Slide Lecture with Audio
This CE activity is based on a 40-minute slide lecture presented by Dr. James McKenney. This program is available as read only and with accompanying audio.
*Scroll to read lecture and/or following along with audio.
Hello and welcome to Omega-3 Fatty Acids and the Management of Hypertriglyceridemia: New Findings and Formulations. My name is Dr. Jim McKenney. I am president/CEO of National Clinical Research of Richmond, Virginia, and Professor Emeritus at Virginia Commonwealth University School of Pharmacy. I have served on the last 2 adult treatment panels that have written the national guidelines for treating cholesterol in this country, most recently updated in the summer of 2004. It is my pleasure to be your presenter today. This teleconference is sponsored by Bimark Center for Medical Education. It is supported by an educational grant from Reliant Pharmaceuticals. Thank you for joining us and now let's consider Omega-3 Fatty Acids And The Management of Hypertrigylceridemia: New Findings and Formulation.
To sort of put this into some context, let me just observe the obvious and that is we have spent the last 2 decades in our attempt to reduce coronary events in this country by focusing on LDL cholesterol and I think that focus is fully justifiable. Certainly the randomized clinical trials, of which there are a plethora, involving over 100,000 people attest to the benefit of lowering LDL cholesterol. The last adult treatment panel, in reiteration of treatment guidelines for the country, we begin to focus additionally on triglycerides as a new way, an additional way, to lower the risk of coronary disease. I am going to reference some of that material today. Triglycerides are important. A lot of our patients have high triglycerides in addition to high LDL cholesterol. Think about the metabolic syndrome population of people. Now, something like 25+ percent of the patients we see every day often triglycerides are a prominent feature. Also, think about the diabetic patients of which there is now an epidemic as rising obesity in our country affecting 6% to 8% of the patients we see and that number is growing every day as well. And then finally, just patients who have mixed hyperlipidemia, have either metabolic syndrome or diabetes, but have a mixture of high triglycerides and high LDL cholesterol. So, these are the populations of people we are focusing in on today as we think about omega-3 fatty acids.
The second slide after the title slide shows you the triglyceride continuum. Anything above 200 should be an indication for some attention to triglyceride-related risk. That is in patients who have already had their LDL cholesterol lowered to goal. As you see in this slide, there really are 2 concerns. One is the coronary risk and that patient population is defined by triglyceride between about 200 and, let's say, about 800. That range of triglycerides may include people who have a risk of, an increased risk, of coronary disease because of this level of increase. At the bottom of that left-hand side, you see the reason why is they have this atherogenic dyslipidemia or abnormal remnant particles that are rich in cholesterol or small-dense LDL or increased concentration or number of particles. So, it is a mixture of problems that cause us to call this a dyslipidemia. On the right side, starting at about 500 but especially above 1000 mg/dL of triglycerides is the risk of pancreatitis. Of course, this is a deadly, potentially deadly, risk and should get our attention right away. There are many familial disorders that produce triglycerides in this level. There are some acquired disorders, such as metabolic syndrome and diabetes, that may be found in this area but whenever a patient has levels of triglycerides in that area should get our attention immediately as a patient who is at risk of pancreatitis. So, how do we approach these patients?
Well the next slide, which now focuses specifically on high triglycerides between 200 and 500, and again in a patient who has a risk of coronary disease, the first option is to seek LDL goal. It is tried and true; we know it is going work and it is important. But if the LDL goal has been accomplished and the patient still has a triglyceride level between 200 and 500, then we establish a second goal, that defined by non-HDL cholesterol. Non-HDL cholesterol basically is a cholesterol being carried in all of the particles that move cholesterol from the liver to the periphery. We determine non-HDL by simply subtracting HDL cholesterol from the total cholesterol leaving behind basically VLDL plus LDL cholesterol. The treatment of these patients is first emphasis on therapeutic lifestyle change with a specific emphasis on weight reduction and increased physical exercise. Those 2 things, frankly in many cases, can cure this problem. You also want to eliminate secondary causes, such as poorly controlled diabetes, and sometimes drug therapy, such as beta-blockers, as well as alcohol intake. This, the drug therapy, which we call second-line therapy here, starts with statins of course to get the LDL under control and then additional therapy to help get the non-HDL goal. There you see for the first time fish oils or omega-3 fatty acids. Let me add here, and I am going to show you this in just a moment, there is an additional benefit, we think, from omega-3 fatty acid therapy, in these patients that is achieved through a non-lipid mechanism.
