Welcome, my name's Dr. Auric Bishop. I'm a cardiologist, an author and a keynote speaker. I'm 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, cholesterol, for better health. If you enjoy this podcast, I would be honoured for a five-star review. You can share it with your family and friends. It may well save someone you love. G'day, it's Warwick Bishop here and welcome to my podcast and videocast station. I really am grateful that you've tuned in and I really hope you find the information informative and interesting and hopefully it helps you. on your best health journey. Look, I'd really like to invite you, if you do listen regularly, please share this podcast because you may be in a circle of people who may appreciate it. So thank you for at least considering that. Today I'd like to pick up on part two of talking about triglycerides. In the first part I spoke about... that a triglyceride is simply three fatty acids attached to a glycerol backbone. And it's probably the most common form of lipid or fat in our bodies. We consume fats, our intestine lining, the cells within our lining, repackage those fats, put them together as triglycerides. bundle them up into things called micelles and chylomicrons which make their way into the blood through the lymphatic system and then to the liver where they're then used and contribute to the very low density lipoproteins the intermediate density lipoproteins and so on we also spoke in part one about triglycerides not actually ending up in atherosclerotic plaque but probably being closely linked to cardiovascular disease, not because they end up in the plaque, but because they're a marker of the metabolic processes that are going on in someone who has raised triglycerides, such processes as insulin resistance, central weight gain, central adiposity, visceral or fat around the organs, so visceral adiposity, things like inflammation as well, raised blood pressure. All these things tend to hang out together and triglycerides sit right in the middle of that nasty pack that we want to avoid. Anyway, if you did miss part one, go back and have a listen. We talk about alcohol as well and how alcohol drives triglyceride levels and diet. But I'm going to go beyond that now. I'm actually going to talk about how we manage triglycerides when they're elevated in an individual. So let's do that because it's super important. Well, when it comes to managing almost any condition, we always try and look at the simple lifestyle manoeuvres as a first step and triglyceride lowering is no different. Importantly, we talk to people about changing their diet. Obviously, if you eat saturated fatty acids, if you provide the body with lots of these long chain fatty acids, then the body can make triglycerides. So the first thing you want to do is stop eating as many fatty acids. That makes perfect sense. So you reduce fat in the diet. We also spoke in part one about how glucose can be converted to pyruvate. can be converted to acetyl-CoA, which ends as a backbone or a beginning or foundational block for the formation of fatty acids. So you want to reduce your sugars as well, your foods that can turn into glucose. Exercise is super important. Does exercise directly alter the triglycerides? the muscles deal with sugars and therefore altering the body's insulin resistance. But the triglycerides can also be used as fuel. So if you're burning more energy, using more energy, then you're going to lower the level of fuel in the body and you're going to lower those triglycerides. Exercise is super important for getting triglycerides down. Alcohol is a big player as well. And if you've listened to part one, you'll understand that Alcohol, through a series of enzymatic pathways, gets converted to acetate. Acetate could also be converted to acetyl-CoA, that foundational building block for fatty acids, and drive more fatty acid production, and therefore more triglycerides. So lifestyle, super duper important. But the remainder of this podcast, I want to talk about two ways. that are not lifestyle one is fish oil and fish oil is probably the most consumed um over-the-counter supplement in all of the western world there's been so much information about it over the years and i think many many people take fish oil uh hoping to be doing the right thing for themselves so i want to talk a bit about that and i also want to talk about a medication that we use for lowering triglycerides This medication is a group of medications called the fibrates, and I'll specifically talk about phenofibrate, but that's later on. Well, what are the fish oils? Well, we talk about marine triglycerides because triglycerides are formed within the ocean, not by fish. Fish actually don't produce fish oil per se. What happens is that omega-3 fish oils are produced by plankton, and those plankton are then eaten by little fish, those little fish by bigger fish, those bigger fish by even bigger fish, and so on, until that oil is passed on through those different levels of the food pyramid. And when we consume fish that have consumed fish, that have consumed fish and so on, that have consumed those marine triglycerides, we get the benefit of those oils. Well, what are the omega-3 oils? Well, we refer to them as eicosapentaetolic acid and docohexionic acid. So EPA and DHA. I'm going to refer to them as EPA. and DHA because they're much easier to say. We know that these marine triglycerides decrease triglyceride production and increase the clearance or how the body gets rid of these