**EP340: Fish Oils and Where We Are** **Dr. Auric Bishop:** Welcome, my name's Dr. Auric Bishop. I'm a cardiologist, an author, and a keynote speaker. I'm the CEO of the Healthy Heart Network. I'm all about trying to help people live as well as possible for as long as possible. Heart disease is huge in Australia. Every 20 minutes, someone suffers a heart attack. Most of these could probably have been avoided if only we knew what to do. This podcast is all about helping you understand blood pressure, weight, and cholesterol for better health. If you enjoy this podcast, I would be honored for a five-star review. You can share it with your family and friends. It may well save someone you love. Welcome! Today, what I'd like to discuss is omega-3 fish oil or marine triglycerides. What are they? Where do they fit in? What's some of the research, and what do we know about them? So, a quick reminder: omega-3 fish oils or omega-3 fatty acids include three main fatty acids that we think of: ALA or alpha-linoleic acid, EPA, which is eicosapentaenoic acid, and DHA, which is docosahexaenoic acid. All these different oils have been studied for primary and secondary prevention trials, meaning stopping people from having problems in the first place and preventing people from having problems after they've had an event. There's mixed research and mixed information, so it's important to be aware that that information is a little bit confounding and can confuse the situation fairly regularly. It turns out that not all omega-3 fatty acid formulations are the same, and this is very, very important, particularly for those of us who like the idea of supplementing. When we think about the structure of omega-3 marine fish oils, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), they are very similar. DHA has a slightly longer tail, and it's that polyunsaturated fatty acid that gives rise to the acronym PUFA. There are common garden variety supplements available, and these are the things that you'd buy over the counter. There's a preparation that was produced a number of years ago called Omacor, and quite recently, the new kid on the block is a thing called icosapent ethyl. What's the difference? These preparations are all a little bit different, and we've just started talking about marine fish oils. The actual oils are slightly different; EPA is slightly different from DHA. The common garden variety supplemental fish oil, when it's studied, shows a variable amount of EPA and DHA. It's not TGA (Therapeutic Goods Administration) indicated for the reduction of cardiovascular risk. The manufacturing impurity is the critical issue about this, so I'm going to touch on this presently. What class or classification does it have to fulfill? It only has to fulfill a food classification; it doesn't have to fulfill a drug classification. It is unknown what impact the standard garden variety over-the-counter fish oil tablets have on LDL-C, the so-called bad cholesterol. Omacor, on the other hand, is a drug. It is at a purification, which is pharmaceutical level. It's strictly regulated in Australia; it's not TGA approved, and its contents are a combination of EPA and DHA at approximately 460 plus 380 milligrams of EPA and DHA, respectively. This means that we're talking about 900 odd milligrams of marine triglyceride. The new kid on the block, icosapent ethyl, is only one component of marine triglycerides—only icosapent ethyl, which breaks down to EPA in the body. This is a very pure form of one of the forms of marine triglyceride. It is TGA approved for the reduction of cardiovascular risk. It is strictly regulated because it's a pharmacological agent and therefore very pure. Its impact on so-called bad cholesterol is that it's neutral. So that's the ground or foundation that I want to put in place: two drug options, highly purified, and multiple over-the-counter options that we can access at our local chemist, through the net, or at our local vitamin store. So, lots of people do take these vitamins. Well, there was a study done in New Zealand. They used Australian and New Zealand products. The study was done back in about 2014. The authors looked at multiple different types of fish oil that are common on the market, looking for whether they really delivered on what they promised. It turned out that only three out of the 32 supplements contained the EPA and DHA that was said on the label. Most of them contained about 60 to 70% of what was advertised. But really importantly, most of them exceeded the levels of oxidation that are recommended to try and ensure that the oil is fresh and works. Only 8% of the supplements, the 32 odd supplements that were reviewed, met the recommendations for oxidation, meaning that they were going to be effective and therefore therapeutic or at least beneficial for the individual taking them. Some of the brands that we would be aware of include things like Blackmores Fish Oil, which is quoted at 1000 milligrams. The triglyceride in there is 300 milligrams, with EPA being 180 milligrams and DHA 120. So, 1000 milligrams on the bottle, but only 300 milligrams actually in there for each capsule. The rest is made up of saturated fatty acids. The same story was found with Blackmores Triple Strength and Nature's Way Odorless Fish Oil. We're talking about displayed or advertised milligrams on the jar that really just do not match up with what was measured when these agents were subject to strict critical scientific analysis. Importantly, what was making up the difference was saturated fats and other fats. So these could have been anything, really. As far as we know, saturated fats, because we've learned this before, will raise LDL cholesterol. So it's quite possible that people are taking these fish oils with a well-meaning intent to try and improve their cardiovascular health, but because of the impurities, they may actually be undoing some of the good that they're hoping to achieve. The story gets even more complicated because when you drill down and look at those marine triglycerides separated out to EPA and DHA, people have been doing research on EPA alone and EPA plus DHA together. When they've done studies on this, and there's complexity around doing these studies, they've found that EPA has been shown to reduce major adverse coronary events in high-risk statin-treated individuals. This is a study that came out fairly recently, and I'll talk about it a little bit more in a moment. The combination of EPA and DHA has not replicated that result. So isn't this interesting? Our over-the-counter supplements have a combination of both with impurities. The research to date tells us that the only component that's been shown clinically and scientifically to reduce major adverse coronary events is pure EPA. So how does it work? We believe that EPA maintains normal cholesterol distribution, preserves membrane stability, and importantly, it seems to interact with nitric oxide. It reduces plasma triglyceride levels