Then the next slide focuses in on those patients who have by definition very high triglyceride levels — that is above 500. Again, these patients have increased risk of pancreatitis and that becomes the principal focus of our treatment: lowering triglyceride levels, in this case not non-HDL, but lowering triglyceride levels to less than 500 in order to prevent pancreatitis. Now you do that, as you look there, by the same kinds of things: weight control, but now really strict weight control; very low-fat diet, something approaching a vegetarian-type diet; obviously physical activity. And here, fish oils have a dominant place because they are very effective in lowering triglycerides, I will show you that in just a moment, as well as fibrate therapy, niacin therapy, and quite frankly, in our clinic, patients who have really severe hypertriglyceridemia, we often end up combining these therapies to achieve best reductions. Statins are not indicated here; they are not the best therapy for lowering triglycerides and resins are actually contraindicated because they may raise triglycerides. But there you have seen 2 different places that omega-3 fatty acids fit in.
In the next slide, I am going to show you the effect of each of the categories of drugs we work with and their effect especially on triglycerides - look at the right-hand column there. You will see that the least effective, but still moderately effective therapies for lowering triglycerides are the statins. Resins are not effective; in fact, they may actually raise triglycerides. Niacin is sort of the next best method of lowering triglycerides, and the 2 best are fibrates and fish oil products. We will talk about now the fish oils and where they fit into the armamentarium.
Take a look at the next slide in which we ask the question, what are omega-3 polyunsaturated fatty acids and how do they differ from other essential fatty acids? Well, as the title suggests, they are essential fatty acids, which means the body cannot produce them; we must consume them in our diet. The omega-3 fatty acids, all depicted on the right column in that box, and you will see there alpha linolenic acid, which is really derived from natural vegetarian-type sources, as well as fish and oils and flax seed and the like, eicosapentaenoic acid, or EPA, and docasahexaenoic acid, or DHA. EPA and DHA are the critical fatty acids of the class called omega-3 that produce the therapeutic benefit. We will be saying a lot about EPA, DHA today. Just a quick look at the nomenclature here, I want you to see that the chemical structure has a proboxy group on the very right-hand side; that is called the alpha end. On the other end, which is called the omega end, if you count the number of carbons between the omega side and the first double bond, you'll see that's always 3 in all 3 of these examples. That's where the name is derived. This is an omega-3 fatty acid, or some people call this an N-3 fatty acid because again, it denotes where the beginning double bond is.
The next slide puts into some context what happens to these fatty acids once they are consumed. They are utilized in a variety of ways, as you see depicted on this slide. The action of cyclooxygenase and lipoxygenase producing ecosinoids and thereby also producing prostinoids and leukotrienes. You recognize this. There are many mechanisms here of disease, especially the omega-6 derived ecosinoids are pro-inflammatory; pain, fever, swelling is involved. Platelet aggregation, vasoconstriction, control of kidney function, reproduction, even weight gain or loss in patients with cancer, so there are many things going on and, quite often, the omega-3-derived ecosinoids are counteractive or at least not as severely active, so they are more likely to be anti-inflammatory. Lots of activity here, which lets you see where everything fits in. So, let's now focus in on omega-3 fatty acid therapy in the next slide.
I already made this point and I want to make it again, because it is key, and that is the critical ingredient of omega-3 fatty acid is EPA and DHA. They are responsible for the therapeutic benefit that we are going to be talking about today. Now I have used already a number of terms, and I thought maybe it might be nice just stop right here and recognize those terms. I have used the term "fish oils" and I want to make sure you understand that that is a very generic term that fish oils do contain omega-3 fatty acids but maybe only about a third or even a quarter of the fatty acids are in fact omega-3. There is many other stuff there, omega-6s and so forth. Then the more precise term is omega-3 fatty acids as it denotes but not all omega-3 fatty acids are EPA or DHA. And then the more specific term would be EPA/DHA therapy. So, where do we get EPA/DHA? The second bullet suggests we can derive, potentially derive, this from a breakdown of linoleic acid, omega-3 fatty acid, which is very prevalent in our diet and easy to get. But, the research is telling us now that not much of that is actually converted EPA/DHA. We have to, more than likely, we have to get EPA/DHA through direct sources so that is primarily the fish source as I will show you on the next slide. Or, if not in our diet, and there are some people of course who do not like fish and do not eat fish, then we may actually take dietary supplements, which are the oils extracted from fish. And then most recently, the FDA has approved a prescription grade of omega-3 fatty acids to be used in the medical management of lipid disorders and triglyceride disorders, which we will be talking about also today. There are 2 doses, or 2 indications, that I am going to track for you. One is the cardiovascular end point or benefit that we think is derived from Omega-3 fatty acid therapy and the dose for that is only about 1 gm/day. Now to lower triglycerides for the prevention of pancreatitis, the dose is higher and typically, at least for the more concentrated prescription-grade, around 4 gm/day.