triglycerides. And there's a whole lot of trial data to support or give us some information around whether this is useful or not. From years ago, I remember one of the most significant trials was the one called Gisi Prevenzoni, which was done in Italy. That's why I had that slight accent there. Gisi Prevenzoni, or we tend to refer to it as the Gisi P study. It was a fairly large trial, over 10,000 people. The participants were given one gram of fish oil a day versus control. And what they found was a significant reduction in sudden cardiac death. That was a really significant reduction of about 45% in the omega-3 fatty acid group, with a reduction in overall mortality of about 20%, which is... as good as medications we see on the market. Now, it's not a super high dose. It was in a high risk group of people. But this is really a trial that flagged potential good outcomes with this sort of intervention. Very significant. Trouble is, not all trials that followed were quite as glowing for fish oil and subsequent. to GCP was the vital study. The vital study looked at 25,000 Americans adults. They were given a gram of fish oil a day and there was potentially shown a benefit for reduction in heart attack, but no major overall cardiovascular event reduction in a primary prevention population. So in this setting, The vital study took people who hadn't had an event. The GCP people took people who had had a recent heart attack. What does that tell us? Almost certainly, if you've had a heart attack and you could fit into that GCP group, fish oil is probably going to be beneficial for you. Are we so sure about primary prevention? It's a little bit more complicated. Another trial came along called the Ascend trial, looking at about 15,000 people. These were people, again, who hadn't had a problem with their hearts. There was no significant reduction in serious vascular events in the Ascend trial. And again, they used about one gram per day, which is one of those big tablets. This really didn't show a great deal of benefit in terms of primary prevention, even for... diabetic patients. More trials came along, one called OEMI, O-M-E-M-I, which was using again fatty acids, omega-3 fatty acids, on this occasion almost 2 grams in an older population who'd had heart attack. And this did again suggest limited benefit of this supplementation in this population. Again, reminding us that it seems this oil is particularly useful when it comes to individuals who've had an event. The Origin trial came out looking at 12,000 odd people. Again, a gram a day. These are people who looked like they were going to develop diabetes or had early type 2 diabetes. Again, these people hadn't had any cardiovascular event. And if you want, you can guess. There was a question as to whether it was beneficial in terms of cardiovascular prevention. So again, a little bit borderline. The studies that seem to help us are the ones, well, the studies that seem to show a positive impact of the fish oil are the studies where the fish oil has been taken after someone's had an event. But to be honest, that just seems a little bit too late. There was a trial where they've not... used combination for sure, but instead have used one of those marine triglycerides, in particular EPA. And there was a study called the Japan EPA Lipid Intervention Study. If you take those letters, they spell out J-E-L-I-S, Jealous Study. That was done in 2007. They looked at about 18 odd thousand people. The individuals received nearly two grams of EPA. They followed them up for about five years and they were looking to see would there be a reduction in coronary events. It turned out that as I watched these people, EPA was shown to be well tolerated without any significant side effects. And the conclusion was that adding EPA to therapy for these individuals who'd already had other medications could further reduce risk of major coronary events. So a positive trial and interestingly this positive trial using only one component of marine triglycerides. Why is that important? Well there's more to come so we'll cover that in a second. The STRENGTH trial came out in about This was statin residual risk reduction with epinova, which was an official preparation in high-risk cardiovascular patients. They used omega-3 carboxylic acids to reduce major cardiovascular events. They looked at nearly 12,000 individuals with high cardiovascular risk, high triglycerides, despite being on statin therapy. The study concluded that the omega-3 carboxylic acids did not provide additional cardiovascular benefits beyond the statin therapy alone in the high-risk individuals. Again, these individuals didn't necessarily have an event. They were considered high-risk. So, a biggish study, again, causing more confusion. And in 2019, they reduced it. study reduction of cardiovascular events with icosapent ethyl intervention trial and icosapent ethyl is a pro drug for epa so this is really a study of epa alone uh they took about 8 000 people they took high risk uh individuals and uh really just wanted to follow and see what happened so these are people who'd had events but also um people had high risk equivalent features. These are diabetics as well. They randomised these people to icosapendethyl or the equivalent of EPA because it gets converted in the body to EPA and found that the icosapendethyl significantly reduced the risk of major adverse cardiac events in these high risk patients with elevated cholesterol levels over and above the statin therapy. So