Triglycerides: Is It the Company They Keep?
Triglycerides: Is It the Company They Keep?
Hi. I'm Dr. Henry Black. I'm Clinical Professor of Internal Medicine at the New York University School of Medicine, a member of The Center for the Prevention of Cardiovascular Disease, and immediate past president of the American Society of Hypertension.
We have made enormous progress in using pharmacologic agents to reduce cardiovascular risk factors -- blood pressure and cholesterol in particular. One of the things that my colleagues, Dr. Howard Weintraub, who has joined me today, is particularly good at and interested in is how do we treat some lipid disorders, particularly high triglycerides. Is this really a risk factor?
Howard S. Weintraub, MD: Henry, you are reading ahead. Many people feel that triglycerides alone, particularly when they are subjected to meta-analysis don't hold up as an independent risk factor, because largely they migrate with a disease that you are eminently familiar with: hypertension, and low HDL [high-density lipoprotein] and obesity. It's the company it keeps. Unfortunately the treatment of obesity has not been all that successful and an organization with which you are familiar, the US Food and Drug Administration (FDA) has not been enthusiastic.
Dr. Black: Does it really matter whether it is an independent risk factor?
Dr. Weintraub: Let's put it this way: We should address triglycerides because the underlying cause of them which is obesity and/or diabetes is something that we don't adequately treat.
Dr. Black: But generally if a patient has just high triglycerides, pancreatitis seems to be the biggest thing.
Dr. Weintraub: Exactly, and between 200 mg/dL and 500 mg/dL is the level just below the pancreatitis risk. It depends on which meta-analysis you read. Sarwar in 2007 reported in Circulation a compendium of 7 studies in which there was a relative hazard ratio of 1.7 with triglyceride levels that were between 200 mg/dL and 500 mg/dL.
Dr. Black: With no other risk factors?
Dr. Weintraub: Right.
Dr. Black: But again, does it really make that much difference? Most of the time we see people with high triglyceride levels who have something else.
Dr. Weintraub: Exactly, but a more recent meta-analysis did not suggest that triglyceride levels were independently predictive. When you did not do multivariant reduction and you didn't look at high-density lipoprotein (HDL), blood sugar, blood pressure, obesity, abdominal girth, or when you looked at them, it fell out substantially.
Dr. Black: It's hard to find a patient who fits that number and doesn't have one of those things.
Dr. Weintraub: Exactly correct. And as you know, the partners in pharmaceuticals would be very discouraged if we didn't treat triglycerides.
Dr. Black: So what do you do with someone with metabolic syndrome, which is an element of diabetes?
Dr. Weintraub: We would make every effort to have them recognize the role of lifestyle in this and that would be watching their diet, both qualitatively and quantitatively (to not get into this in length). The treatment of blood pressure in this patient is extraordinarily huge. Clinicians undertreat blood pressure in these patients, perhaps because of some ambiguity that has been generated in some trials, which is unfortunate. The recommendation for a patient who has a mixed lipid abnormality is to first treat them with a statin drug. That is important, because our first goal of treatment is low-density lipoprotein (LDL) and our next goal of treatment is non-HDL cholesterol, because that is where we have some epidemiologic data. Non-HDL is the total cholesterol, minus the HDL, and whatever your LDL goal was, adding 30. So for example if your total cholesterol is 200mg/dL, your HDL is 40 mg/dL, your non-HDL is 160 mg/dL and if your LDL goal for this patient was 70 mg/dL, your non-HDL goal is 100 mg/dL.
Dr. Black: Now after the patient has the statin on board and his LDL is down to 85 mg/dL, what do you do next?
Dr. Weintraub: That's a good question. The next step would be to look at HDL as a discriminator. If HDL is low, I go for a drug that has trial data; we have 2 very good studies imminently coming forward. One that we are doing in this country, which unfortunately may be underpowered, is called AIM-HIGH [Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes], which involves a statin alone vs. a statin plus Niaspan. A study that is being conducted in the United Kingdom by the Heart Protection people is called THRIVE [Treatment of HDL to Reduce the Incidence of Vascular Events], which looks at a statin plus Merck's proprietary combination of niacin and a prostanoid that reduces flushing. So that's a larger, better-controlled trial. All the other niacin studies have been about plaque -- Greg Brown's data from Seattle, and other studies. This study will look at events and it will be able to tell us whether there is a relationship between triglyceride reduction and reduction in events. We know only that high triglyceride levels are correlated with events, but we don't know whether lowering triglyceride levels matters. For example, in a study called VA-HIT [Veterans Affairs High-Density Lipoprotein Intervention Trial] they were able to identify a group of individuals who had myocardial infarctions but who were not on statins - had not needed statins because their LDL was 100 mg/dL or lower. These patients were given gemfibrozil, a fibrate, and investigators were able to discriminate that the effect was based on HDL change.