The next slide shows us where we can find omega-3 fatty acids. And, by the way, this table is taken from a very nice review, if you would like to look at it at some other time, from the American Heart Association, including much more than I would be able to get on this slide, but shows you an average amount of EPA/DHA that is derived from various fish. You can pick out your favorite fish there in the second column. You will see the amount in grams of these fatty acids and the 3 oz. serving of fish in the right-hand column, the question is asked, how many ounces of fish would you need to eat in order to provide 1 gram of EPA/DHA in your diet? Just glancing down that column, you can see that for the most part, between 1 ½ and maybe 4 ounces of most of these fish products is enough to give you EPA/DHA for the prevention of coronary disease, which I am going to show you in just a moment. And then, as I suggested earlier, the other way of receiving EPA/DHA is through supplements and one way, the old-timey way is through cod liver oil. You can see there, you have to take 5 gm/day to get your daily allowance of EPA/DHA from simply the body of the fish will give the extracted from the carcass, as I suggested earlier, produces about a third or less of omega-3 fatty acids so you would have to consume at least 3 capsules of the typical dietary supplement fish oil product in order to get about 1 gram of EPA/DHA per day. The omega-3 fatty acid concentrate — that is another form of dietary supplement. Some of the manufacturers of these supplements have found ways to concentrate the omega-3 maybe as much as 50% of the oil being omega-3-derived. And that case, of course, requires 2 capsules a day. Prescription-grade omega-3 is highly concentrated, producing almost 90% of it in the form of the omega-3 fatty acids and, of course, only 1 capsule a day would be required for that product.
It is important to pause here and take a look at that product, prescription-grade omega-3 fatty acids and the next slide is derived from a very protracted and repetitive distillation process which concentrates the omega-3 components at each step to the point that 85% to 90% of the 1000 mg or 1 gram capsule will be, in fact, delivering omega-3 fatty acids, and the vast majority of that being EPA/DHA. That is an important process, not only in concentrating the active ingredients, but also in eliminating the toxins that may be involved and as you see from the list there, this is a process that does pay attention to the amount of mercury, the amount of toxin that is derived from the fish products and also to assure that there is consistency in the amount of omega-3s being delivered from batch to batch, so it becomes a pharmaceutical grade or a consistent concentration that you can count on to actually dose patients to a certain level and treat them medically for hypertriglyceridemia-type problems.
The next slide shows you a pie chart of the kind of content in each capsule of this prescription-grade product. And there you see about 840 mg of the 1000 mg in the capsule is, in fact, EPA/DHA. Another 60 mg from another omega-3 fatty acid makes this a total of 900 mg of omega-3s per 1000 mg capsule. And the others you see are omega-6, 7, and just other material — again, though, making sure that there is no detectible toxins and other materials that might be disadvantageous. So, that sort of sets up our discussion for the use of these products as we think about various patient groups who have triglyceride disorders.
Let's look first at cardiovascular benefits. And as I suggested earlier, the cardiovascular benefit would be presumed, based on adult treatment panel guidelines, current guidelines, would be presumed to be derived from a reduction in non-HDL cholesterol and actually, that has not been proven for fish oils at this point in time. Research is ongoing. The manufacturer of this omega-3 prescription product is actually conducting studies to demonstrate the ability of these products to reduce non-HDL cholesterol. But there are other apparent benefits, or at least one other apparent benefit, that is derived through a non-lipid mechanism. I am going to show you that. It may be an anti-arrhythmic effect or may be a variety of other things that are occurring here that is important to the cardiovascular benefit. And all this is derived from the results of the GISSI Prevenzione trial shown in the next slide.
