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Charting A New Course in Severe Hypertriglyceridemia Care: Optimizing Diagnosis, Therapeutic Strategies, and Pancreatitis Prevention in sHTG and FCS

Dr. James Underberg (Bellevue Hospital Lipid Clinic): The two of us have been in the National Lipid Association meetings for the last several days, and there has been a lot of excitement in this space for those of us who manage this condition. It has been frustrating because for a very long time, there has not much we have been able to do for our patients. To be able to offer therapeutic options for a life‑threatening disorder that, for most of my professional career, there has been no therapeutic solutions, it is an exciting time for us as providers, but even more so for the patient population that suffers with this condition.

sHTG and FCS: High‑Burden, Underrecognized Diseases

We are going to talk a bit about FCS, which falls under the broader category of what we call sHTG or severe hypertriglyceridemia. I will tell you, this is becoming more codified in its definition. I used to say if you put 10 lipidologists in a room and ask them to write down their definition of severe hypertriglyceridemia, you might get 10 different answers, but I do not think that is the case anymore. We are pretty much in agreement on how we think about this, but here is a quote from a patient. This is not an uncommon presentation or statement. "I was misdiagnosed for 23 years. It was a long, long road to finally get a diagnosis."

Our colleague Michael Davidson wrote a paper several years ago about behavioral and other aspects of FCS. One of the things that they captured in that was how many clinicians, experts, or providers a patient would actually touch or see before they were given a diagnosis in FCS. It was somewhere between six and seven providers. You can understand the frustration from the patient perspective.

Interpreting Triglyceride Levels in Clinical Practice

When we think about triglyceride levels, we often say normal is less than 150. I actually do not even agree with that. 150 is average in my mind. The risk for atherosclerosis actually takes off somewhere between about 90 and 110, even a little lower for women. Moderate hypertriglyceridemia is now defined as 150 to 499. Severe hypertriglyceridemia, I think we all agree on now is anything greater than 500. That is where the risk of pancreatitis starts to take off, which is why we use that definition.

Extreme can be listed as greater than 1,000. However, many people will also say 880. The reason we say 880, 880 is 10 millimoles. That is where you start to see chylomicrons in the blood. Chylomicronemia is really the risk factor for pancreatitis.

Now pancreatitis risk starts above 500, but you do not see chylomicrons in the blood until you get between about 880 and 1,000. What is the concern about 500? We all know the guidance. If your triglycerides are greater than 500, lower the triglycerides ostensibly to prevent that increased risk of pancreatitis. We will get to that in a little bit, but there are some interesting features of some of the enzymes and proteins at play that are involved in triglyceride metabolism that lead to this concern about 500, even though 1,000 or 880 to 1,000 is really where this takes off.

Signs and Symptoms of Severe Hypertriglyceridemia

What are the signs and symptoms of sHTG? Recurrent pancreatitis. It is increased in familial chylomicronemia syndrome. There is a syndrome that often can be confused with FCS, called MCS, which is multifactorial chylomicronemia syndrome. These patients are also at increased risk for pancreatitis.

Abdominal pain or subclinical pancreatitis symptoms. This is often one of the areas where the diagnosis is missed. People can come in with low‑grade gastrointestinal symptoms, and they are often labelled or misdiagnosed as having irritable bowel syndrome, GERD. I have seen pancreatic insufficiency syndrome, malabsorption syndromes, failure to thrive. I have seen lactose intolerance. All of these things. If the patient actually does not end up in the hospital with your classic acute pancreatitis, this smoldering process can go on for years without anyone ever putting the two together. I have missed it before. I have had one of these. I had a V8 moment, you know what I mean? I could have had a V8, and I cannot believe I missed these symptoms. I was writing down GERD, and I missed subclinical pancreatitis.

Other physical findings: eruptive xanthoma. Kind of a vesicular rash or eruption when the triglycerides get into that 880 to 1,000 range. Often, these patients will go to dermatologists, and then the dermatologist ends up doing a biopsy, and they end up referring them to us.

Lipemia retinalis. The ophthalmologic findings that you see here.

Lipemic plasma. I remember when I trained, we would spin the blood before it went to the lab. That does not happen anymore, but you can actually see the lipemic or lactose in plasma and hepatosplenomegaly. These patients often get splenic sequestration and can develop thrombocytopenia as part of their presentation.

FCS Manifestations Affect Daily Living: Cognitive, Emotional, and Physical Impairments

What are some of the manifestations of this? These patients can have neurocognitive symptoms. They often get labelled as being lazy or being noncompliant with work or with school. Because of the hyperviscosity syndrome, they have difficulty concentrating, brain fog, forgetfulness, impaired judgement and memory loss.

Because of the emotional nature of not knowing when their symptoms will emerge, part of the problem for these patients is they cannot eat outside of the home because they are restricted to a severe low‑fat diet. Until recently, that was really the only effective therapeutic option we had for these patients. Imagine that you could never consume food that you do not make out of your own home.

That means that you cannot go to that work dinner. You cannot go to your friend's party because you do not really want to eat their food, because you do not know how they made it, and you do not want to not eat it. People often will not go to restaurants. I have had patients call me from restaurants saying, "I am on my way to the emergency room because even though I told them not to put butter or fat in the food, I know they did because of the way I feel." They become very restricted in many of these behavioral options the physical symptoms, the bloating, the abdominal pain, fatigue, indigestion. You can imagine how this affects people. They often get accused of non‑adherence or non‑compliance. Often, these patients are told, "You are not taking your medications," when they are, because the medications do not work. They often get told you must be drinking alcohol, even though you told me you are not. Imagine being accused of lying every time you go to a provider. You stop going to a provider. A lot of these patients just drop out of the health care system because you cannot do anything for them, and they often get accused of non‑adherence when that is not the case. It is a tremendous emotional burden in these patients.

FCS: Lack of Lipoprotein Lipase Activity Increases Risk of Pancreatitis

What happens in these patients? They have little to no lipoprotein lipase. That is the defect in FCS. Lipoprotein lipase is that enzyme standing between breakfast and all of us ending up in the emergency room with acute pancreatitis because lipoprotein lipase hydrolyses triglycerides out of chylomicrons as they leave the gut and head to the liver. The risk of pancreatitis is 360 times higher in patients with LPL deficiency, and you can see the odds ratio here. This is a required enzyme for triglyceride metabolism.

The Link Between Triglycerides and Atherosclerosis

When we think about elevated triglycerides, it is important to remember, though, that sHTG puts patients at risk for pancreatitis, and FCS, the most severe form of sHTG. Triglycerides are atherogenic on their own, and triglyceride‑containing lipoproteins and their remnant breakdown particles are highly atherogenic. There is this duality to triglyceride management that we always have to worry about. There is pancreatitis risk, but there is also risk of ASCVD. You cannot forget about that when you are thinking about patients with severe hypertriglyceridemia. There is a heightened and increased inflammation and oxidative stress.

Endothelial dysfunction. I have been lucky enough for years to have, as our chief of endocrinology at NYU, Ira Goldberg. Ira always reminds me, Jamie, hypertriglyceridemia is associated with ASCVD independent of atherogenic ApoB‑containing lipoproteins. The triglycerides themselves are proatherogenic.

VLDL and Chylomicron Synthesis and LPL‑Mediated Lipolysis

Just a little bit about what is happening from normal pathophysiology. I always remind my trainees, think of the gut and the liver in the same way when you think about lipoprotein and lipid physiology. If you remember your embryology, the gut and the liver evolved out of the same Pangaea‑like organ. Every physiologic process that takes place in the hepatocyte, from the perspective of lipid metabolism is replicated in the proximal jejunum. The same thing goes for the opposite direction.

