Chapters Transcript Lipid Lowering - Beyond Drugs and Monoclonals Course: Updates in Endocrinology 2025 So, what I'm gonna talk about is um lipid metabolism. I can tell you about some issues that you'll see. Um, I have this basic feeling that there is, um, there is no reason that an endocrinologist should ever refer a patient to a cardiologist for lipid therapy. You should be doing it. And in fact, until statins came in, I don't think uh cardiologists even knew what lipids were. And you probably know that the basic medical textbooks like Harrison's, the lipid metabolism chapters have always been written by endocrinologists. Including me once upon a time. So Uh, these are disclosures. Um, I'm going to tell you about, um, drugs that are by these, several of these companies. We do clinical trials here. Actually, I have another company that we consult for because lipid metabolism is controlled by the liver, and the liver is really an easily targeted organ. So everybody gives their patients statins, and we've been doing this since about the 1990s. I now tell my patients when I start them on statins, I say, you're on statins now, but in 10 years, we're gonna do something different, and I'm gonna give you a sense for that. So, first, the good news for those of us who take care of patients in an endocrine clinic. So, patients that see me with type 2 diabetes, um, sometimes type 1 diabetes, I usually say to them, look, as the endocrinologist, I have two jobs. One is to get your glucose down, prevent you from having ketoacidosis, prevent you from being hospitalized. But my other real job is to prevent you from getting secondary complications. And in the setting of diabetes, the major secondary complication is cardiovascular disease. And then I tell them, here's the good news. So this is a study that came out from the UK looking at people with type 2 diabetes from 20 years ago, actually, and more recently. And if you look at the coloring of it, so, um, circulatory problems are in the different parts of blue, and we look to see what's happened over the 20 years. Cardiovascular disease has markedly dropped. In fact, cancer is a bigger cause of death in this patient population than cardiovascular disease. This is a recent study from Scandinavia. I put a line there to show you, cardiovascular disease in Scandinavia has dropped 60% over the course of 20 years. So what that means is if you have diabetes and you're in Sweden, your chances of having a cardiovascular event are less, are less than somebody without diabetes 20 years earlier. We are really doing a good job. This is the US data. Same kind of thing, cardiovascular disease is markedly decreasing. So I'm actually glad I'm not in charge of the cath lab, because in the next 10 years, if the number of cardiovascular procedures are not dropping, we are doing something wrong because we can prevent this kind of disease. It also is the reason that your colleagues now who are cardiologists are to a great extent seeing people without cardiovascular disease, and you probably see it all the time. They come into you, they say, oh, I've see my cardiologist. I say, do you have cardiac disease? They said, no, but he prescribed statins, you know, he, he takes care of my cardiovascular risk, he takes care of my hypertension and hyperlipidemia. He does primary care. Disease, because there's not enough people necessarily with cardiovascular disease, and it's gonna be even more so in the next 10 or 20 years. OK, so this is what I'm gonna tell you about though. I'm gonna tell you about hypercoagal microemia and pancreatitis, because this is a disease that we now have new therapies for, and if you don't know those therapies, you will, hopefully, by the time I finish. Then I'm gonna tell you something about risk reduction in people or lipid and risk reduction, and then I'm gonna tell you something that's been a controversy. Um, for the last 50 years, which is the role of triglycerides in cardiovascular disease. So these are the findings of severe hyperlipidemia. If you look at the blood over here, let's see. There we go. So When I see a patient who has severe hypertriglyceridemia, I kick their blood while they're in the clinic. I spin it, I hold it up, I guess what the triglycerides are. And I show that to them. So if they have blood that looks like this. They're in trouble. So this is a triglyceride that's about 8000. So how do I know it's 8000? Because it looks like cream. Cream is 8000 mg per deciliter. If it looked like milk, it'd be more like 4000. If it looks like 1% milk, it's like 1000. You get pretty good at doing this, but it's a little bit of a guessing game, and then I pat myself on the back if I'm close enough. But, but I can show it to the patient, and they walk out, and I have a pretty good idea that this person has a real big problem. The other physical findings are lipemia retinalis. I, you look, I always look in people's eyes. If their blood looks like cream of tomato soup and starts to look white like that, they're gonna have a triglyceride level probably 5000 or greater. And the other physical finding is eruptive xanthomas, so they look little papules, they look almost like acne in the back of the arm, in the buttocks, down on the back of the thighs. So those are occur in long-standing hypertriglyceridemia. So, pathophysiology, right? So triglycerides come in two forms. No, they're one form, but they come in two different particles, so