This trial, again called GISSI Prevenzione, conducted in Italy, took a look at mortality, the most, arguably, the most solid of end points. Certainly it is easy to count the number of people who are still alive at the end of the study and it is the toughest one to demonstrate. This total mortality study was conducted in 11,324 patients who had experienced an MI within 3 months. Patients were assigned to the omega-3 fatty acids and, by the way, this omega-3 fatty acid product is exactly the same one that has now being, been approved by the FDA and has been made available in this country, so they were assigned to this omega-3 fatty acid therapy or Vitamin E or a combination of the 2 or neither of the 2. And at the end of the follow-up of 3.5 years, you can see that there was a significant 20% reduction in total mortality. And as impressive as that is, I am impressed with the fact that these lines separated literally within weeks of the onset of the study and within 3 months as shown here on this slide, there actually was a significant, already, a significant difference between those who were consuming the omega-3 fatty acid and those who were not. And this is the origin of and the basis upon which we are talking about a cardiovascular benefit that may not be related to the lipid effects of this drug.
Take a look at the next slide, which actually gives you a listing of the end-point results of the GISSI trial. In the fourth column there, you see the risk reduction from all-cause mortality, as I just suggested, was 20% reduction. Cardiovascular death was reduced by 30%, cardiac death by 35%, coronary death by 35%, and sudden death by 45%. As a matter of fact, at the end of the trial, over half of the benefit of the reduction in all-cause mortality, could be attributable to this reduction in sudden death and sudden death is almost always thought of as a ventricular dysarrhythmia, fibrillation, or flutter, produces a sudden loss of life. And so, here is where the suggestion is that maybe these drugs are anti-arrhythmic in some fashion because that would be the mechanism of a sudden death. On the other hand, non-fatal MI, which is reduced substantially with lipid therapy, like statins, is not affected much at all — as you see here only a 4% reduction in non-fatal cardiovascular events — strokes and heart attacks. So, an interesting profile and a different profile than we have typically seen with therapies.
The next slide is a summation of a meta-analysis: 9 different studies, by the way, including about 5000 patients from GISSI, but now a total of 13,000 patients evaluated. These were patients receiving a variety of different doses of EPA/DHA with and without coronary disease and a mean duration of 20 months, but the results turn out to be very similar. That is, overall mortality in these 9 trials was reduced about 20% as you see on the right-hand side there. In the middle, the sudden death reduction was 30% and that accounted for the majority of the reduction in total mortality. Non-fatal MI did not reach significance. The line of confidence intervals crossed the line of unity and so was not found to be significant as a contributor to a reduction in mortality. Let me put this in some context.
I want to share with you a study that was just recently published in the Archives of Internal Medicine is each of the categories in lipid-lowering therapy were examined for their impact on total mortality and in this slide, you see the statins very clearly, significantly reduced totally mortality in the 33 trials that were evaluated. The only other form of treatment that matched that, and actually somewhat exceeded that, was omega-3 fatty acids and the 12 trials that were included in this evaluation. These are very impressive data that omega-3s, which I do not believe have become a part of the mainstream of treatment of these patients, actually has a pretty significant effect on this component-on mortality, which perhaps, arguably, is the most important, at least one of the most important features of our treatments. So, this, of course, raises the question, "What is going on and why is this cardiovascular benefit being realized?" As I have suggested, the wide thinking is that there is some anti-arrhythmic benefit being derived from the omega-3 fatty acid therapy. There is lots of science being developed around that. There is some demonstration in animal models that there are direct benefits, anti-arrhythmic benefits, of these omega-3 fatty acid therapies. There was a recent trial in which omega-3s were given to patients who had implantable defibrillators with the thought that maybe omega-3s could improve the incidence of ventricular flutter and fib in those patients. It turned out that was not the case and probably argues the point that that case with patients with implantable defibrillators is sort of a different problem than the patient with a coronary risk. This is going to have to be worked out over the course of the next years. It is argued that the anti-platelet effect may also be important as thrombus, sudden thrombus development in an atherosclerotic plaque may produce enough genesis for dysarrhythmia which could kill the patient.