When we consume fat, triglycerides, and cholesterol, essentially are reassembled in the proximal jejunum into a chylomicron. The cholesterol is actively transported. The free fatty acids passively diffuse into the enterocyte, and they are combined into a chylomicron. The structural apolipoprotein that ties that all together is ApoB‑48. ApoB‑48 is a truncated version of ApoB‑100 specific to the gut and chylomicrons. On their way back to the liver through the capillary bed, chylomicrons come in contact with lipoprotein lipase, and triglycerides are hydrolyzed. The chylomicron becomes smaller, less triglycerides. Same identifying apolipoproteins, but as a remnant chylomicron, it is now small enough to be taken up by the remnant receptors. Once the contents of the chylomicron are delivered to the liver, cholesterol and triglycerides are reassembled back into what? A VLDL particle with ApoB‑100 on the surface and they leave the liver.

FCS: Impaired Function of LPL Enzyme

When you have impaired lipoprotein lipase, you cannot make chylomicrons, cannot break them down once they leave the intestine. You also do not break down VLDL because once VLDL leaves the liver, it needs to be broken down into remnant lipoproteins to then ultimately be impacted by hepatic lipase to turn into LDL. LPL activity is essential to prevent chylomicronemia and mutations in lipoprotein lipase, or in the supportive other enzymes and proteins that affect lipoprotein lipase function are what leads to its decreased activity. The majority of the mutations are in LPL. We also have mutations in ApoC‑II, GPIHBP1, lipase maturation factor 1, and ApoA‑V.

Differential Diagnosis of Severe Hypertriglyceridemia

This is our differential diagnosis of sHTG. Most of these are what we call MCS or polygenic. You can see lipodystrophy, dysbetalipoproteinemia, another lipid disorder, an abnormality in ApoE metabolism. Then, finally, FCS. It is important to assess for secondary causes history, medications, labs, rule out diabetes, thyroid disease, a whole bunch of other factors, including renal disease in some cases, and IgA nephropathy.

Poll 3

Which scenario is most suggestive of FCS?

A. Triglycerides of 600mg per deciliter with obesity and diabetes, partial response to therapy

B. Triglycerides greater than 1,000 with recurrent pancreatitis and poor response to therapy

C. Triglycerides of 800 with alcohol use, improves after cessation

D. Triglycerides 500 to 700 with metabolic syndrome responding to standard therapy

Okay. Most people thought triglycerides greater than 1,000, with recurrent pancreatitis and poor response to therapy. Traditional therapeutic options, omega‑3s, and fibrates work primarily by upregulation of lipoprotein lipase. If you do not have any lipoprotein lipase, the drugs do not work. It is like having a door with no keyhole, and I give you five different keys. It does not matter which key you use. There is no keyhole, so they are not going to work. That has been the issue up until now.

I am going to pass the baton back to my chair, Dr. Ahmad. He is going to talk about mechanisms to diagnosis.

From Mechanisms to Diagnosis: Distinguishing FCS From Multifactorial sHTG

Dr. Zahid Ahmad (Lipid Clinic Parkland Health): Thank you so much, Jamie. Thank you for going over that in such a nice, simple way. The main question we have in clinic and that you will have in clinic is, is this FCS or is this something else? Something else that is very common is what we call multifactorial chylomicronemia syndrome, or MCS, or as we are calling here, multifactorial severe hypertriglyceridemia.

Primary and Secondary Causes of Hypertriglyceridemia

The most important step is to identify secondary causes of high triglycerides. The vast majority of patients will have secondary causes. If they do not, that raises your suspicion for FCS.

The list of secondary causes is quite long. For endocrinologists, obviously, I am sure all of you see the uncontrolled diabetics or triglycerides in the thousands. That is probably not FCS. That is probably MCS or multifactorial chylomicronemia syndrome.

Other things you should look out for include chronic kidney disease. The most common lipid abnormality in chronic kidney disease is actually high triglycerides.

HIV, if they are on antiretrovirals, especially protease inhibitors.

Pregnancy in the third trimester is a time when triglycerides can get quite high because of the estrogen surge.

A lot of the inflammatory conditions or even Cushing's syndrome. Has anyone ever checked the lipid panel in a Cushing's syndrome patient? It is not the primary concern, but please remember those patients are at a high cardiovascular risk. They do have a lot of cardiovascular events. Most of the time, the triglycerides are only slightly elevated, but if they also happen to have uncontrolled diabetes or something else going on, then the triglycerides can get quite high.

Alcohol is a very interesting one. The vast majority of people drink alcohol, and they have no problem. However, there are some people who have a polygenic predisposition to getting very severe hypertriglyceridemia. Oftentimes, pancreatitis if they drink on a daily basis.

Estrogen is another one. Again, many women take estrogen and have no issues. However, there are some women who take estrogen either as oral contraception or as hormone replacement, and their triglyceride levels get extremely high. We do anticipate that this is going to increase in frequency in incidence because hormone replacement is becoming popular.

There may be people who show up at the endocrinologist's office with triglycerides in the thousands. The very first thing is re‑evaluate the estrogen. You can consider using something with lower dosage, like a patch, but every now and then, we still see estrogen patch causing very high triglycerides. It takes a little bit of monitoring to see what happens.

Steroids is another one. I do not have to preach to this choir, but there are so many people who take too much steroids. For them, triglycerides can get high. I have even seen it with steroid injections for joint pain, neck pain, or something like that.

If they have diabetes, you guys know the blood sugars are going to be higher for a little while, even if it is a local steroid injection, and the triglycerides can also get higher.

There are other drugs too, like sirolimus, which we see in transplant patients quite a bit. Beta blockers and some other cardiovascular medicines, like thiazides, they can raise triglycerides a little bit. I have never changed that in a patient for their triglycerides because it is really just a little bit, not much of a change.

L‑asparaginase with arsenic is now used by the oncologists quite a bit for different lymphomas and other neoplasms. That combination actually can raise triglycerides quite a bit. In children, L‑asparaginase is used for, I think, AML. Every now and then we get called about a kid with triglycerides in the thousands, and it is almost always L‑asparaginase.

Differential Diagnosis: FCS vs MCS

How do you distinguish between familial chylomicronemia syndrome and multifactorial chylomicronemia syndrome? There are all these criteria, and I will tell you, we have created a calculator to help you with this. It is called the North American FCS Score. You can look that up or Google it, and you will find it. All of these things are on there.

FCS is monogenic. It is Mendelian. People manifest with the disease very early in life. We have seen three‑month‑olds with triglycerides of 6,000. Typically, someone with FCS presents at the latest, maybe in their teenage years, but definitely early in life. Oftentimes, they present with pancreatitis or with blood that is lipemic. Sometimes they have a blood draw. It goes to the lab, and the lab is the one that tells them, "Your blood is lipemic."

People with FCS tend to have persistent triglycerides above 1,000. They may dip every now and then, like if they are hospitalized and are NPO or something, but almost always the triglycerides stay above 1,000.

There is this very interesting manifestation with the ratio of triglycerides to cholesterol. People with FCS are accumulating chylomicrons. The ratio of triglycerides to cholesterol within a chylomicron is about 10:1. When you look at lipid panel, you will often see triglycerides of 2,000 and cholesterol of 200. That is a really nice giveaway and a simple way to identify people who have FCS. There are some mimickers. Like if you give a statin to somebody with triglycerides in the thousands, that can lower the cholesterol and affect the ratio, but if they are not on a statin, you can rely on that ratio quite a bit.

ApoB levels is another one. ApoB levels in FCS tend to be lower because the chylomicrons are fewer ‑ there is a less particle number of chylomicrons, and there is a VLDL in MCS. It is a bit confusing to understand this, but just know that if you check ApoB‑100, it can be low or even normal, and MCS is almost always elevated.