really interesting, and the relative risk reduction was in the order of 20%. One of the really interesting things when you drill down on this study is that that improvement didn't necessarily relate to the change in the triglycerides, speaking to the fact that perhaps the fish oils were having, and in this particular situation, a cosapent ethyl. or EPA, was having a specific effect on things like inflammation, things like insulin resistance. So very, very interesting, but really supporting again that we're probably seeing some benefit with using marine triglycerides in reduction of risk. I'll pause momentarily here to talk about EPA DHA. feeling to a degree is that EPA is particularly good for the heart. But we know DHA is really important for say development of a baby. So we want to give both marine triglycerides to a pregnant woman to help the baby develop brain and eyes. We know DHA is probably more important for eyes and brain health. So it's very interesting that There's been this separation of these two components, and I'm really not sure myself how to deal with that. Well, when we think about fish oil supplementation and where it all fits, I've just given you a whole lot of studies, but let's step back and look at larger, if you like, more prospective observational. And the Physician's Health Study is an excellent way to get some of that data where they've collected omega-3 levels within the blood and compared that omega-3 ratio in different quartiles. So they've looked at the lowest 25% of omega-3. ratios compared to the next 25%, compared to the next 25%, compared to the next 25%. So what they found is that there's a 90% relative risk reduction in the highest quartile of omega-3 index individuals. So the people with the highest omega-3 levels in their blood consistently had a significant reduction in cardiovascular events. And when they looked at predictors of sudden cardiac death, the single strongest predictor was not cholesterol levels. good or bad, wasn't even inflammation levels, the single best predictor was the omega-3 index. So the lower your index, the greater your risk of dying from sudden heart attack. We know from the PREDIMED study that it confirmed for us that the saturated fatty acids that were 12, 14 or 16 carbon molecules long tended to drive worse cardiovascular disease outcomes. And this could be improved if these C12, 14 and 16 saturated fatty acids could be replaced with monounsaturated fats or polyunsaturated fats, particularly like fish oil, which are puffers. Interestingly also, there's been some observation that the source of saturated fatty acid can be quite important. in trying to understand cardiovascular outcomes as well. So saturated fats from pastries and processed foods tend to increase risk of cardiovascular disease. Saturated fatty acids from dairy probably also increase risk of coronary artery disease. But saturated fatty acids from fish, vegetables, nuts can reduce cardiovascular disease and similarly very Long chain saturated fatty acids. So these are 20, 22 and 24 length saturated fatty acids can also have a positive or beneficial effect on reduction of cardiovascular risk. Well, when we're trying to understand what someone's omega-3 level is, we do an omega. three ratio and that's done by looking at red blood cells we know that if we tried to measure the omega-3 level in the blood free blood it would fluctuate and change from minute to minute depending on what you've eaten as you might imagine if we look at the fatty tissue that's very slow in its turnover so if we took a biopsy of someone's tummy fat and try to evaluate the omega-3 levels, and that would have an idea of what their exposure to omega-3 levels would be, but that would be over months to years, which is probably a bit too long for clinical relevance. It turns out that the omega-3 oils, EPA and DHA, accumulate in the membrane of red cells, and red cells last in our body 90 days. So if we've got levels of EPA and DHA in our red cells, basically three months, we've got a weeks to months measure of what that person's omega-3 consumption and total body level of omega-3 is like. Absolutely fascinating. So fish oils, where are we with them? They certainly seem like a powerful component of a healthy diet. There's no question if you can get fish in on a regular basis. Couldn't recommend that more. I didn't even touch on the epidemiological data, which would really be supportive of fish as a regular component to a healthy diet. Where are we with supplementing? Should you be supplementing? Probably there's a role to be said that if you're not sure about where you are with your omega-3 index and whether you're deficient or not, then there's really a good... argument to be made for measuring and actually testing and knowing where you are. In Australia, the Medicare rebate, there is no Medicare rebate for testing of omega-3 index, so you would have to pay for that out of pocket. The test is about $100, but it would inform where you are. And based on that physician's health study, you know you want to be in that top 25% of omega-3 index to minimize your risk of sudden cardiac death. Also, what do we do in terms of EPA plus DHA or EPA alone? Well, in the cardiac space, I get the sense that we're going to go down the path of EPA in isolation. But for total well-being, so that we're looking after our brains and eyes, I can't help but think that supplementing with both components of those marine fish oils is probably the sensible way to go. Head into the final