you eat a meal. The fat gets reassembled in your gut. It's secreted not into the blood, it's secreted into the lymph, and the chylomicrons circulate. They hit this enzyme lipoprotein lipase, highly expressed in the heart, skeletal muscle, adipose tissue. It breaks some of the triglycerides apart. About 50% of the triglycerides delivered peripherally, and the other 50% in what we call chylomicron remnant goes back to the liver. The other triglycerides are in the particle called VLDL, so this is secreted, secreted from the liver. It's secreted from, it's made from triglyceride that came back from the chylomicrons. It's fatty acid that comes from adipose tissue, so some of your patients with really poorly controlled diabetes will have high triglycerides because those those fatty acids are going back into the liver and coming back out. We also make fatty acids, and we make it from glucose and amino acids. So that circulates as this particle with this terrible name, right, VLDL. If you're not in this field, you forget these names. And it has the name because of how it spins in the centrifuge. But the VLDL are the precursor to atherogenic low density lipoproteins, so we have two forms of high triglycerides. When your triglycerides are above 500 and certainly above 1000. You always have chylomicrons besides just the VLDL. So High triglycerides are the 3rd most common cause of pancreatitis. Um, our house staff almost never misses this. Somebody comes in with pancreatitis, they know, they know. Sometimes the diagnosis is made by the lab techs. They draw the blood, they spin it, they say, oh, your blood is really lipemic. Um, apparently, this is the number 2 cause of pancreatitis in China. Number 3 in America, but number 2, because um I think the government has decided alcohol can cause disease in China. So it has to be triglycerides and gallstones. So what do we do with these patients? So there's some controversy on how you treat this, because just like you heard from Nan, this is not a field where there are randomized controlled trials. So there are no real randomized controlled trials of people showing up with hypertriglyceridemic pancreatitis. So people do things that seem reasonable. So, sometimes people get insulin drips. We do that on people with high triglycerides. The goal is to block the fatty acids from coming out of the adipose tissue and going back to the liver. You might think that the role of insulin is to lower glucose, but the real role of insulin is to prevent fatty acid from coming out of the adipose tissue. Just by accident, it also lowers the glucose. Um, so we do it and we do it at very low dose. If the patient has diabetes, obviously, you have to give them more insulin, but very low dose insulin, like one unit an hour, mostly will stop lipolysis in the adipose tissue. Triglycerides drop. So sometimes we just watch the people, sometimes we do this. Um, there's no great evidence for plasmapheresis. I think I've done it once over decades and decades. It was somebody we wanna get their triglycerides down out of the hospital and back to Florida. But otherwise, no great evidence. Sometimes you do it in somebody who's pregnant, near the end of pregnancy. You treat the pancreatitis. You make sure that they don't give them propochol because propocol is dissolved in intralipid. And then when they're out of danger, you treat them with a fibrate. You could probably start the fibrate in the hospital. We do discharge people with triglycerides of 1000. They're told to exercise, they're told to put on a diet. Um, there are data, if you look at the Endocrine Society guidelines, triglycerides from, um, as a cause of pancreatitis really don't have, uh, a cause until the triglycerides are above 2000. So we discharge people. I have people whose triglycerides run 1000 all the time. Sometimes you just can't get them down. Um, you put them on various drugs. We don't use probably enough orally stat, so you heard a little bit about that as a weight loss drug. Really hard to get it from insurance companies, but really easy to get from Amazon. So you could buy it as Ali, A L L I. It's a lower dose, so they have to take two pills instead of one pill, but they could buy it from Amazon and it'll cost about $50 a month. For some reason, it's really hard to get it from insurance companies, even with hypertriglyceride pancreatitis. It's a forced low fat diet. OK, So, what do you do? You have to figure out why this happened. So this happens because people have poor diabetes control. Um, this happens because people have obesity. Occasionally, it can happen from an autoimmune cause. Pregnancy raises triglycerides, and then there's a whole bunch of other things. Drugs do it that you can take away. The biggest drug is alcohol, alcohol, alcohol. Anybody who has pancreatitis. Their prescription is zero alcohol, 0 alcohol for the rest of their life. There's actually some discussion about what you do with these patients, and so some people think that anybody who's had pancreatitis, certainly hyperlipidemic pancreatitis, if they don't have diabetes, there's people who say maybe you should put them on a CGM like once every 6 months, so you could pick up diabetes because they're at risk, even if they don't have diabetes to begin with. So you can see the list of medicines, a whole lot of things. In fact, I usually look it up. Actually, I usually just tell the fellows, look it up, check every one of these medicines