Dr. Black: But that HDL change was pretty trivial, wasn't it?
Dr. Weintraub: It was in the single digits. Hanna Rubins, who was the lead investigator, insisted that the 23% reduction in triglycerides was not the motivator. That is why I'm saying that when you look at the guidelines for triglycerides, but they are not derived from event-driven piece of information.
Dr. Black: So what do you do if you are successful with LDL and the HDL is okay - how do you get the triglyceride level down?
Dr. Weintraub: The first choice, if triglycerides are my target, is a fibrate. If the patient is on a statin, I would start fenofibrate. Fenofibrate comes in 2 flavors now; one is fenofibric acid, which is not a prodrug -- it's the active component. Fenofibrate has to be metabolized into fenofibric acid. The commercially available forms are TriCor and Trilipix. If the triglycerides are not quite as high, there are 2 other choices. One would be Niaspan, which is a very good drug. We have plaque data with it, and we have some event data with the older nonsustained release tablets. The other choice would be fish oil. Now fish oil has become very popular, it's an extraordinary market. I was floored when I heard that the market for prescriptive fish oil exceeds a billion dollars a year.
Dr. Black: That's astonishing.
Dr. Weintraub: The amazing part is, that's in excess of all the stuff that Costco and all the other people sell. Currently in this country the indication for prescriptive fish oil is a triglyceride over 500 mg/dL. I can assure you, based on the statistics of the epidemiology; they are not just treating people whose triglycerides are more than 500 mg/dL. They are throwing fish oil at everybody.
Dr. Black: Is this the fish oil that you buy in the store?
Dr. Weintraub: No, this is the stuff called Lovaza. It is a combination of 2 omega-3 fats, DHA and EPA. Recent data would make some of us question the wisdom of doing this. I wrote a review article with Arthur Schwartzbard that was published in October 2010. Some of the data truly don't support the role of the currently available prescription fish oil.
Dr. Black: Why do you think it became so popular?
Dr. Weintraub: People perceived it as natural. How bad could it be for me, it's natural? It comes from these good things that swim in the water and are called fish. Doctors tell me to eat fish, why not just take a pill? It doesn't smell bad.
Dr. Black: With the type you buy in a healthfood store, you need to take a much larger dose and it does smell funny.
Dr. Weintraub: Yes and not only that, you don't know how much mercury you are getting in the process because our FDA has no role in quality evaluations for this product. Any part of the fish that they can squeeze oil out of is what you are going to get. The ratios of EPA and DHA are also different. Recently, if you listen to one of the commercials on TV you will hear them say that some people will have a rise in LDL when they take this fish oil, a rise that can be up to 20%. Now imagine the chagrin of the patient who is exuberant about the reduction to a statin and all of a sudden their triglyceride become a little disordered, they go on fish oil, and all of a sudden their LDL rises by 20%.
Dr. Black: Do people gain weight taking this?
Dr. Weintraub: They can but it's more related to the fact that there is a change in your LDL composition, you make more LDL, and actually your LDL can rise.
Dr. Black: Do we have any events trials using that compound?
Dr. Weintraub: No we don't. Yes there is one called the GISSI study (from the Italian group) in which patients were post-myocardial infarction and on 1 g a day. In otherwise healthy people, a study was conducted in Japan, called JELIS [Japan EPA Lipid Intervention Study], which used an EPA-containing compound. EPA does not raise your LDL, and Japanese men who took statins plus this EPA compound had a significant reduction in events. We know how things work. A company is now vying to bring out an EPA-only fish oil. They obviously smelled the air, took a look at this money and said "Wait, there are a billion dollars that people are spending on this, count us in."
Dr. Black: Natural products don't get tested the way pharmaceuticals do, and I wish they would.
Dr. Weintraub: It's extraordinary that people can make this little comment, "By the way, for those of you who are on statins and otherwise, if you take this drug your bad cholesterol may go up, and poof!" They don't say anything more. You can be sure that if a lot of people using this medicine paid attention to this little commercial, some of the exuberance may be tempered.
Dr. Black: Thanks very much Howard.
