Icosapent ethyl (brand name Vascepa) in a previous blog post in 2015 there was no data supporting its use:

A fish oil preparation, VASCEPA,  available only by prescription, was approved by the FDA in 2012.
Like the first prescription fish oil available in the US, Lovaza, VASCEPA is only approved by the FDA for treatment of very high triglycerides(>500 mg/dl).
This is a very small market compared to the millions of individuals taking fish oil thinking that  it is preventing heart disease.
The company that makes Vascepa (Amrin;$AMRN)would also like to have physicians prescribe it to their patients who have mildly or moderatelyelevated triglycerides between 200 and 500 which some estimate as up to 1/3 of the population.
The company has a study that shows that Vascepa lowers triglycerides in patients with such mildly to moderately elevated triglycerides but the FDA did not approve it for that indication.
Given the huge numbers of patients with trigs slightly above normal, before approving an expensive new drug, the FDA thought, it would be nice to know that the drug is actually helping prevent heart attacks and strokes or prolonging life.
After all, we don’t really care about high triglycerides unless they are causing problems and we don’t care about lowering them unless we can show we are reducing the frequency of those problems.
Data do not exist to say that lowering triglycerides in the mild to moderate range  by any drug lowers heart attack risk.
In the past if a company promoted their drug for off-label usage they could be fined by the FDA but Amarin went to court and obtained the right to promote Vascepa to physicians for triglycerides between 200 and 500.
Consequently, you may find your doctor prescribing this drug to you. If you do, I suggest you ask him if he recently had a free lunch or dinner provided by Amarin, has stock in the company (Vascepa is the sole drug made by Amarin and its stock price fluctuates wildly depending on sales and news about Vascepa) or gives talks for Amarin.
If he answers no to all of the above then, hopefully, your triglycerides are over 500.

And although elevated triglycerides confer an elevated CV risk nearly all prior trials evaluating different kinds  of triglyceride-lowering therapies, including extended-release niacin, fibrates, cholesteryl ester transfer protein inhibitors, and omega-3 fatty acids have failed to show reductions in cardiovascular events
REDUCE-IT, Amarin trumpeted widely in September (before the actual data was published)  now provides impressive proof that it prevents cardiovascular disease. Has the skeptical cardiologist changed his mind about fish oil?

Vascepa Is Not Natural Fish Oil

Although Amarin’s marking material states “VASCEPA is obtained naturally from wild deep-water Pacific Ocean fish” the active ingredient is an ethyl ester form of eicosapentoic acid (EPA) which has been industrially processed and distilled and separated out from the other main omega-3 fatty acid in fish oil (DHA or docosohexanoieic acid).

Natural fish oil contains a balance of EPA and DHA combined with triacylglycerols (TAGS).
So even if the REDUCE-IT trial results can be believed they do not support the routine consumption of  over the counter fish oil supplements for prevention of cardiovascular disease.

Does REDUCE-IT  Prove The Benefit of Purified High Dose EPA?

REDUCE-IT was a large (8179 patients) randomized, double-blind placebo controlled trial
Eligible patients had a fasting triglyceride level of 150 to 499 mg per deciliter  and a low-density lipoprotein (LDL) cholesterol level of 41 to 100 mg per deciliter  and had been receiving a stable dose of a statin for at least 4 weeks. In 2013 the protocol was changed and required a triglyceride level>200 mg/dl.
Participants were randomized to icosapent ethyl (2 g twice daily with food [total daily dose, 4 g]) or a placebo that contained mineral oil to mimic the color and consistency of icosapent ethyl and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group.
More importantly, the hard end-points of CV death, nonfatal stroke and heart attack were also significantly lower in the Vascepa arm compared to the “placebo” arm.
These results are almost unbelievably good and they are far better than one would have predicted given only a 17% reduction in triglycerides.
This makes me strongly consider prescribing Vascepa (something I heretofore have never done) to my higher risk patients with triglycerides over 200 after we’ve addressed lifestyle and dietary contributors.
Perhaps the high dose of EPA (4 grams versus the 1 gram utilized in most trials) is beneficial in stabilizing cell membranes, reducing inflammation and thrombotic events as experimental data has suggested.

