In this presentation, Anand Rohatgi, MD, discusses the use of fish oils and the benefits.
it's a pleasure to be giving this presentation on fish oil here in this conference. And they really thankful for the invitation from dr kneeland, a close friend and colleague from our days at UT Southwestern. So 5, 10 years ago um getting asked this question emotionally 18 fish. Well it was very easy sure why not? How harmful could it be? It should probably help you. But now it's a more nuanced discussion and hopefully this presentation will delve into those nuances. We're gonna focus on three particular fino types pancreatitis, coronary disease and atrial fibrillation for this talk. And as a by way of background, if you focus on the top, Omega three fatty acids are essential fatty acids and they must be obtained via the diet. If you look to the left, the three most common remain omega three fatty acids or alpha linolenic acid, L. A. Acosta, Penton, OIC acid, ePA or doc Saxon OIC acid D. H. J. Um And they're called omega threes because they have a double bond at the third carbon position from the methyl group side. And if you look at the right, this is a nice easy systematic I pulled from the web that shows you how we can get the sources of L. A. D. H. N. E. P. A. Is on the top. You can see the variety of food products that can lead to L. A. And then our body can convert L. A. To E. P. A. And D. H. A. But of course we can directly obtain E. P. A. N. D. H. A. From the foods shown below mostly fatty fish but also chicken and eggs and beef. And then of course we can derive these from um supplements that have highly concentrated and purified forms of both E. P. A. And D. H. A. So focusing on hyper trackless redeem mia and the risk of pancreatitis. Um for example. Uh this is not an uncommon presentation. Um a person with diabetes who has a high trackless ride of 650 mg per disa leader. Not really on any other medications except for their diabetes and also for blood pressure. What is the target? Well actually um elevated triglyceride levels are not targets themselves except when they're very high. So when the triglycerides are elevated but not over 500 in the 200 to 4 99 range the target is actually non HDL and LDL cholesterol. To lower their risk for A. S. C. B. D. Actress Scarlett cardiovascular kids. However If their triglycerides are greater than 500 mg per desk later. Especially with over 1000. Then they do have an increased risk of pancreatitis which can be serious and sometimes even fatal. The target. And that Situation is to primarily reduce the trackless rides down to below 500. To reduce the risk. We look at various lipid lowering agents bile acids of quadrants actually increased request. Right so they're relatively contra indicated in the setting of hyper triglyceride denia collapse. Strong absorption inhibitors have weak effects nicotine IQ. And vibrant acids have strong effects and lowering triglycerides. But they are used less commonly these days because of a lack of um significant benefit or hard cardiovascular outcomes. And then statins have modest effects in the setting of relatively normal triglyceride levels. But when triglyceride levels are very high they can have upwards of 50% lowering interest rates that can be very potent. Then of course the omega three fatty acids, also called Rufus or probably on straight into fatty acids have significant effects at the highest dose is 3 to 4 g of E. P. And D. J. Combined per day. So that lends itself to the main problem. If you're going to use fish oils to lower triglycerides over the counter supplements aren't going to do the trick. Typically if you look on the left most supplements have less than 500 or 1000 mg. So you need about 4 to 5 servings per day just to get to two g and you need double that to get to four g per day which is somewhat prohibitive. Mhm. Which is what leads to their prescription Omega three pupils and their main role there are four prescription strength omega three profiles that are FDA approved for Lowering triglycerides when they're elevated above 500 mg per desk leaders and you can see the four here and there are varying effects on triglyceride lowering as well as their varying effects called. LDL cholesterol. So these are the agents that are available to lower triglycerides. So if you come back to this case really you start with life now we've lost an alcohol in particular significant effects um in being able to lower triglycerides. But if the trickling streams remain above 500 despite lifestyle changes, then it's reasonable to start a medium to high potency statin first. Especially if they have intermediate or high as even the risk. And then you can start concurrent or serial ePA and D. H. A. At four g per day. And these prescription drugs because they're highly purified and concentrated have a lower rate of side effects. But the most common ones are G. I. And skin types of side effects. So moving to cardiovascular risk reduction. The main uh theories behind how omega three proof this work are based on pre clinical observation alone and um focus transitional studies. They have anti inflammatory and anti therapeutic effects. You have favorable effects in the lipid profile and they can stabilize plaques as well as cell