As we have discussed, people with FCS do not respond to treatment. They are refractory. You can give them omega‑3, you can give them fibrates. You will never see the triglycerides come down below 1,000. The only thing that gets them down that low is to starve them, like when they are NPO. Maybe plasmapheresis or some of them are so good at following a low‑fat diet, essentially removing triglycerides from their intake that their triglycerides can come down to something reasonable, but even with that, most of the time the triglycerides are in the thousands.

The lifetime pancreatitis risk and the incidence is quite high in FCS compared to MCS. For MCS patients, maybe 25% of them will have pancreatitis. For FCS, it is as high as 90%. Of all the FCS patients I have seen, probably several dozen, I can only think of one or two that never had pancreatitis. In those cases, they were identified early in life and put on a low‑fat diet so that they never got pancreatitis.

As I mentioned, you do not have to memorize these things. There is a calculator that helps you figure this out. If you ever want to prescribe these newer drugs for an FCS patient, you probably need the score from that calculator. I would highly recommend you use that calculator and put it in your notes. It does help you get the drugs approved.

Genetic Load of FCS vs MCS

In terms of genetics, everyone in this room has to memorize this slide. I am kidding. You do not need to know everything about the genetics. Just understand that there are five genes that are known to cause FCS, and it is biallelic, which means homozygous or compound heterozygous mutations in these genes that cause FCS.

When you switch down to the MCS population, there is far fewer people who have biallelic mutations. Some are heterozygotes, but the vast majority are polygenic.

One time, I gave a similar talk at a very similar meeting full of endocrinologists, and I said the statement that MCS is not usually genetic. Somebody very loudly said, "That is BS. How is my diabetic with the triglycerides of 6,000 not genetic?" I clarified that it is genetic, but it is not Mendelian. It is not a monogenic condition. It is not like sickle cell anemia. You get one mutation, and you get one disease. It is more polygenic. You accumulate a bunch of minor mutations, mutations with smaller effect sizes, and in aggregate, and in the right background of the environment, like uncontrolled diabetes, your triglycerides get into the thousands.

That is the basics of the genetics. Genetic testing is available. For years, we did not have it at a commercial level, so we did it in our research lab, but now it is available commercially. There are many labs that do this. It is often labelled as a dyslipidemia panel. There are also what is called sponsor test. Sometimes, you can find that the manufacturer of the drugs will actually pay for the test to be done.

I always get asked, "How do you order a test?" Actually, nowadays it is not that hard. You can log into the website of the genetic testing company or create an account, put in your patient's information, and they will send a kit to the patient. The patient collects saliva and sends the kit back. Then the insurance company... I am sorry. Most genetic testing companies will check with insurance to see if it is covered, so they will do the benefits analysis. Your office does not have to do it. There are some genetic testing companies that still make the offers to do it. We do not use those. We do not have the resources. No one has the resources to do that. I mean, just getting prior authorization for drugs is hard enough. It would take a lot of time to do genetic testing too. We rely on the companies that will do the benefits analysis for us. That is about it.

It takes a month or two to get the results. It does help if you understand genetics a little bit so that you can explain the results. They can be a bit confusing, especially when you are trying to explain polygenic diseases, or you can refer to a genetic counsellor if you have one available near you.

Clinical FCS Score Calculator: North American Algorithm

This is a little bit about the FCS score. On the website, you can put in many of these variables, which we just talked about, their age. I did not talk about BMI, but FCS patients typically, not always, but typically have a normal BMI or a non‑overweight non‑obese BMI. Again, not always, but often the case. We talked about they have pancreatitis. Secondary factors are typically absent in FCS patients. The lab values are another clue. The triglycerides are almost always above 1,000. Then you get more points based upon the age of onset and lack of secondary factors.

When you put in the numbers in the score, it interprets it for you as definite, probable, or possible, and definite score is above 60. We did validate this in a cohort of patients with FCS. It is highly predictive of genetically proven FCS. It is a very good calculator. We spent a lot of time making it. I say we. Actually, people from the U.S. and Canada who see a lot of FCS patients got together and made this calculator.

There is a European version two, but ours is better. Go American if you can.

Genetic Testing Recommendations

The recommendations for genetic testing are not universal. The National Lipid Association does not necessarily endorse genetic testing for all patients with very high triglycerides. If you have a suspicion for FCS, we do say that the diagnostic gold standard is genetic testing. If you suspect FCS, it is reasonable to do genetic testing; it is not necessary. You can still make a diagnosis based on a score or your own clinical suspicion if you feel that way, but genetic testing does help with several things, including confirming the diagnosis for the patient and cascade testing or family screening. People often forget that with these recessive conditions like this, the siblings are at a very high risk for having the same condition. I actually follow several siblings in our clinic with FCS, and the second sibling was always identified because the first sibling was identified. The advantage there is the second sibling was almost always identified at a very young age, was put on a low‑fat diet, and never had pancreatitis, whereas the first sibling suffered through many episodes of pancreatitis.

My, and I think Jamie's recommendation is test if you are suspicious for FCS. At the same time, some of the other conditions that Jamie mentioned in the differential, if you are suspicious for lipodystrophy or dysbetalipoproteinemia, go ahead and test. Most payers will pay for it.

We also get people coming to our clinics who are convinced that their condition is genetic. If they ask nicely, we often do genetic testing too.

Central Role of Endocrinology in sHTG and FCS Care

What is the role of the endocrinologist in these patients? We are the central people who see these patients. We are the ones who should be diagnosing and managing these conditions. We are the ones who should be guiding treatment and doing the differentiation between severe hypertriglyceridemia and FCS. We are the ones who I think are best equipped to address for secondary causes like diabetes, fatty liver, obesity, and alcohol intake. We are the ones who should be initiating and escalating therapy and coordinating the multidisciplinary care. These patients do need to see a nutritionist. They often need to see a pancreatologist as well. That can help.

If you see someone with triglycerides above 500, then do our usual evaluation, check all the labs we need to check, do a good physical exam. My mentor, Dr. Abhimanyu Garg, who is the world's expert on lipodystrophy, will say that we do not take patient's clothes off enough and put them in a gown, obviously, but ask them to put on a gown. Take a look at their arms and legs. Take a look at their abdominal area. Take a look at their buttocks. Is there fat there? If you see areas without fat, that could be lipodystrophy, and that is a different diagnosis. If it is generalized lipodystrophy, there is a separate treatment for that. There is metreleptin available. It is worth taking a look at your patient and identifying lipodystrophy if you see it.

Guideline Perspective: Risk Stratification in Severe Hypertriglyceridemia

The new guideline and other guidelines do talk about hypertriglyceridemia. Has anyone read the 2026 dyslipidemia guideline, that is, the AHA/ACC? Yes. I gave a talk about it yesterday at the Endo conference, and no one had read it there either. People were familiar that it exists, but very few people are reading it. It is 150 pages or 130 pages. I think Jamie turned it into a book. He has a book that he shows around everywhere. In those guidelines. They actually do talk about triglycerides. Remember the previous guidelines were called the Blood Cholesterol guidelines. These guidelines are referred to as Dyslipidemia. They do talk about other lipids other than just LDL. There is a conversation in there about triglycerides.

As you all know, as we talked about already, if the triglycerides are below 500, you are really focused on ASCVD risk. If they are above 500, you still think about ASCVD risk, but now you are starting to think about pancreatitis risk. If they are above 1,000, then you are really thinking about pancreatitis risk, and you are evaluating for FCS.

When sHTG and FCS Are Misattributed

We recently wrote this consensus statement about FCS. We are very proud that we included the patient perspective. If you have a chance and you are interested, please Google "National Lipid Association, FCS Expert Opinion," and you will see that we start off every section of that paper with quotes from patients. These were the quotes when we asked people about genetics. We ask patients with FCS, "Do you think genetic testing is worth it?" As I mentioned, there is a few benefits, but you do not need it. You do not absolutely need it to make a diagnosis.