Dr. Weintraub: Thanks Henry.
Hi. I'm Dr. Henry Black. I'm Clinical Professor of Internal Medicine at the New York University School of Medicine, a member of The Center for the Prevention of Cardiovascular Disease, and immediate past president of the American Society of Hypertension.
We have made enormous progress in using pharmacologic agents to reduce cardiovascular risk factors -- blood pressure and cholesterol in particular. One of the things that my colleagues, Dr. Howard Weintraub, who has joined me today, is particularly good at and interested in is how do we treat some lipid disorders, particularly high triglycerides. Is this really a risk factor?
Howard S. Weintraub, MD: Henry, you are reading ahead. Many people feel that triglycerides alone, particularly when they are subjected to meta-analysis don't hold up as an independent risk factor, because largely they migrate with a disease that you are eminently familiar with: hypertension, and low HDL [high-density lipoprotein] and obesity. It's the company it keeps. Unfortunately the treatment of obesity has not been all that successful and an organization with which you are familiar, the US Food and Drug Administration (FDA) has not been enthusiastic.
Dr. Black: Does it really matter whether it is an independent risk factor?
Dr. Weintraub: Let's put it this way: We should address triglycerides because the underlying cause of them which is obesity and/or diabetes is something that we don't adequately treat.
Dr. Black: But generally if a patient has just high triglycerides, pancreatitis seems to be the biggest thing.
Dr. Weintraub: Exactly, and between 200 mg/dL and 500 mg/dL is the level just below the pancreatitis risk. It depends on which meta-analysis you read. Sarwar in 2007 reported in Circulation a compendium of 7 studies in which there was a relative hazard ratio of 1.7 with triglyceride levels that were between 200 mg/dL and 500 mg/dL.
Dr. Black: With no other risk factors?
Dr. Weintraub: Right.
Dr. Black: But again, does it really make that much difference? Most of the time we see people with high triglyceride levels who have something else.
Dr. Weintraub: Exactly, but a more recent meta-analysis did not suggest that triglyceride levels were independently predictive. When you did not do multivariant reduction and you didn't look at high-density lipoprotein (HDL), blood sugar, blood pressure, obesity, abdominal girth, or when you looked at them, it fell out substantially.
Dr. Black: It's hard to find a patient who fits that number and doesn't have one of those things.
Dr. Weintraub: Exactly correct. And as you know, the partners in pharmaceuticals would be very discouraged if we didn't treat triglycerides.
Dr. Black: So what do you do with someone with metabolic syndrome, which is an element of diabetes?
Dr. Weintraub: We would make every effort to have them recognize the role of lifestyle in this and that would be watching their diet, both qualitatively and quantitatively (to not get into this in length). The treatment of blood pressure in this patient is extraordinarily huge. Clinicians undertreat blood pressure in these patients, perhaps because of some ambiguity that has been generated in some trials, which is unfortunate. The recommendation for a patient who has a mixed lipid abnormality is to first treat them with a statin drug. That is important, because our first goal of treatment is low-density lipoprotein (LDL) and our next goal of treatment is non-HDL cholesterol, because that is where we have some epidemiologic data. Non-HDL is the total cholesterol, minus the HDL, and whatever your LDL goal was, adding 30. So for example if your total cholesterol is 200mg/dL, your HDL is 40 mg/dL, your non-HDL is 160 mg/dL and if your LDL goal for this patient was 70 mg/dL, your non-HDL goal is 100 mg/dL.
Dr. Black: Now after the patient has the statin on board and his LDL is down to 85 mg/dL, what do you do next?
Dr. Weintraub: That's a good question. The next step would be to look at HDL as a discriminator. If HDL is low, I go for a drug that has trial data; we have 2 very good studies imminently coming forward. One that we are doing in this country, which unfortunately may be underpowered, is called AIM-HIGH [Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes], which involves a statin alone vs. a statin plus Niaspan. A study that is being conducted in the United Kingdom by the Heart Protection people is called THRIVE [Treatment of HDL to Reduce the Incidence of Vascular Events], which looks at a statin plus Merck's proprietary combination of niacin and a prostanoid that reduces flushing. So that's a larger, better-controlled trial. All the other niacin studies have been about plaque -- Greg Brown's data from Seattle, and other studies. This study will look at events and it will be able to tell us whether there is a relationship between triglyceride reduction and reduction in events. We know only that high triglyceride levels are correlated with events, but we don't know whether lowering triglyceride levels matters. For example, in a study called VA-HIT [Veterans Affairs High-Density Lipoprotein Intervention Trial] they were able to identify a group of individuals who had myocardial infarctions but who were not on statins - had not needed statins because their LDL was 100 mg/dL or lower. These patients were given gemfibrozil, a fibrate, and investigators were able to discriminate that the effect was based on HDL change.
