Does omega-3 reduce cardiovascular disease? Comparing major trials REDUCE IT, VITAL, and STRENGTH
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Clinical trials evaluating whether supplemental omega-3s can achieve the same cardiovascular benefits as fish intake have yielded mixed results. Large clinical trials completed over the last two decades have produced mixed findings, possibly due to inconsistencies in trial design.
In the REDUCE-IT trial, participants took 4 grams of EPA (a prescription EPA-only formulation called icosapent ethyl) per day or placebo. After nearly five years, those taking the omega-3 had a 25 percent reduced rate of ischemic events, including cardiovascular death, than people taking the placebo. In contrast, a similar large trial, STRENGTH - which evaluated a free fatty acid formulation of EPA and DHA at 4 grams per day, was stopped early due to the unlikelihood of producing a favorable outcome.
Scientists have speculated why these similar trials have had such different findings. Some researchers suggest that the addition of DHA may negate the effects of EPA or that the high dose and pure formulation of EPA is the determining factor in the success of REDUCE-IT and the failure of STRENGTH. In this clip, Dr. Bill Harris describes the recent large clinical trials evaluating whether omega-3 decrease heart disease risk.
Dr. Patrick: What are your... So we talked a lot about cardiovascular disease and some all-cause mortality. We didn't talk about all the studies. I mean, there were too many, I mean, the VITAL study. Well, I do want to get your thoughts on, you know, the STRENGTH study and why this was...they used Lovaza, what did they use?
Dr. Harris: No they used a thing called Epanova.
Dr. Patrick: Epanova.
Dr. Harris: Which is EPA plus DHA, same ratio as in Lovaza except they're free fatty acids, not ethyl esters. So they're unesterified EPA and DHA, which they had previously shown are more readily absorbed. You don't have to hydrolyze them, they're already free fatty acids. But the trouble with those is they're also pretty irritating. They're GI irritants. Free fatty acids are. So they had to enterically coat the pills. So that's fine. Why did STRENGTH, which was a bigger study than REDUCE-IT, but in virtually the same kind of patient, high cardiovascular risk, high triglycerides, on statins, that's...everybody had to be in there 13,000 people worldwide and placebo was olive oil, I believe stripped olive oil. They found no effect at all. They stopped the study early as a matter of fact for futility. And it was the biggest shock to everybody in the omega-3 world that it didn't work. And nobody really has a good understanding of why.
And, you know, people come up with ideas, you know, like they were healthier. Well, I mean, it was done like two years after REDUCE-IT was done. I mean, and probably recruiting out of exactly the same sites as well around the world, multiple countries are involved. I don't think that makes any sense. To me, if I had to guess, there may be some chronic, I mean, your GI tract is not designed to be taking in 4 grams of free fatty acids every day. It's just not designed for that. And that may induce some kind of chronic inflammatory response that's going on systemically from taking these detergents. And they've only been studied for 12 weeks in other studies and they show nice absorption, lower triglycerides. They do very well. But for four or five years of taking this every day, I bet there was just some kind of chronic inflammatory thing going on that erased any omega-3 benefits.
Dr. Patrick: And they didn't measure any inflammatory biomarkers.
Dr. Harris: CRP, even they didn't see any difference.
Dr. Patrick: CRP is not very sensitive.
Dr. Harris: Yeah. I mean, that's all they measured. So that's the only metric they have. So nobody knows. I don't know. Yeah. I don't know. Put it that way.
Dr. Patrick: So they cut off the study so early, and you said they were, you know, the participants were of the same sort of health status as the participants in the REDUCE-IT trial. But if you look at the adverse or the fatalities, there were much fewer. Is that because they stopped it earlier? Is that why? I mean...
Dr. Harris: No, no. I mean, yeah, I've got an interesting slide showing the event rate in REDUCE-IT in the placebo group, which is like this and the event rate in the treated group, which is lower, 25% lower. And then you look at the event rate in STRENGTH and both placebo and active were even lower than the event rates in the treated group and REDUCE-IT. So there's something...there were fewer events, a lot fewer events, and maybe...nobody knows how to explain that either. And you really, I mean, theoretically, you can't put these curves on the same graph. It's not the same study, but it was very close to the same study in my view.
Dr. Patrick: Well, the other thing is that the EPA versus the one that had EPA and DHA, and what are your thoughts? Like, you know, I hear people...I mean, you see headlines that say, oh, DHA can negate some of the positive effects of EPA.
Dr. Harris: I don't believe that. I mean, I think there's an effort by those who want to promote the EPA-only product to vilify DHA in any way they can. Which I don't think is appropriate. I don't think we have the evidence for it. Just because this study didn't work doesn't mean DHA counteracted the effect of EPA. Can't draw it. You need to do a study with DHA. That's what needs to be done. Pure DHA versus pure EPA versus maybe a combination would be optimal versus a placebo. So a four-arm group like VITAL, you know, VITAL at 225,000 people four arms in vitamin D. And I'd love to see if VITAL with four arms of EPA alone, DHA alone, the combination, and a placebo and see what would happen.