The next slide on blood pressure may also suggest another mechanism, although I think this not quite reaches the significance of the first 2 comments but it is nonetheless important to point that omega-3 fatty acids, at the doses we are talking about here, do produce a very modest, extremely modest, reduction in blood pressure. We are talking about 1 gram a day so we are talking about the effect on blood pressure on the left-hand side there less than 3 grams/day and you see the reduction in systolic/diastolic is on the order of 1.3/0.7 mm in blood pressure. Perhaps more to the point and more of an enticing explanation is the effect on heart rate and that is shown in the next slide.
Some work from Dr. Harris, who is an expert in this field, not yet published but his, actually this work, actually a work like it, has been published fairly widely demonstrating that patients who receive omega-3 fatty acid therapy at 1 gram/day, by the way, do have a reduction in heart rate of some size. Here you see the average heart rate was 74 versus 69 in those patients who were on therapy. This may well be important findings in explaining why there is a reduction in sudden death. We will have to wait for the science to catch up with all of this, but I think it is an important part of it. Now I am going to shift even further or to the next rung and ask the question about triglyceride lowering with omega-3 fatty acids. And the mechanisms behind this now are shifting toward more of a mechanistic lowering of LDL and VLDL particles. So, as a matter of fact, patients with high triglycerides, typically VLDL particles that are secreted from the liver are larger and chocked full of triglycerides and so the action of omega-3 fatty acids apparently is to inhibit triglyceride synthesis in the hepatocyte so that the particles that are secreted have less triglycerides in them. I think there is good proof that that does happen. But there also may be some stimulation of fatty-acid oxidation and so these fatty acids are simply not available to be utilized as triglycerides in the VLDL particle. Once secreted into the bloodstream, there are enzymes, most prominently LPL or lipoprotein lipase which helps strip away the triglyceride to these particles and store the fatty acids in obvious places in the body. There is some evidence that omega-3s up-regulate the activity of LPL so all 3 mechanisms, or any of the 3, may be in order.
I think the next slide, which is a look at the kinetics of lipoproteins in patients receiving omega-3 fatty acids helps illustrate what is going on behind the scenes in spite of what the mechanisms may be.
This study was done in 24 men all with essential obesity, all receiving 4 grams, which is the therapeutic dose for triglyceride lowering, and they were assessed at baseline and then 6 weeks later. The pool size is simply the concentration of VLDL and LDL particles at any given time. And there you see under the influence of omega-3 fatty acids, the pool size of VLDL is about a third less, suggesting some of the things I was taking about. The ultimate effect of this therapy is to reduce the VLDL particles, which is the main carrier of triglyceride lipids. LDL is marginally affected by the 5% increase in the pool size. Production rate, the amount of particles that are, that show up, probably from the secretion via the hepatocyte, important to note that VLDL production rate is cut by about a third — again in keeping with what we would understand omega-3 fatty acids to produce. The production rate of LDL particles is actually increased slightly. We think the reason for that is the conversion rate. This is a conversion now of LDL — of VLDL to LDL by stripping away triglycerides, reducing the size of the particle to a point that the particle actually becomes LDL, is actually quite enhanced. That will play out in just a moment in some slides I'm going to show you. Let's take a look then at how omega-3 fatty acids affect triglycerides.
The first slide, I am comparing 2 different studies. I want to make the point: in the GISSI trial where there is the dose of EPA/DHA was 900 mg, the effects on lipids were quite nominal whereas, of course, the effect on total mortality was quite significant. On the other hand, a study by Leaf, with doses of EPA/DHA around almost 8 grams a day in this fairly borderline high triglyceride patient population produced a 25% reduction. So, there is a dose-related effect on triglycerides is the point I am trying to make.
In the next slide, where prescription omega-3 fatty acid is being studied in patients with very high triglycerides, that is over 500, and here is where the prescription omega-3 fatty acid product is actually approved by the FDA for the treatment of patients with very high triglycerides to prevent pancreatitis. Here you see a very substantial effect at a dose of 4 g/day, a 45% reduction in triglycerides. In this study these patients achieved the goal of a triglyceride level of less than 500 after treatment. This is an important effect in reducing pancreatitis risk.