membranes. So I'm going to show you a table with most of the main studies but I'm going to focus on reducing and strength. The two main randomized controlled trials that came out recently that really stirred the pot in terms of what is the utility of fish oils. So the reduce it trial was a large multi center randomized double blind placebo controlled trial. Um And they randomized 8000 patients who had either cardiovascular disease or diabetes with at least two risk factors and they had triglycerides at 1 35 to 4 99. So this was a high risk population And they were randomized to a gossip and ethel at four g per day or placebo. And their primary endpoint was a composite endpoint of cardiovascular death, my stroke or revascularization as well as unstable engine up. And the primary outcome was remarkable. There was a 25% relative risk reduction that translated to a 5% absolute risk reduction in a number of years to treat 21. Furthermore, when you look at the uh individual endpoints, in terms of death, there was a 20% reduction in cardiovascular death which was significant and a 13% relative risk reduction in total mortality that was not significant. Most trending in the same direction. And this really generated a lot of interest in using um gossip and ethel for reduction in cardiovascular endpoints Contrast that reduce it trial to strength. The strength came out about a year later strength randomized 13,000 patients. Also, they were high risk um and had high triglycerides. Um And in this case they used omega three car box like assets. And this is a combination of E. P. And D. H. A. And the comparator with corn oil. I failed to mention this but and reduce it. The comparator was a mineral oil placebo and that would become important in terms of trying to interpret the effects of these studies. So in this case this was like corn oil placebo. Primary outcome was similar to reduce it and unlike reduce it there was absolutely no benefit of omega three carb oxalic acid compared to corn. I'll over about five years. Mhm. Looking at some of these studies together um jealous and reduce it where the two trials that were positive both used E. P. A. Without any D. H. A. Component. Um uh jealous was open label without a placebo. In japan. They both had elevated trackless rides over close to five year follow up and you can see here the positive outcomes contrasted that with origin ascend and vital and these were accommodation of primary and secondary populations. They were combinations of ethyl esters. So E. P. A. And D. H. A. At relatively low doses and olive oil or inert placebos as the comparison. I'm also a long term follow up and no apps, no benefit at all. We already reviewed the strength trial and then the last one that was just published in 2020 was oh mammy, this was a trial and elderly age 70 for post M. I. Trial. They also used the ethyl ester a combination of E. P. And D. H. A. And also used corn oil as a placebo A composite endpoint over two years and there was absolutely no benefits here. So why were some trials positive and others negatives? Well it could be related to differences to study population differences in the effects on mediators like lipids. Maybe it was differences in the formulation of E. P. A. Or the fact that some had combination of E. P. And D. H. A. And some only had A P. A. Or it could have been the placebo comparator produce. It was the only trial that had the mineral oil, placebo and all the other ones have some other type of placebo oil. Okay so if you look at comparing reducing and strength in particular um if you look at the effects of the cost and ethel and light orange versus the omega three probe oxalic acid in strength and blue to the far right you can see here that and reduce it a cost and ethel head I greater effect in achieving EPA concentrations. But despite that there were very similar effects on inflammatory marker and adverse lyrics compare that to the placebo oils and the two arms and then reduce it. The mineral oil and light orange had significant elevations in inflammatory marker as well as the adverse lipids. Whereas the corn oil and strength the in blue had almost no effects. So this is why some people suggest that maybe the mineral had something to do with it. Um The overall effects. Yeah this study tries to figure out well if we if the effects are if the fish oils are mediated through the lipid markers and inflammation then let's see what the effects are in another population. So what they did is they took the results of reducing and strength and they figured out what the effects were on LDL and triglycerides and crp. And they mimic that effect in a population study called the Copenhagen general population study. And then they mimicked what the changes in those lipids effects would be on outcomes in this population study comparing it to the trials. So for reduce it, if you compare EU. A. to the mineral oil, the between group difference should be about 12%. That's what they see when they mimic the effects on the lipids and the population big study. But the actual benefit was over double that 25% in the reduce it trial and in strength. If you look at the effects of the fish oil on E. P. A. On lipids versus the mineral oil effect. You see a between group