Category Archives: Omega-3 Polyunsaturated Fatty Acids

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,-

ACP

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.

 

 

Omega-3S From Fish Oil Supplements No Better Than Placebo For Dry Eye 

Yesterday, a patient I’m seeing for atrial fibrillation told me that he was taking fish oil supplements that his eye doctor had recommended and sold to him for dry eyes. This patient reads my blog and knows that I strongly recommend not taking fish oil supplements (unless your triglycerides are >500). At the time I told him I didn’t know the literature on fish oil and dry eyes but that I was skeptical of any proven benefit.

It turns out that in April of this year an NIH-sponsored study concluded that Omega-3s from fish oil supplements are no better than placebo for dry eye.

The NIH story on this study notes that

Despite insufficient evidence establishing the effectiveness of omega-3s, clinicians and their patients have been inclined to try the supplements for a variety of conditions with inflammatory components, including dry eye. “This well-controlled investigation conducted by the independently-led Dry Eye Assessment and Management (DREAM) Research Group shows that omega-3 supplements are no better than placebo for typical patients who suffer from dry eye.”

I suspect that one by one the various alleged benefits of fish oil supplements will be proven to be nonexistent.  I’m not sure the general public will stop buying snake or fish oil  then but I feel like one by one I’m getting my patients off them. Doing my part to save the ocean bottom-feeders.

Krillingly Yours,

-ACP

N.B. I’m writing this while flying to Miami to begin the great Galapagos adventure and the Voyage of the Samba.

Three More Nails In The Omega-3 Supplement Coffin: Stop Taking Fish Oil Pills (The Complete Post)

If by now you are still taking fish oil supplements despite my last post on the topic I present three more reasons to stop wasting your money and destroying the ocean’s ecosystem.

The first nail: No Reason To Take Fish Oil Pills

A Cochrane review showing shows there is little or no effect of omega 3 supplements on our risk of experiencing heart disease, stroke or death.

This is the most extensive systematic assessment of effects of omega-3 fats on cardiovascular health to date. Moderate- and high-quality evidence suggests that increasing EPA and DHA has little or no effect on mortality or cardiovascular health (evidence mainly from supplement trials). Previous suggestions of benefits from EPA and DHA supplements appear to spring from trials with higher risk of bias. Low-quality evidence suggests ALA may slightly reduce CVD event risk, CHD mortality and arrhythmia.

Second Nail. Peruvian Anchoveta: Put Them On A Pizza Not in A Pill

Paul Greenberg’s recently published book, The Omega Principle, emphasizes the damage the fish oil supplement business is doing to the ocean environment,

During a recent interview on Fresh Air on NPR he summarized the concerns:

GREENBERG: So omega-3 supplements come from this critical layer of the ocean biosphere that are small – what are called pelagic fish. They’re the silvery, little fish like anchovies and herring and other fish called menhaden that most people haven’t heard of, but it’s actually the most caught fish in the lower 48 of the United States. These fish are really essential for ecosystem dynamics in the ocean.

So the way that oceans work is that all the energies coming from the sun – it goes – all that energy is processed by plankton, by phytoplankton. And it’s really these fish that are – these little fish that are used for omega-3 supplements that transfer the energy from plankton to larger fish. So in other words, you know, you have the solar energy going into the plankton. The little fish then eat the plankton. And then they are in turn eaten by larger fish. So if you harvest this middle layer – if you overharvest this middle layer of anchovies, of herring, of menhaden – if you take them out of the picture, there’s no way for the energy to be transferred from phytoplankton up to larger predators. So I guess that’s my main concern here.

So in particular, where are the omega-3 supplements coming from? Most of the omega-3 supplement oil is coming from a fish called a Peruvian anchoveta. And it is the most caught fish in the world. In some years, Peruvian anchoveta harvests have equaled as much as 10 million metric tons. Just to give you some perspective, that’s like one-eighth of all the fish caught in the world. And the crazy thing about it is that those fish are completely, totally edible. I’ve eaten them. They’re delicious. You can have them on a pizza. You could do anything with them. But 99 percent of those Peruvian anchoveta are ground up into animal feed, boiled down into oil and turned into supplements. So to me, to my mind, that is not necessarily the wisest use to be made of this really, really important source both for the ecology of the ocean but also for humans

Nail Three. Save the Krill!