cause there's so many you can't remember it. So I see patients, especially in this area who are sent to me who have really severe genetic hypertriglyceridemia, a condition we now call familial chylomicronemia syndrome, and that's usually due to a defect in lipoprotein lipase or one of the other genes that do this. This occurs in about 1 in 500 people. The special thing about these people is the usual therapies don't work in them. Fish oils, fibrates don't, don't help them. This is especially common in this area if you have somebody who has a French Canadian background, because there's a founder effect up in Quebec. So if you have a patient like this, the high triglycerides and pancreatitis, you wanna know what their sort of family background is, but it occurs in everything. It's about 1 in 500,000 people. Most of the people who have high triglycerides and pancreatitis that we all see have a condition we call um um sort of mixed hyper mixed uh hyperkal microemia. So that's kind of a way of saying we don't really know what happened. We know that they have some diabetes, maybe they have some obesity. They probably have some genetic disorder. Maybe they're heterozygous for one of these rare defects, um, but they're not homozygous. And then there are lots of people with high triglycerides, and we'll talk about them in a minute. So, we have a new therapy for this disease, the people with the genetic disorder that basically don't respond to any other therapy. The story of it starts with this science paper a number of years ago. They were studying the Dutch Amish in Lancaster County, Pennsylvania, and Alan Schuliger, who was at the University of Maryland at that time, was the endocrine section head. He had a clinic up there, and he did a genetic search and he found that there were people with low triglycerides, low risk of cardiovascular disease, and they had a defect in this protein called AOC3. AOC3 is a small protein. It's on chylomicrons, it's on VLDL. It's also on HDL, and it's thought that what this protein does is it blocks the lipoprotein lipase reaction. But it also blocks the uptake of lipid particles by the liver, so it has two functions. So because it's in the liver, it could be targeted, and so pharmaceutical companies have jumped all over it. They made something called an antiense, a small piece of nucleotide with some abnormal nucleotides that will bind to the message, prevent the AOCC3 from being made. Uh, other companies have made what's called silencing RNA, so it matches the message and also leads to the degradation of the message, and both of them basically eliminate AOC3 production. So this is new genetic therapy. And the treatment of lipid abnormalities is going to be genetic therapy. That's why I tell my patients, in 10 years, I'm not sure you're gonna be taking statins. So these drugs work. In fact, they drop lipids about 60% and some studies, 80% in almost everybody, whether they have the genetic abnormalities, or whether they have this sort of multi-factorial, high, high, uh, high triglycerides. And so these are some of the studies we've had patients in both of these studies, you'll see I was a co-author of this one. And we still have ongoing studies right here, mostly for people who have triglycerides above 500 and don't have the genetic abnormalities. So why that? Because one of these therapies was already approved by the FDA. This was a drug that we knew antiense called Oesarsan. It was approved in December. Um, so they're trying to sell this. I can tell you, I have not yet put a patient on this, but I have forms that the company has sent me to try to get this. I looked on Google, they said that the, um, the sale price, if you want to buy it yourself, is only like $500,000 a year. So they need to recoup all the money for a very rare disease, and that's what they're going to try to do. It's not yet approved for the non-genetic forms, and that's why some of the studies are still going on. But I suspect it will, and I suspect the silencing RNA will be approved within the next couple of months. And I suspect when there's enough patients. And two different therapies, maybe the price will come down. We'll see. OK What about somebody with diabetes and increased cardiovascular risk? So here's a patient, 55 year old man, he had a high LDL, he had coronary artery disease. This is like the kind of people you see all the time, right? So we know that if we take somebody like this with coronary disease, and we lower his LDL to 70, 2/3 of people will either have stabilization or regression of plaques. So not only can we prevent people from getting disease, but once they have atherosclerosis, we can actually stop it or improve it. So 2/3, who, who are the other 1/3? Who are the 3 that don't look, they do that they get the regression or stabilization? There are people who do cigarette smoking. There are people who have hypertension, and then there are people who have diabetes. So that's what this shows. This was a human study where they did a, a procedure called IVIS. They looked at the size of plaques, and they found that people with diabetes, they just um don't regress or stabilize as much as other people. And we don't really know why this is true, and it's being studied here and in Seattle and Washo and a bunch of other places. So what do we do with this guy? Well, we try to make his LDL as low as we could get it. So, anybody with cardiovascular disease who's on a