I want you to see in the next slide all the studies that have been done on this prescription product. You can see studies going back actually about a decade ago. This product has been around a long time in Europe and it's just making its way into the United States. There is lots of literature on it; here is an example. In all these examples, the dose is almost always the same, 4 g/day. I have ordered these studies according to the baseline triglycerides so you can get some sense that as the triglyceride levels in the patient population are higher, so is the triglyceride reduction. There is a relationship between the dose of EPA/DHA and also between the baseline triglycerides which will determine its efficacy.
The next slide speaks to the effect of a prescription omega-3 fatty acid effect on HDL, the same population of patients with very high triglycerides. There you see a 9% increase in HDL; that is an important effect at a dose of 4 g/day.
The next slide, again in the same population of very high triglycerides, same dose of 4 g/day, now we are looking at the affect on non-HDL cholesterol. And, I will argue the point, of course, that the most important effect of this population to prevent pancreatitis is the reduction in triglycerides. But you also see, as you would predict from the kinetic study I just showed you, that the VLDL particle concentration is going to reduce, therefore the VLDL cholesterol is going to be reduced and there you see a fairly sizable reduction. But the LDL concentration may actually increase somewhat as you shift or strip away triglycerides from the VLDL particles and shift them to the LDL side. Overall, importantly, however, the total cholesterol in these atherogenic particles is reduced. There you see — 14%. That is phenomenal, by the way, increasing the LDL and decreasing VLDL is very typical of the other therapies also. For example, fibrates and niacin are no different in that effect than fish oils.
And here is the illustration. Here is a head-to-head comparison. Patients were randomly assigned on this particular study to either gemfibrozil or to omega-3 fatty acids and you see the profile across the top there giving you the baseline triglyceride, VLDL, and LDL levels and you have seen, you see there the percent impact, percent change, with each of those therapies: 4 grams of prescription-grade omega-3 fatty acids and 1200 mg. of gemfibrozil, a very comparable profile, quite frankly. Nothing in the high 40s reducing triglycerides, substantial reductions of VLDL cholesterol and the increases in LDL cholesterol.
And in the final slide of this series is the effect of these products on triglycerides in combination with the statins. This is the best study I could find but it is not the best study because triglycerides were barely abnormal, arguably not abnormal at 151, but nonetheless in the highlighted row there for triglycerides, I wanted you to see that there may be an additive affect between, in this case, atorvastatin and omega-3 fatty acids, both of which lower triglycerides, and in this case it looks like there is an additive affect on lower triglycerides when used together. And, in particular, I want you to see the remnant particles which carry this also atherogenic cholesterol is substantially reduced with the combination of the 2. So, that holds hope for the combination of a statin/omega-3 fatty acid therapy.
So in the final analysis, how do we use these products? Here are the recommendations from the American Heart Association and then from the National Cholesterol Education Program. Most patients without coronary disease should eat fish at least twice a week, the American Heart says. In fact, lay patients who have coronary artery disease ought to be considered candidates for 1 gram of EPA/DHA per day but this is something that is done in the context of a physician's management of the patients not something that should be done by the patients themselves. In fact, the FDA has suggested that that would be against the concept here. It is likely, however, that cardiologists will be using the product this way and you may see this in your pharmacies and practice. Then finally, patients who need to lower their triglycerides, that is when around 4 grams of EPA/DHA will be prescribed under a physician's care to prevent pancreatitis.
According to NCEP, ATP III guidelines for cholesterol management, these are very similar kinds of recommendations. Patients with high triglycerides as an alternative to fibrates and niacin, omega-3 fatty acids may be used and in patients with coronary disease, same kind of setup. As an option, the physician may wish to use this to prevent coronary events, especially to reduce death rates.
Now I want to turn to a few comments about the adverse events. These products turn out to be very well tolerated and the adverse events associated with them are quite small. We have to be concerned and mindful of the potential for environmental toxins to be included in these products, and so we will pay attention to that. I will have a slide to tell you about that in just a second. Because there is a reduction in the platelet aggregation of omega-3 fatty acid-treated patients, bleeding time may be changed to the point that some bleeding episodes could, at least theoretically, occur. In the studies in which these products are used for extended periods of time along with either aspirin or warfarin, the context of bypass surgeries and PTCAs procedures, bleeding is, frankly, just not reported. However, some antidotal reports of bleeding and bruising especially have now begun to surface as patients are being treated with a combination of aspirin plus clopidogrel and on top of that omega-3 fatty acids. I think bleeding episodes is still an issue we need to be mindful of them. The most obvious side effect, although again occurring in the minority of patients, is this fish taste or burp that some patients who take these products have or just upset stomach that comes along with it, dyspepsia. They claim that there may be a weight gain but quite frankly, 1 gram of fish oil omega-3 fatty acid, especially prescription grade, just 1 capsule a day produces only 9 calories a day to your diet and so that is not going to have an impact on weight.