Lingering Concerns About The Study

Despite these great results I have some concerns:

  1. The placebo contained mineral oil which may not have been neutral in its effects. In fact, the placebo arm had a significant rise in the LDL cholesterol.
  2. Enrolled patients were predominantly male and white. No benefit was seen in women.
  3. Higher rates of serious bleeding were noted in patients taking Vascepa
  4. Atrial fibrillation developed significantly more often in Vascepa patients (3.1%) versus the mineral oil patients (2.1%)

Finally, the trial was sponsored by Amarin Pharma. This is an aggressive company that I don’t trust.  The steering committee consisted of academic physicians (see the Supplementary Appendix), and representatives of the sponsor developed the protocol,  and were responsible for the conduct and oversight of the study, as well as the interpretation of the data. The sponsor was responsible for the collection and management of the data. All the data analyses were performed by the sponsor,
After i wrote my negative piece on Vascepa in 2015 a number of Amarin investors attacked me because Vascepa is the only product Amarin has and any news on the drug dramatically influences its stock price. Here is the price of Amarin stock in the last year.

The dramatic uptick in September corresponds to the company’s announcement of the topline results of REDUCE-IT. Since the actual results have been published and analyzed the stock has dropped 20%.

High Dose Purified and Esterified EPA-Yay or Nay?

I would love to see another trial of high dose EPA that wasn’t totally under the control of Amarin and such trials are in the pipeline.
Until then, I’ll consider prescribing Amarin’s pills to appropriate patients* who can afford it and who appear to have significant residual risk after statin therapy*.
But, I will continue to tell my patients to stop paying money for useless OTC fish oil supplements.
Megaskeptically Yours,-
N.B.* Appropriate patients will fit the entry criteria for REDUCE-IT described below.

Patients could be enrolled if they were 45 years of age or older and had established cardiovascular disease or were 50 years of age or older and had diabetes mellitus and at least one additional risk factor. Eligible patients had a fasting triglyceride level of 150 to 499 mg per deciliter (1.69 to 5.63 mmol per liter) and a low-density lipoprotein (LDL) cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter) and had been receiving a stable dose of a statin for at least 4 weeks;

So either secondary prevention (prior heart attack or stroke) or primary prevention in patients with diabetes and another risk factor.


13 thoughts on “Has REDUCE-IT Resurrected Fish OIl Supplements (And Saved Amarin)?”

  1. Dr. P,

    Did you see the recent EVAPORATE study results? Seems like there are some concerns on several things. I know you were.discouraging patients about fish oil and wanted to see a replication of REDUCE IT-Vascepa to support icosapent ethyl as a viable treatment. I was curious if you felt EVAPORATE is a reliable study or good science and does this provide the empirical data for recommendation?

    • Chistian,

      I don’t know whether you saw the interim analysis of EVAPORATE a year ago. It is strange that vascepa had apparently no effect on LAP during the first 9 months, and suddenly went in the opposite direction in the final analysis. This gave me concerns. And I would like to hear what Dr.P will say about this. Thanks!

      • I’m still sorting out the latest EVAPORATE data on plaque regression (after progression) and hope to write my thoughts soon. Lots of odd things to analyze.

  2. No, really. I would like to know how a diet in which the major source of protein is from fresh wild cold-ocean fish compares with Vascepa in hard end-points.

  3. I just read the review of the important REDUCE-IT (RI) trial you wrote shortly after it was published. Since then, more information is available you might want to consider. For full disclosure, for several years I’ve been a big fan of Vascepa based on the JELIS trial and conversations with doctors. I’ve been taking it off-label ($9/90 days insurance co-pay with Amarin coupon) and am a long-time Amarin investor.
    I fully understand your skepticism as a general starting point, but I am unaware of any misbehavior by Amarin. The trial was administered by the hospital associated with Harvard Med School, and the lead investigator, Dr. Bhatt, is a Harvard prof with impeccable reputation (over 1100 publications). The double blind trial design was approved by FDA with a SPA, and statistics were independently confirmed.
    The mineral oil (MO) issue was seized on by skeptics and highly exaggerated. The maximum possible impact on RRR would be 2%-4%, and there’s very strong evidence it’s closer to zero. That’s common sense, since it would be hard for 2 g of min oil to coat a 20+ foot long small intestine very thoroughly. The LDL increase was consistent with normal variation (which is reported to be higher for high trig subjects like RI). Also, from K-M curves, almost all benefit was from the Vascepa arm bending down, not the placebo arm bending up. I did a deep dive on the placebo issue I could email on request (see also the Amarincorp.com FAQ page). Evidence is overwhelming MO is at most a minor effect, leaving RI results as blockbuster. Total statin absolute risk reduction (ARR) is only 1-2%, and the small LDL increase couldn’t reflect a MO impact more than about a tenth of that (~0.1%-0.2%), where RI reported 4.8% ARR. BTW, prof. Bhatt reported the placebo subjects whose LDL rose actually had slightly fewer events, which should settle the matter for the science-minded.
    RI results were very strong over a wide range of subgroups, suggesting a very large number of people who would benefit. JELIS was overweight female and showed strong benefit (19% RRR with dose less than half of the RI dose). Natural fish is good for you, but there are particular benefits to excluding the DHA, which has been proven to raise LDL and lacks several benefits (including ability to displace AA). That’s why several trials of DHA/EPA blends failed. As more data has come out, I hope you’ve taken another look.
    I honestly believe you do your patients a disservice if you don’t prescribe Vascepa for them, especially those who could have about a third less risk for $3/month with many insurance plans. Also, the K-M curves show a startup period of a year or more before full benefit, which implies long-term benefit will be substantially higher than initial reports (probably over 40% RRR for heart attacks).
    I look forward to seeing your updated view of this important issue.