The supplement industry is incredibly creative in their marketing. As the uselessness of fish oil supplementation has become clear, supplement manufacturers have begun touting krill oil as superior to fish oil.

Claims like the following are all over the internet:

Krill have an edge over your ordinary fish – when you take a krill oil supplement, you also get astaxanthin along with your DHA and EPA. It’s an antioxidant. In terms of antioxidant power of potency, it’s been found to be 500x to 6,000x stronger than regular vitamins like vitamin E and vitamin C.

This is just hogwash. There is no good clinical evidence to support any health claim for krill oil in general or astaxanthin in particular. Please read my post on the failure of anti-oxidant supplements and vitamins and recognize that claims of antioxidant power do not indicate any health benefit.

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??!

Let me reiterate my original 2013 fish oil post pithy summary:

the bottom line on fish oil supplements is that  the most recent scientific evidence does not support any role for them  in preventing heart attack, stroke, or death. There are potential down sides to taking them, including contaminants and the impact on the marine ecosystem. I don’t take them and I advise my patients to avoid them (unless they have triglyceride levels over 500.)

Prokrilly Yours

-ACP

 

 

 

 

Flaxseed: Plant-Based Omega 3 Super Food or Faux Fish Oil?

Ground flaxseed plus Trader’s Point Creamery full fat plain yoghurt. It’s not pretty but tastes pretty good.

The skeptical cardiologist has a confession to make: he’s been adding ground flaxseed to his typical late morning full fat yoghurt plus berries and almonds.

Adding flaxseed seems dangerously close to dietary behaviour I have been advising against: supplementing instead of eating real food.

Also, I am philosophically opposed to going out of my way to eat any edible that is consistently promoted as a “super food” or a “functional food.” To me, these are meaningless terms and marketing blather

When I began writing this post in 2017 I was getting my flaxseed from Stober Farms (Est. 1901) who had been producing “for over 100 years  the finest flax in the world.”  Stober Farms provided me with “organic Golden Flax Seed which has been Cold-Milled Processed.”

Stober Farms (who have since mysteriously gone into bankruptcy) also informed me:

Flax is digested most effectively when ground. Some grinding methods generate heat when milled, spurring early omega-3 oxidation. Stober Farms uses a unique cold-milled process, which gently grinds the seed without significantly raising the temperature. This proprietary method preserves the nutrients, flavor and extends the shelf life to 22 months.

Honestly, I don’t recall exactly why I began “flaxing” but I suspect I felt it was a good way to boost the fat content in my full fat yoghurt (yes, I am now spelling yoghurt with an h) and berries and perhaps sufficiently satiate me that it would be the only food I would need to consume until dinner or late afternoon.

Two tablespoon (14 grams) is what I typically  imprecisely add. These tablespoons provide 75 kcal of energy which comes from 3 grams of protein, 6 grams of fat, and 4 grams of carbs.  Three of the four carb grams are soluble fibre.

About half of the fat in flaxseed is in the form of alpha-linolenic acid (ALA)(18:3) an omega-3 polyunsaturated (PUFA) fat.  Flaxseed oil contains five times more ALA than walnut oil or canola oil, which are the next highest sources of ALA.

Is Flaxseed A Super Functional Food?

Many seemingly authoritative sites on the internet proclaim that flaxseed is incredibly healthy. For example, Healthline.com’s “Authority Nutrition” (they must be authoritative as authority is in their name)  presents their 10 health benefits of eating flaxseed “backed by science”  and concludes:

They can be used to improve digestive health, lower blood pressure and bad cholesterol, reduce the risk of cancer and may benefit people with diabetes.

But typical of  Authority Nutrition’s overblown claims  these are not truly proven by science. The studies cited are weak; typically short-term tests of biomarkers or animal studies or human studies with very small numbers. Most importantly. these studies , which are often funded by flaxseed promoters are highly likely to be biased in favor of positive results.