The next slide shows you some of the side effects reported with the prescription omega-3 fatty acid product. Note that the top one there, the discontinuation of the product because of adverse events is quite small in only 1% of patients above placebo discontinued therapy. And then under "digestive," the eructation, which is belching or burping, maybe only about 2 ½ % of patients above placebo actually had that side effect. And then taste reversion in the last row in that table, again about 2 ½% of patients had some taste reversion who were taking the fish oil problem.
One of the most important, I think, issues is shown on the next slide is the mercury level or the presence of other toxins, such as dioxin and other pesticides, that are in our rivers and waterways. Fish who breathe water are going to have a certain level of mercury and other toxins in them. And, quite frankly, those fish that are the largest that augmentally breathe the water but also eat the smaller fish have this additive impact of higher mercury levels. So, the larger the fish, the more likely the concentration of mercury is going to be higher, such as in swordfish or king mackerel, tile fish and sharks. Tuna may also be on that list as it is a very large fish. Smaller fish, such as trout and bass, have intermediate concentrations of mercury and small fish, such as catfish and the shellfish, are going to have very low concentrations. So, how we, when we eat fish to get our omega-3s, we actually may be taking in some of these toxins thereby. Look at the analysis of mercury in omega-3 supplements and you see that even in some of those products, there is negligible amounts of mercury being detected even though you would not predict that because mercury is a water soluble, and you would not expect it to be much in the way of oil from these products, but there is detectible amounts. I think that is an important observation.
The prescription-brand omega-3, which is shown on the next slide, because of the quality assurance that must be a part of its manufacturing, does not detect heavy metals or these dioxins and other polycarbons. That is an important quality assurance agreement. From a practical point of view then, omega-3 fatty acid dietary supplements may be available for patients who do not like to eat fish who simply want to supplement their diet with a dose or 2 of the fish oil per day, but when you get to the point of actually treating hypertriglyceridemia for either cardiovascular risk or for pancreatitis risk, we are probably talking about, not talking about the use of dietary supplements, we are talking about using a more refined product.
As shown in the next slide from Consumers Reports, one would have to take an inordinate amount of capsules of these dietary supplements in order to get to a dose that is realistic.
The next slide is simply to remind you that there is a vast difference between dietary supplements and how they are regulated. Their proof of efficacy is not as great as prescription products, and so if we are actually going to use these products to manage medical issues with respect to triglycerides, we certainly should understand the differences between these products and select accordingly. I think this gives pharmacy a great opportunity to interact with patients and you may have heard some things I have said that will be important for you to review with patients and with the prescribers.
I have listed here on the next-to-last slide some of the things I think that would be included. There certainly could be others but I think the patient needs to understand what is trying to be accomplished with omega-3 fatty acid therapy, why they are taking this medicine. I think if they are at risk of pancreatitis, it is especially important that they be encouraged in the strongest possible way to comply with their diet, with their therapy, and other recommendations for keeping them alive basically, and preventing pancreatitis. If the patient has taken aspirin and especially along with clopidogrel or warfarin, I think there ought to be some warning about bruising and the importance of reporting that. And then, finally, I think it would probably be a good idea to ask patients to take their therapy with food, as was done in most of the clinical trials.
In summary today, I have tried to review for you the 2 forms of triglyceride issues: the high triglyceride levels that are associated with atherogenic dyslipidemia and coronary disease and the very high triglycerides that are associated with pancreatitis. I tried to point out to you in the patients with high triglycerides that the standard of care is lipid LDL lowering and non-HDL lowering. The fish oils may help us with non-HDL, although that is under investigation, but most especially, at 1 g/day, they seem to have this effect, important effect, on reducing mortality. On very high triglyceride patients, I have tried to make the point that fish oils are important to us in helping to lower trigylcerides and preventing that problem. And then, finally, I think the prescription-grade product is going to be of a great advantage as we try to manage patients at risk from these triglyceride disorders.