statin. If they're not also on azetami. There's no reason that they shouldn't be on both. If we believe, and the data's there, that the lower the better, you put somebody on a statin, you drop their LDL to 65, why not put them on another generic drug with very few side effects that then we'll drop them to 55. And I can tell you, if you were in Germany, it's standard. Nobody with cardiovascular disease is only on statin, and we're starting to do that because it kind of makes sense, and that's what we would do with him. We would do it because this is what we think. The lower, the better. We could drop them with one, and you could add a second drug. Um, the newer drugs, the PCSK9 monoclonal antibodies, will drop them a whole lot more. So if somebody with cardiovascular disease actually has an LDL that's 65, we'll ask your insurance company, we'll write, I'll write a prescription for PCSK9, and often I can get it. If they're 40, I won't get it so easily, but they have to have cardiovascular disease, and these drugs are getting easier and easier to get, these monoclonal antibodies. And this also now has a generic, genetic therapy. So this is a drug called inclycerin. So it's a silencing RNA. People take it every 3 months. They set up this thing that they're supposed to go to an infusion center. If you're in your private practice office, you could probably do this yourself. But here we have to send them to an infusion center. It's no cheaper, but it's like a forced way to take the drug. And it works not quite as well as the monoclin antibody, but it does pretty well. So I told you, the future of lipid therapy is gonna be changing or blocking production in the liver. Here's an idea that's in clinical trial. Why couldn't you use CRISPR? And totally get rid of PCSK-9 forever. And so, there are several companies already doing this, and a whole bunch of new biotech companies whose goal is going to be to do CRISPR modification of liver genes. Knock out PCSK9 once, and you're done. No more pills, no more, no statins, no muscle side effects. No more patients going to a lipid clinic. OK, So, what do we do to look at risk? Well, we look at LPA levels, you heard a little bit about. We do a lipid profile, some people do an Aple-B. You probably heard, you probably do this. Our second kind of mode is to do a coronary calcium score. Um, some people get inflammatory markers like CRP, you know, it's a calcium score usually trumps everything else. There's a whole bunch of other stuff you can get. I see patients that often they come from cardiologists. They come in with a stack of, sometimes endocrinologists, a stack of vitamins and zinc and Apo Apo C's, AOE's, AOA1, and all kinds of stuff. F LDL, small LDL, small HDL, waste of money. You need a lipid profile. If I need something else, I'm gonna get a coronary scan. I do an LPA because it's a genetic marker. Also because LPAA is a risk factor for aortic stenosis. It's the number one genetic risk factor, and so I wanna know that in my patient going forward. So what other risk factor is there? So we know people with lupus are at high risk, but this is a study from the UK Biobank. Every autoimmune disease is associated with increased risk. Your patient shown like here with Hashimoto's disease, your patient with Graves' disease, they have a 50% increased risk of cardiovascular disease. So I plugged that into my equation, my mental equation. This patient has an autoimmune disease, they're at increased risk, and it's not just type 1 diabetes, it's any autoimmune disease, including autoimmune thyroid disease. OK. Let me finish up with the last kind of thoughts that I'll do in 10 minutes. Um, what about triglycerides and cardiovascular disease? If you don't have triglycerides of 2000, 3000, or 5000, and Is this patient who I showed you, who's our typical patient with type 2 diabetes, is his triglyceride a risk? So when I was a medical student, Which happened at one time, I guess. Um. You would go on rounds, and believe it or not, since it was before statins were widely used, which was about 1990. Um, you would get asked as a medical student, you know, we have this patient like the one I just showed you, what's more important for his cardiovascular disease, the cholesterol or the triglycerides, right? And you'd always ask the medical students like the question that nobody knows the answer to, right? That's, you know, you don't ask the resident cause you don't wanna embarrass the resident, but you're gonna embarrass the medical students. They don't have to know. You would ask, ask that question because this paper came out from University of Washington in the Journal of Clinical Investigation, and you can read the bottom, but it suggested, at least in the group that was looked at, they looked at people with coronary disease, and they said high triglycerides were found in as many patients as high cholesterol, and they wondered whether triglyceride was just as important a risk factor as cholesterol. And then the problem with this paper is the guy who's the first author is a guy named Joe Goldstein, who was the fellow. And so he left Seattle. He moved to Dallas Southwestern. And instead of studying triglycerides, he studied cholesterol. And then he won a Nobel Prize for studying the LDL receptor, but he never answered the question of, is triglycerides as important as cholesterol. So this guy, you know, we treat his cholesterol, his LDL goes down. How about his