as EPA alone. EPA plus DHA both do that. But triglyceride levels are quite possibly an innocent bystander or simply a marker of metabolic processes that are going on, meaning that altering the triglyceride levels on their own may not be the driver of the cardiovascular benefit that we see with these agents. There is certainly evidence that EPA and EPA plus DHA reduce inflammatory markers, which is pretty exciting. EPA can reduce lipoprotein oxidation, and these are things that we believe are important, particularly in the formation of atherosclerosis. The other thing that's really important in the concept or in that process of atherosclerosis is that EPA has been shown to localize vulnerable plaque, leading to plaque stability, a thickened fibrous cap, reduced inflammation, and reduced cellular density within those high-risk plaques within the arteries, therefore giving a real chance to reduce future risk. EPA also appears to have a role in improving glucose tolerance and working towards those metabolic processes that may well be behind features like raised triglycerides and raised inflammation. So what are some of the trials that fatty acids have been shown to be beneficial in? Well, when you bunch them all together, it's hard to see a benefit. There have been multiple trials over the years, and when you combine all the data, it's really not very compelling that there's a cardiovascular benefit from all the trials that have been done. You can't just throw all the information, which looked at relatively low or single tablet interventions to multiple tablet interventions with single marine triglycerides or combined marine triglycerides. When you throw all those together, there just isn't a profound signal that it's useful. Even with some recent trials looking at EPA and DHA using both of those marine triglycerides, there are a couple of major trials called Vital, Ascend, and Strength. Each of these was looking at reasonable doses of those omega-3 supplements. The dose in Vital and Ascend was in the order of two tablets, while in the Strength trial, it was four tablets. These first two trials were in primary prevention, while Strength was in high-risk secondary prevention individuals. Nonetheless, this intervention, even though it was looking at large numbers of people, just didn't seem to show benefit with using these omega-3 oils as a supplement to these individuals. As a supplement, it didn't seem to show improvement in major endpoints. However, when you tease out some of the detail around EPA and EPA plus DHA, it turns out that if you look at the EPA trials alone, specifically for cardiovascular disease outcomes, there are three major trials called the JELUS trial, the RESPECT EPA trial, and the REDUCER trial that all produce a signal suggesting that EPA in reasonable dosing has a significant clinical statistical benefit in reducing cardiovascular disease outcomes. So, the JELUS trial was run in Japan with men and women with elevated cholesterol. The RESPECT trial was again in Japan. Japan tends to lead the world in some of their management of omega-3 oils. Interestingly, not only do they have experience in the interventional trials, their diet tends to leave their population with the highest levels of omega-3 oils. Importantly, a recent trial called the REDUCER trial enrolled men and women with established cardiovascular disease or a cardiovascular disease equivalent if they had raised triglycerides. Now, those raised triglycerides historically have been something that we've wanted to use fish oil to treat. In the REDUCER trial, they looked at taking these people with those high triglyceride levels and enrolling them into the study. Remember I said that there's a chance that those triglycerides alone are not the active component or the causative agent that we're looking to modify. They're quite possibly just the representative bystander, if you like, of a process that's occurring. So, really nicely, we've seen that the JELUS trial in primary prevention was negative, but all the other trials were positive in secondary prevention, including RESPECT and REDUCER. Importantly, we know that in REDUCER, particularly because we've seen that recently, they had maximized or really improved cholesterol lowering and looked at reducing the risk of recurrent events in individuals. By the addition of these omega-3 oils, we were able to see a 15 to 20% relative risk reduction of future events. Now, it's been a holy grail to try and find ways to reduce second, third, fourth events and so on in individuals who've had a cardiovascular event because it's a big deal, basically. So where does all that leave us? Well, the clinical trials using low-dose omega-3 fats for cardiovascular prevention are inconsistent. Some of the modern trials where they use EPA and DHA—that's the combination of what you'd get from a fish oil tablet over the counter—have not shown clear cardiovascular disease benefits. There are three main trials using high doses of EPA: the JELUS, RESPECT, and REDUCER trials. All three of those trials appear to have demonstrated a benefit in secondary prevention in the reduction of cardiovascular disease. Interestingly, in the REDUCER trial, they used four grams of EPA daily—two tablets in the morning, two tablets at night. These were one-gram tablets approximately. A reasonable take-home from this, I think, is that the over-the-counter fish oil supplements are not necessarily delivering on what they promise because they only need to fulfill a food quality classification. The over-the-counter preparations are often oxidized and therefore won't work as they should. So how do you get around that? Because highly processed pharmacological EPA is prescription-based and only just making its way to the market here in Australia, the best way around it is actually eating fresh, fatty fish. If you think of a piece of fish of say 200 grams, about 20% of that will be fat and oil. If we think 20% of that, that's 40 grams; you'd get nearly 20 grams of EPA and 20 grams of DHA or at least very high levels. The nice news about that is that these oils hang around in the body and in the bloodstream for a number of days, so the half-life is long enough that you only need to eat fish once or twice a week. Well, I hope you found this fishy story interesting. I think I'll pause there. If you have any queries or questions about what I've just shared, please drop me a note at [email address]. If you've got any suggestions for future podcasts, let us know at the same email address. For now, however, I would like to wish you the very best and hope you live as well as possible for as long as possible. Take care and bye for now. Join the Healthy Heart Network and become part of our growing community. If you're interested in your heart health and the risk of heart attack, then join the Healthy Heart Network for only $5 as a lifetime member. This represents $55 worth of value. 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