The patients, though, really appreciate having a definitive diagnosis, and it gives them something to show doctors. Many of the patients told us that doctors labelled them as an alcoholic because their triglycerides are just so high. Just assumed that it has to be something. "Oh, the patient must be lying about alcohol."

You do genetic testing, and if it is positive, the patient now has something to show doctors and say, "Look, this is why my triglycerides are high." There is a benefit to doing genetic testing and confirming that someone has FCS as opposed to MCS.

On the Lookout: Surveying New Clinical Insights in FCS and sHTG Care

Now, to talk a little bit more about surveying new clinical insights in FCS and severe hypertriglyceridemia care, I will ask Dr. Underberg to come back to stage.

Dr. Underberg: Okay. On the Lookout: Surveying New Clinical Insights in FCS and sHTG Care. We have another poll.

Poll 4

Which statement best reflects the role of emerging ApoC‑III targeting therapies in sHTG and FCS? Make your choice now.

Okay. Majority of folks correctly chose they reduced triglycerides by inhibiting ApoC‑III production via RNA‑based mechanisms, different mechanisms, but ultimately two different RNA‑based mechanisms, so that is correct.

Treatment of TG ≥500 mg/dL

The other choice, ApoC‑II, could be a right answer, but it does not work that way. Enhancing ApoC‑2 does help activate lipoprotein lipase. When we think about the treatment of triglycerides greater than or equal to 500mg per deciliter, the first step always is to rule out secondary causes. These are the things that we teach our trainees to do on every patient who comes in with a lipid disorder. There are some specific to hypertriglyceridemia, and it is obviously lifestyle, number one, it is making sure there are not any secondary disease states present that can raise triglycerides, make sure you are not missing kidney disease, liver disease, thyroid disease, diabetes, etc. There are some less common disorders that are inherited in nature that associate with hypertriglyceridemia that are rather uncommon, but have presenting phenotypes that would make you think along those lines, but it does not mean you have to do them for every patient because they are rare and uncommon.

Implement a very low‑fat diet and optimized lifestyle. What do we mean when we say a low‑fat diet for these patients? It is 15 to 20g of fat a day. I would tell you, if any of you try to do that, I will give you two or three days, and you will fail. It is almost impossible. We have a fellow every year in lipidology and heart disease prevention, and my first task for them is for the first week to see if they can maintain this diet and to see how long they can go. It is very, very difficult. If you ever prescribe it, try it yourself first.

To do it properly, it really needs to be done in conjunction with a registered dietitian nutritionist who is trained and understands how to manage this type of dietary implementation. Obviously, optimized glycemic control in any patients who have diabetes, consider fibrate and/or prescription omega‑3 fatty acids. If the patients have any lipoprotein lipase activity, these drugs can help, but you have to remember that high‑dose omega‑3 fatty acids represent a fat load. Sometimes, in patients who have complete loss of lipoprotein lipase activity, adding omega‑3 fatty acids can make them worse. That is something you have to remember about.

These drugs can work in folks like MCS patients who do have some lipoprotein lipase activity and then even consider statin initiation. Statins lower triglycerides. How do statins lower triglycerides? They reduce the production of VLDL in the liver. VLDL is the primary carrier of triglycerides outside of chylomicrons. The other thing they do is they upregulate the LDL receptor. The LDL receptor clears LDL, but the LDL receptor also clears VLDL. VLDL, again, a carrier of triglycerides, can be cleared via the LDL receptor independent of remnant receptors that also clear VLDL.

Mechanisms of Action for Novel Triglyceride‑Lowering Agents

When we think about the mechanism of action for novel triglyceride‑lowering agents, I remind you again of that physiologic process that I explained takes place in the liver and the gut. As we ingest fat in the small intestine and we create chylomicrons in the gut, chylomicrons or ApoB‑48, mostly triglycerides, a little bit of cholesterol in that 10:1 ratio, they leave the liver, they come in contact with lipoprotein lipase. Lipoprotein lipase is impaired in these patients.

These new drugs and agents that we have now target ApoC‑III, the first was a drug called volanesorsen, which is not available in the United States. It was only approved in Europe, and now two, olezarsen and plozasiran, specifically targeting ApoC‑III.

ApoC‑III is often referred to as an inhibitor of lipoprotein lipase. This is a fascinating story, though. The chylomicron has on its surface apolipoprotein called ApoC‑II. Many people think of ApoC‑II as the ligand or the binding site for lipoprotein lipase on the surface of the chylomicron. Really, what happens is ApoC‑III, think of it as this large blanketing protein that sits over the surface of the chylomicron, and it blocks ApoC‑II. When you inhibit ApoC‑III, you remove it from the surface, and you unearth that ApoC‑2 site that allows lipoprotein lipase to better attach.

It turns out if you have no lipoprotein lipase, using a drug that enhances lipoprotein lipase should not work. However, it turns out that this ApoC‑III mechanism does lower triglycerides in patients with either zero or minimal to no lipoprotein lipase activity. There must be a non‑lipoprotein lipase‑dependent mechanism. It turns out that when uncovering or removing ApoC‑III, not only do you unearth this binding site for ApoC‑II, but you also reveal ApoE, which sits on the surface of chylomicrons. It turns out that ApoE is an initial ligand, an additional ligand for chylomicrons to be taken up by remnant receptors in the liver. It is most likely that ApoC‑III inhibition increases clearance of chylomicrons by allowing them to better adhere to remnant receptors on the surface of the liver.

This is still a mechanism in process or in development. We have the therapeutic option. Now we have to go back and figure out how did it work, because if it really only worked through its lipoprotein lipase mechanism, it should not work in these patients, but it does.

Now, if you open up and reveal ApoE, you still have to shrink the size of the chylomicron particle a little bit to make it small enough to be taken up by these remnant receptors. How that happens is still up for discussion. It turns out that ApoC‑III is also an inhibitor of an enzyme called hepatic lipase. By inhibiting it, you may upregulate hepatic lipase. That might remove some triglycerides from chylomicrons that make it small enough to be taken up by these remnant receptors.

There is also another way you can lower triglycerides. It is through a mechanism called ANGPTL3. ANGPTL3 is completely reliant on lipoprotein lipase, however. Unlike ApoC‑III, if you inhibit it, it does not work at all in patients who have complete loss of lipoprotein lipase activity.

Management of FCS: Prevent Pancreatitis by Reducing Triglycerides

Diet, key. Low‑fat diet, medications, traditional agents, fibrates, statins, and omega‑3s. I mentioned the potential issue with omega‑3s. You might make these patients worse. You have to be very judicious in their use. Olezarsen is an FDA‑approved ApoC‑III targeted antisense oligonucleotide that inhibits ApoC‑III mRNA, and plozasiran is an FDA‑approved ApoC‑III targeted siRNA that inhibits ApoC‑III mRNA. They are both mRNA‑based therapies, but they work through slightly different technologies.

One of the issues with these patients is that the disorder presents early in life. Pediatric patients' failure to thrive. They often require special low‑fat formulas. Probably my lipidology nightmare, which is FCS in pregnancy. This is an extremely difficult, obviously, length of gestation process. It is very high risk, requires close monitoring, a team‑based approach with maternal fetal medicine, lipidology, endocrinology, and hospital‑based medicine. These are tough patients to manage.

Recognizing the FCS Phenotype

When recognizing the FCS phenotype, I love this quote from a patient, "I was having eruptive xanthoma... the fat coming out of my skin." Many of these patients get referred to us by a dermatologist. If you have seen the eruptive xanthoma, if you had that, you would probably go to a dermatologist, not a lipidologist if you did not know the cause. We do get referrals from our dermatology colleagues at NYU.

At this point, I will pass the podium back to Dr. Ahmad to discuss the emerging evidence around management of FCS and SDG.