    • Charles,
      thanks for your insightful, informed comments and particularly for your full disclosure of potential conflicts of interest which is rare.
      I have learned more since I wrote that piece. There is a nice discussion on omega-3s between the lipidologist Tom Dayspring and Peter Attia on one of Peter’s podcasts I found insightful. In particular I think it is likely that pure EPA in high pharmaceutical doses is effective and safe for risk reduction in high risk populations.
      As I indicated in my post I have been evaluating current patients for Vascepa and have started “writing” prescriptions for it.
      So the ending to my post is still appropriate:
      “I would love to see another trial of high dose EPA that wasn’t totally under the control of Amarin and such trials are in the pipeline.
      Until then, I’ll consider prescribing Amarin’s pills to appropriate patients* who can afford it and who appear to have significant residual risk after statin therapy*.
      But, I will continue to tell my patients to stop paying money for useless OTC fish oil supplements.”

  4. Thank you. And me fresh from a doc who wants me to consume 2000mg fish oil daily. As a side note, I like food but fish is one I have trouble with the taste of. Is there hope for me?

  5. Thank you. And me fresh from a doc who wants me to consume 2000mg fish oil per day. But, side note, for a girl who likes a LOT of food, fish is one I simply cannot stomach. Help?

  6. Our grandparents got it right… again. NO snacking between the daily two or three meals, and Eat “real” fish from the ocean.
    Triglycerides too high?
    Simple! – stop eating the stuff that’s driving the numbers . Cut back (or out) refined ‘edible substances’ in general, and sugars / carbohydrates in particular.
    You’ll be making a useful change in your insulin resistance / Pre-T2 diabetes which ultimately reflects in arterial health…
    Why not extend your overnight fast…? and make the Breaking of your Fast smaller in size. Again with minimised carbs, – Bacon and eggs is looking healthier if you really must eat…
    You’ll save on groceries AND chole$terol-lowering medication$.

  7. Normal fish oil it better. After saying that fish oil has no effect, all the drug companies are now investing in fish oil derivatives they can patent and make money on. Irish pharmaceutical company Amarin sent a glowing announcement to investors Monday that its drug Vascepa
    Irish pharmaceutical company Amarin sent a glowing announcement to investors Monday that its drug Vascepa, surprise, surprise, the public once again are being lied to in the name of big profits for investors.

    • What lie do you refer to? That’s a serious charge. The trial was administered by an impartial third party with the highest possible reputation (the hospital associated with Harvard Medical School, lead investigator Deepak Bhatt is prof at Harvard Med School). FDA oversight of the trial design with a SPA. Published in NEJM, which has the highest reputation. Double blind and independent confirmation of the statistics. Developing this drug that can prevent millions of stokes and heart attacks cost $500 million. Is there anything wrong with wanting to earn back that investment plus a profit?

  8. “After adjustment for a large panel of covariates, fish intake ≥4 times per week was associated with 40% reduced risk of composite CHD and stroke (HR = 0.60; 95%CI 0.40-0.90), and with 40% lower risk of CHD (HR = 0.60; 95%CI 0.38-0.94) as compared with subjects in the lowest category of intake (<2 times/week)."
    Why bother with extraction, refinement, chemical modification, price, and side effects when you can dine on real food?
    The best fish for the purpose are also lowest in mercury – wild salmon, mackerel, sardines, herring, etc.

  9. Great points, Anthony. I appreciate your willingness to challenge the our mercenary Pharma. Their rush to line their pockets using scarce data and fat marketing is legendary, and symptomatic of their ethical anorexia.


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