straight. As I approach the finish line, I'm going to talk about phenofibrates, which is one of the fibrate agents. And these work through a receptor called the peroxisome proliferator activated receptor. And it's an alpha receptor. For short, they're called the PIPA. PIPA. peroxisome proliferate or activated receptor. You don't need to remember that, but phenofibrate acts through that receptor to have an impact on two different components of triglyceride and fat metabolism. One is that PIPA-alpha activates lipoprotein lipase, which increases lipolysis and therefore frees fat into the bloodstream. And PIPR-alpha also can activate APO-C3, therefore increasing triglycerides. So by impacting PIPR-alpha, we can reduce our APO-C3 and therefore reduce our triglycerides. We can alter our lipoprotein lipase. The consequence of vibrate... The consequence of fibrate therapy is lowering those triglycerides. And this has been tested in a study called the FIELD trial. FIELD standing for phenofibrate intervention and event lowering in diabetes. This study was actually run through Australia. They looked at nearly 10,000 patients between 50 and 75 with type 2 diabetes. And most of them had raised... triglyceride levels. The study really didn't show any significant problems with phenofibrate as a medication for the individuals in the trial. But what was found was that the phenofibrate itself did not significantly reduce the primary endpoint of coronary events. So treating the triglycerides alone didn't have a huge impact on outcomes. However, it did have a significant impact on what we would call microvascular complications of the diabetics who were in the trial. So we found that these individuals had improved function of their kidneys. We found they had reduced risk of amputation, which is linked with diabetes. We found they had better... outcomes with their eyes. So the field trial showed us that phenofibrates worked extremely well in some of the associated comorbidities of diabetes and reduced those dramatically, although it didn't have a major reduction in its primary endpoint. So the field trial technically a negative study for the benefit of phenofibrate, but practically showed us that it could really offer great benefit for the diabetic group who was tested in. So where are we with over-the-counter fish oil supplements and how do they tie in with what we've just been talking about? There are a number of issues that are really significant. Probably at the absolute top of the list is quality and purity because over-the-counter supplements don't have the same strict regulations that are required by pharmacological preparations. That quality and purity obviously ties in with efficacy as well and that regulation and labelling is a far less strict situation for over-the-counter. supplements than it is for pharmacological preparations as you might imagine. Probably one of the significant concerns with taking fish oil over the counter is it could be thought to reduce the thinness, sorry, lead to blood thinning if you like and so could potentially interact with other blood thinners and often surgeons will ask individuals to stop their fish oil before surgery. There's possibly a link to some alteration in the immune system as well when it comes to taking fish oil. But in some individuals that could be beneficial, particularly if they have an inflammatory sort of process like arthritis or an irritable gut that's inflamed, the fish oil may well help that. It's important, I think, as, well, global citizens that we think about the... sustainability and sourcing of the products that we use. As always, we have to think about the cost and benefits. Sometimes these supplements can be really quite expensive and you need to be asking for yourself whether it's something appropriate for you or not. So where are we with triglycerides? I believe we would be thinking of them mainly as a marker of metabolic health and of their own. They do not end up in the... coronary arteries and lead to cardiovascular disease, but they are. Because of the company, they keep a significant indicator of who could be at risk. What are the takeaways? Well, diet and exercise are absolutely critical. Reducing alcohol will help. Fish oil probably has a role. Exactly where that sits, exactly what the dose is, and whether it's EPA alone or EPA and DHA together are not entirely clear. We know that they've tried to use fibrids for reduction of triglycerides. And although this had some wonderful outcomes in terms of diabetic complications, it didn't reduce cardiovascular disease as was expected. Well, with that, I'm going to wrap up. I've covered an awful lot. And that's part two of triglycerides and heart disease. And I'm going to exit now. Before I do, I'm going to thank you for listening. That was a long one. If you've made it this far, good on you and congratulations. I really do appreciate you taking the time to listen and I hope I've given you something that you found interesting and informative. For now, I'm going to wish you the very best. As always, I 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 risk of heart attack then join the Healthy Heart Network for only $5 as a lifetime member. This represents $55 worth of value. We offer and help people understand their present state of heart health, what their current level of risk is and the positive steps they can take. to improve their risk of heart attack in the future. Go to www.healthyheartnetwork.com.au and click the join the family button.