From Emerging Evidence to Integrated Management in FCS and sHTG

BALANCE: Olezarsen in Patients With FCS

Dr. Ahmad: Thank you. We are going to go through the two drugs that are now available that are ApoC‑III inhibitors for FCS, then we will go over data on people without FCS or people with MCS. We will speed through that a little bit. There is a lot of studies and a lot of data. This was one of the very first studies of olezarsen in people with FCS. This was two doses, 50mg and 80mg. Out of these two doses, the 80‑milligram dose was superior and is the one that is at market now. With 80mg, the triglycerides reduce by about 40 to 50%.

On the right is the even more important data. The time to first acute pancreatitis episode was much less so. There was far fewer pancreatitis episodes. The red and orange are the two doses of olezarsen, and the greyish color is the placebo group. Each step down is an episode of pancreatitis. You can see that in the groups that got olezarsen, there were very few pancreatitis episodes, but they were far more in the placebo group. For years, we had always said that lowering triglycerides reduces the chance of pancreatitis, but actually, we did not really have the data to show that; that was a presumption. Even the FDA acknowledged that presumption and allowed it. For the first time, now we have big enough studies that we can say that for sure, lowering triglycerides reduces the chance of pancreatitis. You will see similar data with all of these drugs.

BALANCE: Safety

In terms of safety, the only thing that was really imbalanced between the two study arms was injection site reactions; liver function, renal function, and ANC was all fine. There was no real reduction in platelet count. That is important because the precursor drug to this, volanesorsen, did actually reduce platelets. This one does not. The technology was better for making this.

PALISADE: Plozasiran in Patients With FCS

The other drug, plozasiran, was studied in FCS patients in the PALISADE study. Again, two doses were used: 25mg or 50mg. The 25‑milligram one was the one that went to market. Either of these doses, you get fantastic reduction in triglycerides, between 60 and 80%.

On the right, again, the more important thing, the number of pancreatitis episodes was far fewer. Again, that is what we really care about. Some of these patients, as I am sure some of you have seen, they end up in the hospital almost every month with pancreatitis.

PALISADE: Safety

In terms of safety, there were some differences. There was a little bit change in platelet counts at 12 months. Not much, but it was there. There was more nausea and headaches numerically in the groups that got drugs versus those that did not. There were some changes in liver function tests, but no one got liver function tests about three times the upper limit of normal.

ESSENCE‑TIMI 73b: Olezarsen in Patients With sHTG or HTG and Increased CV Risk 

Now that was FCS. What about people with MCS or severe hypertriglyceridemia? This is a study where the baseline triglycerides were around 250. Even in this group, triglycerides do come down quite a bit from 250 to the normal ranges. It reduces triglycerides, ApoC‑III levels, non‑HDL, VLDL remnant cholesterol, ApoB, and LDL a little bit. HDL actually goes up. Very promising profile of what the drug does.

CORE‑TIMI 72a/CORE2‑TIMI 72b: Olezarsen in Patients With sHTG

These are patients that probably many of us more commonly see. This is olezarsen in severe hypertriglyceridemia. These are two studies published in New England Journal of Medicine last year. TIMI 72a and TIMI 72b. In both of these studies, the triglyceride levels were between 750 and 800. In both of these trials, you can see on the left that the triglycerides came down to near normal levels. This drug really affects triglycerides very well in the average person with severe hypertriglyceridemia.

On the right, again, pancreatitis episodes were far fewer in the people who got olezarsen compared to placebo. Very promising to reduce the chance of pancreatitis in our patients.

Just FYI. Olezarsen is currently approved for FCS only. On June 30th, the FDA will announce their decision on whether to open it up to severe hypertriglyceridemia. Based upon the efficacy of this study and others, as well as the safety profile, we fully expect that it will be approved. You may have this available to prescribe soon for your average patient with severe hypertriglyceridemia, not just for FCS.

CORE‑TIMI 72a/CORE2‑TIMI 72b: Lipid Outcomes at 6 Months

At six months, similar to the other data I showed, you get a reduction in triglycerides, ApoC‑III levels, remnant cholesterol, non‑HDL, ApoB, and LDL, and HDL goes up. Sorry, I apologize. LDL actually did go up a little bit. Not by much, but a little bit.

CORE‑TIMI 72a/CORE2‑TIMI 72b: Olezarsen in Patients With sHTG and Diabetes

This is a substudy that was recently presented at the American Diabetes Association meeting, amongst all the chaos there. This is just diabetic patients, the patients that we see. Whether or not they have diabetes, the drug works the same. The inclusion criteria, if I remember correctly, the A1C was probably 8% or 9% or less. Even in a somewhat uncontrolled diabetic, the drug works quite well to lower triglycerides. As you see on the right, it works really well to reduce pancreatitis episodes.

SHASTA‑2: Plozasiran in Patients With sHTG

This is the other drug, plozasiran, in the SHASTA‑2 study. Very similar data. You take people with severe hypertriglyceridemia, and it works. The triglycerides dropped by between 40 and 80%. HDL goes up, LDL goes up a little bit ‑ now that happens with almost every triglyceride‑lowering drug. We do expect that ‑ and ApoC‑III levels come down.

Importance of Multidisciplinary Care

Just to reiterate where we were before, FCS patients require a multidisciplinary team. They need a primary care doctor, they need a dietician, they need a pancreatologist, they need patient advocacy and support groups, which is another benefit of genetic testing. Once you have a definitive diagnosis, it is a lot more comfortable for the patients to join these advocacy groups, which do exist. There is an FCS foundation as well as some other groups internationally.

What is the role of an endocrinologist? We play a very central role. As Jamie alluded to earlier, the average FCS patient sees six to eight providers before getting a diagnosis. We can shorten that because these patients will show up to an endocrinologist's office. We can identify them early and refer them to the specialists they need to see.

sHTG and FCS Management Algorithm

This is a little bit of a management algorithm. If the triglycerides are above 500, then we will worry about pancreatitis. If they are not, then ASCVD risk becomes the priority. We have gone through much of this. The key thing is that if the triglycerides are above 500, you are really thinking about pancreatitis. Otherwise, you are thinking about ASCVD. It is really important to distinguish between FCS and severe hypertriglyceridemia, which we have done, or we have talked about a lot. These ApoC‑III inhibitors may transform care for FCS. Sorry, they have already transformed care for FCS, and they may transform care for severe hypertriglyceridemia very soon.

Recurrent Pancreatitis and Persistent Unmet Needs

More quotes from patients. "If I am not strict with my diet, I get a pancreatitis flare‑up, and I am in the intensive care for a couple of weeks." That is a very difficult life to live, just based upon how much fat you are eating. Dr. Underberg went through this a little bit, but the amount of fat they can have is essentially equivalent to two tablespoons of olive oil a day. It is really quite hard to adhere to. They can use medium‑chain triglycerides, which you can buy on Amazon. Bulletproof actually has a pretty good brand. The average person should not use those. It will raise their cholesterol. For FCS patients, that can be a source of calories and fat when they cook, at least.

Another patient says, "I know that there is a new treatment, but I have not been able to get it yet because of insurance." That is something that our offices can help with, and seeing a specialist actually helps with. Lipid specialists do have experience with getting this through insurance.

When you prescribe these drugs, you are sending the prescription as a form that you download off of the website for the drug, you send it to the central specialty pharmacy. They actually have a lot of help with getting the drug to the patient. They will help do some of the benefits, investigations, and other things to help you get the drug. I would say, do not be scared to prescribe it because of having to have your office do the prior authorizations and stuff like that. There is a lot of help to get the patient the drug.

I will turn this back over to Dr. Underberg to talk about translating current evidence for new severe hypertriglyceridemia and FCS therapies into practice.