difference that should be about 4% between the active fish oil and the placebo. But strength actually had no benefit at all. So this supports the fact that while some of the effects can be attributed to the mineral oil, placebo and reduce it. You cannot attribute really the effects on the active oils. Um and something else is unexplained is 13%% increased benefit in the reduce it. Trial has some other ideology of its benefits. And of course reduce it is an outlier. But maybe it's not a fluke after all. And I'll show you one or two pieces of data that suggests maybe it's real. So they evaporate. Trial was a study that randomized 80 individuals who had similar risk factor profile as reduce it also elevated trackless rides the same exact random ization. I cost spent ethel's to four g per day versus mineral oils exactly like reduce it. And they looked at C. T. Angiograms of coronary arteries to look at plaque characteristics over 18 months. And what they found was that the A. Casa ethel in orange compared to baseline had significant reductions in black features such as the primary endpoint low attenuation plaque and non calcified plaque. These are considered adverse black features as well as total plaque volume but no effect on calcification and then the mineral oil, placebo had progression in all of these features. So this study suggests that in fact the cost of an adult does have favorable effects on actual plaque characteristics that lead to coronary events. And other studies about 5 to 7 of them have shown similar findings with the consequent metal on C. T. Angiogram plaque characteristics. The mineral oil um effect on progression has also been shown in inert placebos. So if you're not doing anything you see progression in these plastic characteristics. So mineral oil does not appear to be out of portion um To inert placebos when it comes to these black progression characteristics. This study was a better regression of all of the trials on omega three pupils and the specific aquarium point of non fatal ami you can see here and reduce it and vital the vital was not a positive trial but the non fatal M. I. N. Points were positive in both of these trials. And uh an aggregate in this meta analysis there's a 19% relative risk reduction in nonfatal Emma. When you look at by dose of E. P. A. And D H J E P A. The higher the dose you have a further benefit in the risk of non fatal M. I. Whereas in D. H. A. C a slight benefit at the lowest doses but a neutral outcome. Attenuation of the fact that the highest doses of th they all of this supporting the fact that UK really does have a biological effect and that supports the risk of Korea ISMs. And then lastly, a brief mention on the risk of atrial fibrillation, observational studies and pre clinical study suggests that Omega three puffers have favorable effects on arrhythmias and atrial in general. However, if you look at the three randomized trials for high dose omega three preface which includes reduce it strengthened MME You see a 51% relative increase in the incidents of the give you see the similar findings on the lower effect size with low dose omega three professors from these three trials you see a 14% increased risk of incident af and so that's a very consistent signal. Sing in all of these randomized trials. So in conclusion for those who transgress rights greater than 500 new statins and high dose omega three puffers at four g per day to lower their triglycerides below 500 to reduce the risk of paper types. There are four preface that are FDA approved for this indication and limit the number of capsules per day to four. And limited side effects for reduction in cardiovascular risk. There is no consistent effect on low dose or high dose omega three profess, reduce it and jealous. We're the only positive trials and both use pure ePA, the benefit seen with a cost and ethel and reduce it is not fully explained by the mineral oil, placebo or lipid inflammatory effects. Of the club. Studies show consistent effects of VPN reducing adverse Corey black features in a dose dependent reduction in non fatal M. I. The weak signal towards reduction in cardiovascular death. The cost and ethel's FDA indicated for adults who have elevated triglycerides over 1 50 have either cardiovascular disease or high risk type two diabetes. As an adjunct to statins to reduce the risk of my stroke revascularization and unstable angel. and despite most inverse relations between levels of Omega three purpose and risk of af several are randomized controlled trials of both high and low dose omega three proof list and high risk individuals demonstrated increased relative risk, although a small, absolute increased risk of incident a fip, in my opinion, I think there's a chance that epa it's useful to reduce coronary risk and select high risk populations, probably those with low fish intake and with high EPA doses, a subsidy from the vital study that I did not have time to present, suggest that this effect could be enhanced in african americans and merits further study. So, um, in the end, it takes a nuanced discussion to look at all of this and with the patient in front of you to decide whether fish oil is a benefit or not. And with that, I'll end. Thank you very much. Yeah.