Dr. Patrick: And measuring the omega-3 index.
Dr. Harris: Totally.
Dr. Patrick: Yeah. I mean, that sounds good for a trial. I think with the VITAL study, you know, it made headlines because the...well...
Dr. Harris: Didn't work.
Dr. Patrick: Well, the primary outcome didn't work, but did it not work in your opinion?
Dr. Harris: No. It did work, in my opinion, it's just the primary outcome was a composite of multiple different kinds of outcomes. And if you look at the individual elements, there was benefit. It reduced major reduction in risk of heart attack. And even in people who didn't, who ate little fish or the lower half of the fish intake, they got a significant reduction in the primary endpoint. So there were good outcomes in that study from taking 840 milligrams. So it's a one-capsule Lovaza. And that's not much.
Dr. Patrick: It's not.
Dr. Harris: It's not much. So I think it was a positive study at the end of the day.
Dr. Patrick: Yeah. And that study itself kind of proves, because it was Lovaza, which is the EPA, DHA combo, that DHA can't be negating any because, you know...
Dr. Harris: Well, I suppose the other side can say, well, it would have been much better if it was just EPA, right? It's the 4 grams of...what was important with REDUCE-IT, it's 4 grams a day, which is really five times higher than anybody's ever used before for omega-3 dosing. And that showed benefit. And I think everybody said, "Oh, okay. That makes sense. You know, we got a high dose finally. Now we see some real serious benefits of omega-3." Just wish that STRENGTH had turned out with the same dose, 4 grams a day of EPA plus DHA. Wish it had turned out, but it didn't. So, you know, you take a big risk in these trials.
Dr. Patrick: Right. And you kind of just mentioned what your ideal trial would be with the DHA, the EPA, and the combination of the two and...
Dr. Harris: Who's going to fund that, I don't know.
Dr. Patrick: Any other clinical trial designs that if people are listening, scientists or...
Dr. Harris: Well, I mean, the fundamental thing to do is something you mentioned earlier is to measure omega-3 levels at baseline and only allow people in who've got a below normal, pick some number, exclude people with already high omega-3 because it's potentially not going to help. It's like recruiting people into a statin trial when their cholesterol is, you know, 100. It's silly. There's no nowhere to go. So I think that would be...that's one of the main things to do. And then, of course, to follow it up with an analysis based on blood levels achieved instead of just by group assignment.
A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. Binding to phosphocholine expressed on the surface of dead or dying cells and some bacteria, CRP activates the complement system and promotes phagocytosis by macrophages, resulting in the clearance of apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures very precise levels in the blood to identify low levels of inflammation associated with the risk of developing cardiovascular disease.
An omega-3 fatty acid found in the human brain and the meat of fatty fish. DHA plays a key role in the development of eye and nerve tissues, and is essential for normal brain function in humans. DHA may also reduce the risk of Alzheimer’s disease1 and cardiovascular disease, and may be useful in treating certain inflammatory conditions, such as rheumatoid arthritis. Dietary sources of DHA include krill oil and the meat and roe of salmon, flying fish, and pollock. [1] Patrick, Rhonda P. "Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer’s disease." The FASEB Journal (2018): fj-201801412R.
An omega-3 fatty acid found in the meat of fatty fish. EPA reduces inflammation in the body and helps counter oxidative stress in cells. It is crucial for modulating behavior and mood and has demonstrated beneficial effects in managing anxiety and depression. EPA may reduce risk of developing certain chronic diseases such as cancer or cardiovascular disease. Dietary sources of EPA include herring, salmon, eel, shrimp and sturgeon.
A fish oil-based prescription medication used to treat high triglycerides. Epanova is composed primarily of the long-chain marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). It is supplied in free fatty acid form, in contrast to other fish oil-based prescription medications Lovaza and Vascepa, which are supplied in ethyl ester form.
A chemically modified form of omega-3 fatty acids. Ethyl esters are produced via distillation of the triglyceride form of omega-3 fatty acids. Some evidence suggests they have lower bioavailability than the triglyceride form. Ethyl esters are found in many omega-3 dietary supplements as well as prescription omega-3 medications such as Lovaza and Vascepa.
A prescription-only dietary supplement used to manage high triglycerides. Lovaza contains the ethyl ester form of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). It is typically used in combination with exercise and diet.
A class of drugs that lower blood cholesterol levels by blocking the production of an enzyme in the liver called hydroxy-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). Taking statins may reduce the risk of cardiovascular disease in some people. Although statins are generally well tolerated, as many as 10 – 20 percent of people taking the drugs experience complications, including myopathy (muscle damage), liver damage, and cognitive problems, including issues with forgetfulness, memory loss, and confusion.
A molecule composed of a glycerol molecule bound to three fatty acids. Triglycerides are the primary component of very-low-density lipoproteins (VLDL). They serve as a source of energy. Triglycerides are metabolized in the intestine, absorbed by intestinal cells, and combined with cholesterol and proteins to form chylomicrons, which are transported in lymph to the bloodstream.
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