Setting Sail: Translating Current Evidence for New sHTG and FCS Therapies into Practice

Dr. Underberg: Okay. How many people remember about 10 years ago or more? There was a product available. You could buy it in a grocery store, in a pharmacy. It was called Enova Oil. It came in a green and gold bottle. It was diacylglycerol, which is essentially a medium‑chain triglyceride. It was around for a while. They had trouble selling it because they could not decide if it should go in the pharmaceutical section or the grocery store. Ultimately, it was taken off the market because some issues about by‑products of the oil and contaminants. It is the only thing I remember, otherwise, that people could get over the counter and cook with and utilize.

These medium‑chain triglycerides can be very helpful and often work. The kind of thing that a good, registered dietitian nutritionist can help with.

We will move forward with another poll.

Poll 5

How comfortable are you with integrating novel therapeutics for FCS into practice? Make your choice now.

All right. We are going to do a bunch of cases now. We are going to go back and forth. We would like you to think about these cases at your tables. We will discuss the story and think about the options. Here is our first case.

Patient Case 1: 24‑Yr‑Old Female With sHTG and Recurrent Pancreatitis

This is a snapshot. This is someone with recurrent acute pancreatitis episodes since adolescence. Triglycerides 1,500mg per deciliter persistently in this range. No history of obesity, diabetes, or alcohol use. No clear secondary causes identified, and mineral response to fibrates and omega‑3 fatty acids. The question really is, do you see patients like this in your practice?

What clinical features raise suspicion for either FCS or, as you heard, MCS? What opportunities are there to improve this patient's care?

I just think about this for a minute. I think the key things that we focused on in the first half of this program are identified in a patient like this. It is someone who does not have any predisposing risk factors, no obvious secondary causes.

Poll 6 – Decision Point 1

Let us go through a decision point. What is the most likely diagnosis?

A. Multifactorial sHTG

B. FCS

C. Dysbetalipoproteinemia

D. Secondary hypertriglyceridemia

Okay. 90% of you thought this was FCS. I think that is a good choice.

Poll 7 – Decision Point 2

How do you confirm your diagnosis? Would it be:

A. ApoB level

B. Coronary artery calcium scan

C. Genetic testing for an abnormality in the LPL pathway

D. Liver biopsy

That is correct. Genetic testing for one of the abnormalities. Again, more than 90% of these will be lipoprotein lipase, but the other helper proteins, so to speak, and enzymes that we identified can also cause this problem. We just identified a patient at Bellevue recently who was homozygous for something called lipase maturation factor 1. You do find these patients, and they are out there. If you check the genetics, you are going to find all kinds of interesting things. Let us go to the next slide now.

Poll 8 ‑ Decision Point 3

What is the most appropriate next step for this patient? Would it be:

A. Intensify fibrate therapy, recheck lipids in eight weeks

B. Initiate ApoC‑III targeted therapy and reinforce a very low‑fat diet

C. Intensify lifestyle modifications and monitor lipids in eight weeks.

D. Initiate statin therapy

E. ApoC‑III‑targeted therapy

Okay. I think B and E both encompass the correct answer, which is ApoC‑III‑targeted therapy, but you want to continue the very low‑fat diet. The ApoC‑III‑targeted therapy was done as an adjunct to diet. That is actually in the indications for the medications. It is not an opportunity to liberalize diet. You can eat through any of these medications if you try hard enough. What it does do is it gives these patients a little more wiggle room. They will say, "For the first time, I could go out to dinner," or "I could go to a party," or "I could actually choose food that I did not make myself and feel a little more comfortable." It is not an opportunity to start eating Big Macs every day and milkshakes, etc. It is really meant to be used as an adjunct to a low‑fat diet. It is important to realize that.

Revisiting Patient Case 1: 24‑Yr‑Old Female With sHTG and Recurrent Pancreatitis

In revisiting this case, again, recurrent pancreatitis, no history of obesity, so no secondary causes identified. Minimal response, I think considering genetic testing is reasonable. This patient's snapshot raises a strong suspicion for FCS.

The immediate priority in these patients is pancreatitis prevention. Again, above 500, the risk of pancreatitis goes up. Above 880, you have chylomicrons. You really need to be above 880 or 1,000 to develop pancreatitis; why do we worry about 500? There is no chylomicrons until you get to about 880 to 1,000. However, it turns out above 500, we supersaturate lipoprotein lipase. All the binding sites are filled up. That means you do not have any wiggle room. Even though you will not get pancreatitis at 650 or maybe 700, if you go out and have a fatty meal at 500, you go to 2,000 like that. You have got this dramatic excursion. You get in trouble very quickly because you have no wiggle room. That is why we worry about keeping the triglycerides below 500.

At this point, the takeaway is early recognition and targeted therapy can significantly reduce acute pancreatitis risk and improve quality of life by giving them a little more leeway when it comes to their dietary choices, but they still have to be vigilant with regarding that.

We will go on to the next case now.

Case 2: Applying the Evidence to Patient‑Centered Decision‑Making

Dr. Ahmad: Thank you.

Patient Case 2: 68‑Yr‑Old Male with Persistent HTG and Increased Cardiometabolic Risk

The next case is a 68‑year‑old male with persistent hypertriglyceridemia and increased metabolic risk. The idea with these cases is that you would discuss them amongst yourselves, which I can give you 10 seconds to do that if you like, but we are a little bit behind. Maybe we will just help everyone. We will all go through it together, maybe.

The snapshot of this patient is he has triglycerides in the five hundreds persistently. No history of acute pancreatitis. His past medical history includes type 2 diabetes and hypertension with features of metabolic syndrome. He has a BMI of 32kg/m². His current therapy includes statin plus lifestyle modifications, and his diet is high in refined carbohydrates, and he is inconsistently adherent to dietary changes.

Maybe by a show of hands, how many people think that this patient might have FCS? How about the more common, multifactorial chylomicronemia syndrome? Yes. Would you focus on pancreatitis risk, or would you focus on cardiovascular risk? Okay. You focus on both, but I would probably lean towards cardiovascular risk myself, too.

Poll 9 – Decision Point 1

Here is a poll for that question. What is the most likely underlying driver of this patient's hypertriglyceridemia?

A. Multifactorial hypertriglyceridemia driven by metabolic syndrome

B. FCS

C. Dysbetalipoproteinemia

D. Isolated dietary hypertriglyceridemia

I am actually glad they put diet on here. We forgot to talk about this, but people on keto or carnivore diet on high fat diets, they can eat their way to severe hypertriglyceridemia. On average, people do not, but there are a few people probably who have a polygenic background that they go on keto or carnivore and their triglycerides get into the thousands. I have seen people get pancreatitis from that. Yes, I would agree with that. I think Dr. Underberg, you would agree with that answer too. Multifactorial hypertriglyceridemia.

Dr. Underberg: Yes.

Poll 10 – Decision Point 2

Dr. Ahmad: What is the most appropriate next step in management to reduce risk?

A. Initiate ApoC‑III targeted therapy

B. Add PCSK9 therapy

C. Intensify glycemic control, and initiate fibrate therapy

D. Continue current therapy and monitor

Okay. Intensify glycemic control, and initiate fibrate therapy. I think that is very reasonable that that is probably the right answer. This is a poll. We want to see what you all do. This is not necessarily a right answer per se.

Poll 11 – Decision Point 3

What should be the primary treatment goal for this patient?

A. Prevent acute pancreatitis

B. Reduce ASCVD risk while addressing metabolic drivers

C. Normalize triglycerides less than 150mg per deciliter immediately

D. Initiate genetic testing for lipid disorders

It looks like most people would want to reduce ASCVD risk while addressing metabolic drivers. That is very reasonable. You could also say that you want to prevent acute pancreatitis because as triglycerides are 550, so they are above that 500 milligram per deciliter cut‑off. In reality, we would do both. We would do what it takes to reduce the risk of pancreatitis, which would mostly be controlling the secondary issues of diabetes, and we would want to reduce his ASCVD risk.