triglycerides? Are they important? So there's a huge body of information that says that if you take people and you give them a high fat diet, a single meal, their ability to clear those triglycerides after a meal um correlates with cardiovascular disease. So you eat a milkshake, your triglycerides stay up. You have a marathon runner, I can tell you the triglycerides hardly go up, and that bulk of what we call postprandial hypertriglyceridemia, which also correlates with fasting triglycerides, is a risk factor for coronary disease. Also, people who have minor genetic abnormalities, so their triglycerides go up. Um, they also are all at risk of cardiovascular disease, so the genetics and the intervention trial, you know, they both suggest that. Even more so Even the Heart Association came out with this idea that you shouldn't just use LDL as a risk, but you should use either AOB, the number of particles, the LDL and LDL, or what we call non-HDL cholesterol. Probably some of your labs might calculate it. What they're saying is that we actually think that triglyceride-rich particles are arogenic. That's what that's saying, and that's why non-HDL cholesterol turns out to be a better marker than LDL. Because there's other particles correlate with risk. OK. So what do we do? We try to lower triglycerides, we change diet, take out alcohol, we get people to exercise. Exercise is really good to lower triglycerides, by the way. We put them on different kinds of drugs. So what do the drugs do? So in the Accord diabetes trial, putting people on fenofibrate actually made no difference, um, overall in the patient population. But this was not a hypertriglyceridemic patient population, and there was a subgroup with high triglyceride, low HDL that looked like they benefited from the Accord trial, and the people who do these trials say, oh, well, that's a subgroup analysis. So, not so clear. So, a couple of years ago, this paper came out with a new fibrate called fenofibrate. They did a, they did the right study. They picked people who had high triglycerides, they put them on the fibrate. Triglycerides didn't actually go down that much on this therapy, um, but it didn't improve anything. And they said, oh, fibrates lowering triglycerides, it doesn't make any difference. Um, the triglycerides did go down. 25%, 26%, but the total number of particles, AOB particles, actually they didn't change. They didn't change because they converted the VLDL to LDL through that pathway. And so while they dropped triglycerides, they raised the LDL. So maybe if they had done the trial where they say, oh, if the LDL goes up, we're gonna We're gonna fix it to the same level, you would have guessed that they would have shown a benefit because they got rid of other particles, but that's not the way they set it up. And so this was sort of a death knell for fibrates, at least as cardiovascular prevention. What else can we use? Um, We could do EPA and there was a study that suggested EPA was good. And then there was another study that said fish oils didn't matter. And then there was an analysis that said most of the benefit of the EPA in this study was because the control group that was put on mineral oil actually did worse. Their LDL went up, their CRP went up, and so it turned out that the control group was a problem. The other problem with fish oil is this. Nothing is always perfect. And if it's too good to be true, you put somebody at EPA, it's only good. That never turns out to be right. So if you follow this literature, one thing, one of the things we know for sure that fish oils do is it increases the risk of atrial fibrillation. So you have a patient with somewhat high triglycerides and you start to worry about this. You know, you might think about using a different triglyceride lowering drug, because fish oil is not totally benign. OK. There's another therapy being developed. I'll tell you quickly. It's an inhibitor of a protein called APTL3. Uh, this therapy also increases LPL activity, lowers triglycerides. It also is a therapy for homozygous um familial hypercholesterolemia. I'm gonna skip that. So, what did I wanna tell you? I wanna tell you the world of molecular medicine is now. We're hopefully gonna have people on less pills, but on more things to uh genetically affect their diseases. Um, pancreatitis in people with really high triglycerides, we can treat them now and prevent recurrent pancreatitis episodes. The, the problem is gonna be getting the medicines, and I'm not sure how that's gonna fall out, but within the next couple of months, we're gonna know how to do it. The people who don't have the genetic abnormalities, well, if you're here in New York, send them to us, we'll put them in a clinical trial, and they'll likely get the medicine. Autoimmune diseases, don't forget about it. They can cause high triglycerides, high cholesterol, everything. Um, your risk profile, um, don't get all the tests that some of the, you know, the laboratories will peddle for you. You need a lipid profile, a coronary scan, uh, hemoglobin A1C, maybe a CRP, um, and the goal of prevention in all of our patients, but certainly our patients with diabetes. is to reduce non-HDL cholesterol and to um to turn all those cardiologists into endocrinologists cause they don't have any patients left with coronary artery disease. So I'm gonna stop Published February 21, 2025 Created by
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