Most websites tout the cardiovascular benefits of the omega-3 PUFA in flaxseed, the high percentage of soluble fibre and  the benefits of a chemical which cannot be named (due to a name which is too difficult to pronounce), SDG.

Omega-3 PUFAs and fibre I’ve touched on previously (and positively) but what about the mysterious and unpronounceable SDF. Per a 2010 review article

Flaxseed is the richest source of the lignan secoisolariciresinol diglucoside (SDG). After ingestion, SDG is converted to secoisolariciresinol, which is further metabolised to the mammalian lignans enterodiol and enterolactone. A growing body of evidence suggests that SDG metabolites may provide health benefits due to their weak oestrogenic or anti-oestrogenic effects, antioxidant activity, ability to induce phase 2 proteins and/or inhibit the activity of certain enzymes, or by mechanisms yet unidentified.

Like so many putative wonder phytochemicals, SDG has a “growing body of evidence” for lots of things but actual proof that it does anything worthwhile in humans is lacking and awaits  well done randomized clinical trials

Poorly researched articles on flaxseed are highly likely to tout its anti-inflammatory properties. These properties are seen in rats but unfortunately haven’t been proven in my favorite species, Homo Sapiens ,  Flaxseed doesn’t seem to decrease the inflammatory marker CRP in humans as reported in this systematic review and meta-analysis.

ALA and Cardiovascular Disease

As I’ve indicated in previous posts, evidence supports fatty fish consumption as beneficial in reducing cardiovascular disease presumably by increasing levels of marine omega-3 PUFAs in the body.

The value of fish oil supplementation, however, is not proven (see here).

How does ALA compare to the seafood omega 3s  in preventing cardiovascular disease (CVD)?

In 2012, researchers at the Harvard School of Public Health published a systematic review and meta-analysis of the existing data on ALA and the risk of CVD..

Their introductory paragraph nicely lays out why ALA could be very important to public health:

A large body of evidence supports a potential protective effect of seafood omega-3 (n−3) fatty acids, particularly EPA (20:5n−3) and DHA (22:6n−3), on coronary heart disease (CHD. However, fewer studies have evaluated how the plant-derived omega-3 fatty acid α-linolenic acid (ALA; 18:3n−3) relates to risk of CHD and other cardiovascular disease (CVD) outcomes, and the results have been inconsistent As an essential fatty acid that cannot be synthesized by humans, ALA is mainly consumed from plant sources, including soybeans, walnuts, and canola oil. Compared with seafood omega-3 fatty acids, ALA from plant sources is more affordable and widely available globally. Thus, whether ALA can reduce the risk of CVD is of considerable public health importance.

If plant-derived ALA can provide our omage-3 PUFA needs then perhaps we can stop stripping the ocean of all the menhaden.

In the Harvard analysis when all 27 studies were combined the authors found a significant risk reduction of 14% in CVD events with flaxseed.

There were lots of issues with the data which I won’t bore you with leading the authors to conclude that “ALA consumption may be beneficial “.  They emphasized the need for additional well-designed observational studies and randomized clinical trials in the area.

Since observational studies cannot prove causality, I await a good randomized clinical trial of ALA supplementation before I can recommend ALA supplementing to prevent heart disease.

After Performing This Review Is The Skeptical Cardiologist Still “Flaxing”?

I am. Because I’ve found that when I consume flaxseed I feel 20 years younger, full of vitality. and with a youthful golden sheen to my hair, nails and skin.

Actually, that last sentence is untrue.

I’m still adding ground flaxseed to my yoghurt but not with any expectation that it is reducing my risk of heart attack and definitely not because I perceive it as a super or functional food.

I like the taste, the convenience, and the extra (presumably healthy) calories it provides but I’m still an advocate of just eating real food rather than trying to identify specific nutrients, nutraceuticals or supplements and add them to your diet.

Flaxseedingly Yours,

-ACP

N.B. I did not touch on omega-6/omega-3 ratios in the diet. I’ve been examining that inflammatory (enjoy the pun) topic for years and once I come across a good study that adds to understanding in the area I will likely publish a post on it.