Revisiting Patient Case 2: 68‑Yr‑Old Male With Persistent HTG and Increased Cardiometabolic Risk

Going back to this case. Again, what we learned was maybe you think about FCS, but this is probably MCS. In his case, you can argue because the triglycerides are not that high, that ASCVD risk is your immediate priority as well as glycemic control and addressing his diet and weight.

Would someone give a patient like this a GLP‑1 or GLP‑1/GIP drug? Yes. Be brave. It is okay. Yes, I would. No history of pancreatitis and the triglycerides are not that bad. I would do it. If he lost weight, his triglycerides would probably improve quite dramatically. As a diagnosis, this is MCS driven by polygenic secondary factors. You do not need to do genetic testing, as you all know. The long‑term strategy is to optimize his statin, and lipid lowering therapy as needed, and prioritize the long‑term metabolic risk control.

That is good. I think you all understand MCS and FCS quite well.

The takeaway here is that effective management of MCS requires healthcare providers to prioritize ASCVD, metabolic, and residual triglyceride risk.

I will turn it back to Dr. Underberg for the third case.

Case 3: Individualizing Care When Risk Persists

Dr. Underberg: All right. I will try and get through this in a timely fashion so we have time for Q&A also at the end.

Patient Case 3: 50‑Yr‑Old Female with Persistent sHTG

Here is our third case. A 50‑year‑old female with persistent sHTG. Here is the snapshot. Her triglycerides are persistently in the 900mg per deciliter range. No history of acute pancreatitis. History of type 2 diabetes and A1C of 6.8, statin plus a fibrate.

Remember, there is no data showing that adding a fibrate to a statin reduces the risk of ASCVD events. We have tried over and over again to show that. It does not work. However, a fibrate is a great drug to control triglycerides. If you are managing both ASCVD risk and hypertriglyceridemia, you can use them together. Just remember why you are using them.

Adherent to those medicines, modest lifestyle improvement, and no clear genetic diagnosis.

Again, this is the type of thing where probably the more common presentation. Not as clear from one perspective or the other.

Poll 12 – Decision Point 1

What is the key management goal here? The decision point. Make your choice. Is it:

A. Genetic testing

B. LDL reduction

C. HDL normalization

D. Pancreatitis prevention

All right. That is great. That makes me feel good because in a patient like that, you can sometimes become distracted. Once those triglycerides get up into that 880 or above range, it is pancreatitis you need to worry about. The guidelines are clear. Lower triglycerides when they are greater than 500, ostensibly to reduce the risk of pancreatitis. Yes, we can also think about other things. I told you there is this duality of treatment in managing sHTG. You always have to think about the ASCVD also. The immediate issue for this patient, again, is pancreatitis concern. Let us move forward.

Poll 13 – Decision Point 2

What is the most appropriate next step?

A. Add ApoC‑III‑targeted therapy

B. Add a bile acid sequestrant

C. Continue current therapy

D. Discontinue the fibrate

Make your choice now.

86% said add ApoC‑III targeted therapy. That is a reasonable choice at this point. We have already tried a fibrate. We have already tried diet modification. We are worried about reducing pancreatitis risk. A bile acid sequestrant would be contraindicated. Bile acid sequestrants actually increase triglycerides when triglycerides are above 300 and absolutely contraindicated above 500. I would not just continue current therapy, and I would not stop the fibrate. I do not know that there has not been some improvement. If you think there is a side effect from the fibrate, then I guess you could discontinue it. I do not know what your thoughts are there.

Dr. Ahmad: I agree.

Dr. Underberg: Yes. All right.

Poll 14 – Decision Point 3

Which factor is most important in long‑term success? Is it:

A. LDL reduction in lipid targets

B. Adherence to therapy and diet

C. Routine imaging follow‑up

D. Coronary calcium assessment

Adherence to therapy and diet. Again, you want to continue with the diet at all times. These drugs are done as an adjunct to diet. I think LDL reduction in lipid targets is reasonable. If you are worried about ASCVD risk, I do not know that a coronary calcium scan would be inappropriate. Remember, you do have to think about this duality of outcomes. If someone had chosen that, I would not say, "No, it is unreasonable," but I do not know that I would do much more than what we have listed here.

When revisiting this patient again, what we have learned raises a strong suspicion for refractory sHTG and an unmet treatment need. The immediate priority is reducing the acute pancreatitis risk. The diagnosis of refractory sHTG with a mixed etiology, obviously, you want to reassess for secondary causes, evaluate adherence, and consider genetic testing. Genetic testing can really reveal things that you were not suspecting. I have been fooled many times and genetic testing has led me down pathways I did not expect to go.

The long‑term strategy is obviously to continue this combination therapy and refer to a specialist as needed.

Effective management of refractory sHTG requires healthcare providers to prioritize risk reduction and escalate to targeted therapy when prior treatment fails.

Key Takeaways

These are our key takeaways. Patients with sHTG and FCS are at high risk for acute pancreatitis, metabolic complications, and reduced quality of life. I think we have made that clear. Endocrinologists are indeed experts in metabolism, can help management patients in their diabetes, insulin resistance, obesity, hypothyroidism, alcohol use, and current therapies.

There are a lot more endocrinologists around than there are lipidologists, and I think the majority of these patients are ending up in endocrinology practices.

HCP should suspect FCS if the triggers are greater than 1,000mg per deciliter. Early onset, recurrent acute pancreatitis, and poor response to therapy. If you like to check ApoB, it tends to be low in these patients.

A very low‑fat diet is essential to reduce chylomicron production in sHTG and FCS. Traditional lipid‑lowering therapies have limited efficacy because they work through the lipoprotein lipase mechanism.

Prioritize rapid and durable triglyceride lowering. The triglycerides are between 500 and 1,000, or a history of acute pancreatitis, with early escalation to targeted therapy to improve outcomes. If you are waiting around and someone has that first pancreatitis event, that is no good because once you have had pancreatitis, your risk of a next event goes up almost by twofold. Mortality from pancreatitis is around 6%. Again, you want to prevent the first event. That is really what we try to do.

Emerging ApoC‑III inhibitors significantly reduce triglyceride levels in FCS and refractory sHTG. Endocrinologists are uniquely positioned to identify and treat these high‑risk patients. You must work with specialists to deliver comprehensive, patient‑centered care. It really takes a team. You saw that Venn diagram of all the people involved in managing these patients.

Now we will move on to the posttest assessment.

Posttest Assessment

Dr. Ahmad: Thank you.

Posttest 1

A 45‑year‑old patient presents with triglyceride levels persistently between 1,200 and 1,800mg per deciliter and a prior episode of acute pancreatitis. The patient has been adherent to dietary counselling and is currently treated with a fibrate and omega‑3 fatty acids, with only modest triglyceride reduction. The patient does not have diabetes, obesity, or significant alcohol use.

Which of the following is the most appropriate next step to clarify diagnosis and guide management?

A. Intensify lifestyle counselling and continue current therapy for an additional six months

B. Initiate statin therapy to address residual cardiovascular risk

C. Order genetic testing to evaluate for familial chylomicronemia syndrome

D. Measure lipoprotein(a) to further characterize cardiovascular risk

Rationale

Very good. Both pre and post, everyone suggested order genetic testing to evaluate for familial chylomicronemia syndrome. Good. We can go to the next question.

Posttest 2

A 38‑year‑old person with recurrent pancreatitis has triglycerides above 2,000mg per deciliter, despite diet, fibrates, and omega‑3s. BMI is 22kg/m², and there are no secondary causes, and ApoB is low. What is the most appropriate next step?