Dr. Black: But that HDL change was pretty trivial, wasn't it?
Dr. Weintraub: It was in the single digits. Hanna Rubins, who was the lead investigator, insisted that the 23% reduction in triglycerides was not the motivator. That is why I'm saying that when you look at the guidelines for triglycerides, but they are not derived from event-driven piece of information.
Dr. Black: So what do you do if you are successful with LDL and the HDL is okay - how do you get the triglyceride level down?
Dr. Weintraub: The first choice, if triglycerides are my target, is a fibrate. If the patient is on a statin, I would start fenofibrate. Fenofibrate comes in 2 flavors now; one is fenofibric acid, which is not a prodrug -- it's the active component. Fenofibrate has to be metabolized into fenofibric acid. The commercially available forms are TriCor and Trilipix. If the triglycerides are not quite as high, there are 2 other choices. One would be Niaspan, which is a very good drug. We have plaque data with it, and we have some event data with the older nonsustained release tablets. The other choice would be fish oil. Now fish oil has become very popular, it's an extraordinary market. I was floored when I heard that the market for prescriptive fish oil exceeds a billion dollars a year.
Dr. Black: That's astonishing.
Dr. Weintraub: The amazing part is, that's in excess of all the stuff that Costco and all the other people sell. Currently in this country the indication for prescriptive fish oil is a triglyceride over 500 mg/dL. I can assure you, based on the statistics of the epidemiology; they are not just treating people whose triglycerides are more than 500 mg/dL. They are throwing fish oil at everybody.
Dr. Black: Is this the fish oil that you buy in the store?
Dr. Weintraub: No, this is the stuff called Lovaza. It is a combination of 2 omega-3 fats, DHA and EPA. Recent data would make some of us question the wisdom of doing this. I wrote a review article with Arthur Schwartzbard that was published in October 2010. Some of the data truly don't support the role of the currently available prescription fish oil.
Dr. Black: Why do you think it became so popular?
Dr. Weintraub: People perceived it as natural. How bad could it be for me, it's natural? It comes from these good things that swim in the water and are called fish. Doctors tell me to eat fish, why not just take a pill? It doesn't smell bad.
Dr. Black: With the type you buy in a healthfood store, you need to take a much larger dose and it does smell funny.
Dr. Weintraub: Yes and not only that, you don't know how much mercury you are getting in the process because our FDA has no role in quality evaluations for this product. Any part of the fish that they can squeeze oil out of is what you are going to get. The ratios of EPA and DHA are also different. Recently, if you listen to one of the commercials on TV you will hear them say that some people will have a rise in LDL when they take this fish oil, a rise that can be up to 20%. Now imagine the chagrin of the patient who is exuberant about the reduction to a statin and all of a sudden their triglyceride become a little disordered, they go on fish oil, and all of a sudden their LDL rises by 20%.
Dr. Black: Do people gain weight taking this?
Dr. Weintraub: They can but it's more related to the fact that there is a change in your LDL composition, you make more LDL, and actually your LDL can rise.
Dr. Black: Do we have any events trials using that compound?
Dr. Weintraub: No we don't. Yes there is one called the GISSI study (from the Italian group) in which patients were post-myocardial infarction and on 1 g a day. In otherwise healthy people, a study was conducted in Japan, called JELIS [Japan EPA Lipid Intervention Study], which used an EPA-containing compound. EPA does not raise your LDL, and Japanese men who took statins plus this EPA compound had a significant reduction in events. We know how things work. A company is now vying to bring out an EPA-only fish oil. They obviously smelled the air, took a look at this money and said "Wait, there are a billion dollars that people are spending on this, count us in."
Dr. Black: Natural products don't get tested the way pharmaceuticals do, and I wish they would.
Dr. Weintraub: It's extraordinary that people can make this little comment, "By the way, for those of you who are on statins and otherwise, if you take this drug your bad cholesterol may go up, and poof!" They don't say anything more. You can be sure that if a lot of people using this medicine paid attention to this little commercial, some of the exuberance may be tempered.
Dr. Black: Thanks very much Howard.
Dr. Weintraub: Thanks Henry.
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