A. Add high intensity statin to reduce residual cardiovascular risk

B. Escalate fibrate therapy and reassess in eight weeks

C. Initiate high dose prescription omega‑3 fatty acid therapy before further evaluation

D. Initiate ApoC‑III‑targeted therapy

Good. Initiate ApoC‑III‑targeted therapy both pre and posttest.

Rationale

People scored quite well. I think everyone recognizes this patient has FCS and would benefit from something way beyond what we traditionally give. Move to the next question.

Posttest 3

A 42‑year‑old man with type 2 diabetes and obesity presents with triglycerides of 1,200mg per deciliter and a prior episode of pancreatitis. He reports inconsistent diet adherence and suboptimal glycemic control with an A1C of 9.2%. He is on a statin and low‑dose omega‑3 fatty acids, in addition to intensifying glycemic control. What is the most appropriate next step to reduce his pancreatitis risk?

A. Add high‑intensity statin therapy

B. Initiate ApoC‑III‑targeted therapy

C. Initiate fibrate therapy

D. Start PCSK9 inhibitor therapy

Pretest, most people put initiate fibrate therapy. Posttest, 58% said initiate ApoC‑III‑targeted therapy.

Dr. Underberg: Good job.

Dr. Ahmad: Okay. Go to the next slide.

Rationale

The actual correct answer was initiate fibrate therapy. People did better pre than post. We may have biased you by talking about ApoC‑III inhibitors, but he is not on a fibrate. He obviously has multifactorial chylomicronemia syndrome. You can try fibrates before you jump to ApoC‑III inhibitors. I would not fault you for going ApoC‑III, but I think you still have something to use. Next question.

Question and Answer Session

Now we are done. We are in the question‑and‑answer section. We have seven minutes. We have got a bunch of questions, and some of them are long. I apologize if we cannot answer every single part, but we will do the best we can.

First question is, can you discuss triglyceride cut‑offs in other ethnic groups, in particular African Americans?

Maybe I can discuss that a little bit. Even though there are differences in triglycerides based upon your racial background or, more consistently, your genetic ancestry, there is no real difference in cut‑offs. It seems like the same physiology happens in an African American as compared to a European ancestry individual if the triglycerides are above 500 or above 1,000, etc. The cut‑offs are the same.

The next person asked a bunch of questions about omega‑3s. We will just answer one of them. Dr. Underberg, what would you recommend as a dose of omega‑3s when triglyceride levels are below 200mg per deciliter?

Dr. Underberg: The current recommendation for the use of omega‑3s is either at a very high dose, four grams a day for lowering triglycerides, or we recommend using them in patients either with diabetes or a risk of ASCVD to reduce the risk of heart attack and stroke at four grams a day based on the REDUCE‑IT trial. The reality is that using low‑dose omega‑3s, there really is not much data behind their cardiovascular benefit, and you would not use a dose that low to lower triglycerides.

Dr. Ahmad: Yes, I agree. We will go on to the next question, which is a very important one. By decreasing severe hypertriglyceridemia, do these medications ‑ I assume you mean talking about ApoC‑III inhibitors ‑ have they been shown to decrease the risk of cardiovascular disease?

Dr. Underberg: That is a great question. If you actually look at folks who have a naturally occurring loss of function of ApoC‑III. They seem to have a reduction in ASCVD events, and ApoC‑III levels track with risk of cardiovascular disease. However, there is no data yet on the impact of using ApoC‑III inhibitors to reduce the risk of ASCVD events. Lowering triglycerides per se may or may not be an effective pathway. We know that ApoB lowering is an effective pathway, but you would have to show an effect in patients with lower triglyceride levels who are at increased risk. Either sHTG or even patients with mild to moderate hypertriglyceridemia with dyslipoproteinemia, meaning increased non‑HDL and ApoB levels. The answer is we do not know yet. Long answer to a short question.

Dr. Ahmad: Someone has asked about genetic testing places where to refer the patients. I think this could be one of two things, like what genetic testing companies there are that will check for FCS. There is actually several. We commonly use a company called GBinsight that has a very comprehensive panel for just about every lipid disorder, and it is just one test. They will check everything. There are other companies. Almost every company has a panel that they will call a triglyceride panel, an FCS panel, or a dyslipidemia panel. People often use Invitae or Ambry.

If the question is referring to where the patient can go to get genetic testing, many lipid specialists are comfortable with genetic testing. Not all, but many are. If they are in Texas, they can always see me. I can see anyone within the state of Texas via telehealth. I am happy to do that and order genetic testing.

If you are looking for a genetic counsellor, the American Society of Genetic Counselling on their website, you can actually search for a genetic counsellor. The genetic counselling world is more focused on cancer genetics because that actually gets reimbursed, and state by state is different. In our state, genetic counsellors do not really get reimbursed much. There are not too many genetic counsellors in Texas.

Dr. Underberg: I was going to add that I run a lipid clinic at Bellevue Hospital. There if the patient has any insurance, we can generally get genetic testing for FCS. If you go to the NLA website, lipid.org, there is a section on documents, recommendations, and guidelines that are all free downloads. We wrote a paper a couple of years ago on genetic testing for dyslipidemia. It is a really great resource, including an infographic and patient‑facing information. The key is learning how to counsel your patients. There are a bunch of great CME programs out there on how to do genetic counselling for the non‑geneticist.

Dr. Ahmad: Yes. Many of the lipid disorders do not require a lot of complex genetic counselling. You can learn it very quickly and do it in just a few minutes before and after doing the genetic counselling.

There are a few questions about GLP‑1 drugs. Would you use them with someone with a history of pancreatitis? Do they have any role in FCS?

Dr. Underberg: That is where I refer to an endocrinologist. Generally, people get itchy about using it in someone with a history of pancreatitis because of the contraindication, and it would not be my first choice of therapeutics in FCS. Again, in MCS, I think managing diabetes or any other dysglycemic issue is important. I have spoken to endocrinologists who say they will use it, but I will tell you, you do have to exercise caution.

Dr. Ahmad: Yes. It requires a very balanced discussion with your patient to explain the potential risk of pancreatitis. I know some people believe that there is no risk of pancreatitis with GLP‑1s. I honestly am not sure myself, but I will say that in the clinical trials of tirzepatide and semaglutide, they exclude people with a history of pancreatitis. We do not know really what happens when you give those people a GLP‑1 or GLP‑1/GIP drug. It is unfortunate we do not have that data, but that is the situation.

In some cases, I might give it to these patients. If they have never had a history of pancreatitis and their triglycerides are below 1,000, I feel much more comfortable giving it.

Dr. Underberg: Someone was kind enough to ask not a question for Dr. Underberg, but congrats to the Knicks. Thank you. There was also a question about omega‑3 in lactation. I saw that. As far as I know, the American College of Obstetrics and Gynecology actually encourages that. I would not use that as a contraindication to put someone on omega‑3 if I thought they needed it.

Dr. Ahmad: Yes. It is a dose‑dependent thing. They recommend, I think, 200mg of DHA and EPA, which is far less than what we give people to lower triglycerides. There is a bit of caution you have to use, but probably it is okay.

Dr. Underberg: It increases bleeding time a little bit.

Dr. Ahmad: There is another question about when choosing an omega‑3 fatty acid, icosapent ethyl has been shown to decrease cardiovascular risk. When do you use the other omega‑3s?

Dr. Underberg: If I were trying to lower triglycerides, generic mixed DHA and EPA has been shown to reduce triglycerides effectively. If you are using triglycerides to lower triglycerides in people with sHTG, I think you can use either of the two preparations that are prescription‑grade omega‑3. What I would not use is nonprescription omega‑3. There is no such thing as over‑the‑counter omega‑3s. They are non‑prescription supplements. They are generally not as purified, and they are low potency, so you have to take a lot of them, which means you end up getting a lot of extra fat. I would only use prescription‑grade omega‑3s.