Exploring the Pathophysiology of sHTG, FCS, and the Patient Experience

Dr Michael Shapiro (Wake Forest University School of Medicine): I am going to start with talking about the epidemiology and pathophysiology of sHTG and FCS, and we will also incorporate the patient experience, which is incredibly important into this discussion.

[00:43:11]

Defining Hypertriglyceridemia and Cut Points

Here, as you can see, definitions of hypertriglyceridemia have evolved over time. This is really looking at a 30-year sweep of different guidelines all the way back to 1993 with the National Cholesterol Education Program. Then more recently, National Lipid Association, American Heart Association statements, and then most recently in 2021, the ACC Expert Consensus Decision Pathway.

What you can see at least in the more recent years, there is generally pretty uniform agreement that normal triglycerides are defined by less than 150 mg/dL. Though, I think it is interesting and important that both the NLA and the AHA highlight that actually optimal is less than 100. In other words, individuals who have the ability to metabolize triglycerides normally, really should have a fasting triglyceride level less than 100 mg/dL.

Then there is various gradations in elevations of triglycerides, borderline, high, very high, and that has changed to some extent. Now, generally borderline is considered either 150 to 199. More recently, the ACC has made that a little bit narrower between 150 to 174, and then high as being either 150 to 499 or 175 to 499. Then very high or severe hypertriglyceridemia is conventionally defined as greater or equal to 500 mg/dL. We specifically call that demarcation out because that is really when the risk of acute pancreatitis becomes tangible.

[00:44:45]

Hypertriglyceridemia in the United States (2009-2012)

If we look at the prevalence of hypertriglyceridemia in the United States, this is NHANES data. This is looking at both amongst men and women then across different age groups. You can see that in general, men have a higher prevalence of triglycerides greater than 150, although females, women above the age of 60 tend to have higher triglyceride levels than men. But if you look across both sexes, all ages, what you see is that this is a highly prevalent condition. Somewhere between 20% to 30% of the US population has triglycerides that are above 150 mg/dL. We are all encountering this every day, and it is extremely important that we understand how prevalent it really is.

[00:45:28]

Consider Chylomicronemia Syndrome if TG >880 mg/dL

Then, of course, if we look at this distribution, above 500 mg/dL, where I said we start to see an increase in the risk of acute pancreatitis. Again, according to the most recent NHANES data, about 1.7% of the US population has triglycerides greater than 500, but then there is this very high group or extreme hypertriglyceridemia, which is variably defined either 880 or greater than 1,000 mg/dL. The 880 basically comes from the European 10 mmol/L, which basically translates into 880 mg/dL.

This 880 or 1,000 is really where, there is a significant risk for acute pancreatitis and what we call chylomicronemia.

[00:46:14]

Chylomicrons May Cause Injury, Leading to Acute Pancreatitis

Now, again, the most feared complication of chylomicronemia is acute and recurrent pancreatitis. There are a few prevailing views as to how chylomicronemia actually causes pancreatitis. One is that when you have all of these chylomicrons getting through the pancreatic tissue, the intrinsic lipases of the pancreas will act on the triglycerides that are carried in the chylomicrons, liberating free fatty acids, which can lead to inflammation of the pancreas and ultimately acute pancreatitis.

The other prevailing view is that severe chylomicronemia actually changes the rheology of blood. You actually cause a hyperviscosity syndrome. You get impaired blood flow, capillary ischemia in the pancreas, leading to ischemia, acidosis, and ultimately acute pancreatitis. Those are the 2 leading views of how that might happen.

[00:47:02]

Fasting vs Nonfasting Lipid Panels

Now, there has been a lot of confusion over the last decade and a half about whether we should be pursuing fasting vs nonfasting lipid panels. Actually, different professional societies have different recommendations on that, but for the most part, in the general population, most professional guidelines say that nonfasting lipid panels are adequate.

Really, the postprandial status really impacts triglycerides more than any other lipid fraction, but in individuals who have normal metabolism and they have normal LPL activity, the excursion in triglycerides, even postprandially, is probably much more modest than most people recognize.

If you were to now draw your lipid panel, say an hour or 2 after your meal, most people will see a very modest increase in triglycerides, maybe up to 25 mg/dL. It is only in people who have impaired ability to metabolize triglyceride-rich lipid proteins where you see this more extreme excursion.

For adults 20 years and older who are not on lipid-lowering drug therapy, most recommend either a fasting or nonfasting lipid profile that can be used to estimate ASCVD risk and document baseline LDL cholesterol. But of course, for those individuals who have nonfasting triglycerides at 200 or more, then it is recommended to do a repeat fasting lipid profile to assess fasting triglycerides and baseline LDL cholesterol.

[00:48:28]

Fasting Lipid Panels: Preferred for Assessing Specific Populations

Here, this is just highlighting some of the special populations where perhaps a fasting lipid panel is preferred. One is if you are trying to establish the diagnosis of metabolic syndrome. Of course, then fasting triglyceride greater than 150 is part of the diagnosis.

Also, fasting is more useful to assess adherence in individuals who are being treated for ASCVD risk reduction, individuals with lipid disorders in the family, or individuals at risk of hypertriglyceridemia-induced pancreatitis. In other words, triglycerides greater than 500.

[00:49:00]

Elevated Triglycerides Convey Cardiovascular Risk

Now, you are all aware of the very consistent association between hypertriglyceridemia and atherosclerotic cardiovascular disease. That association has basically been seen in every single population-based cohort, but what may not be recognized as commonly is that even within the so-called normal range of triglycerides, you can actually see a stratification of risk. There is a risk of radiance.

Here, you are looking at individuals in quartile one, that is blue, that is the bottom curve. These are individuals who have triglycerides less than 82 and, of course, low rates of cardiovascular events. But when you go to quartile 2, which is triglycerides of 82 to 110, squarely within the normal range, you do see an increased risk of ASCVD. If you go to quartile 3, 110 to 153, fairly normal. See increased risk.

Then, of course, quartile 4, in purple, individuals with triglycerides greater than 150, you see a much more substantial risk. You can see increased risk even within the normal range of triglyceride levels.

[00:50:01]

Primary and Secondary Causes of Hypertriglyceridemia

Now, just like we evaluate patients with hypercholesterolemia, we have to rule out secondary causes before we say somebody has a genetic diagnosis. In fact, for hypertriglyceridemia, this is even more important because it is so common to see secondary factors that lead to hypertriglyceridemia.

I tend to group secondary causes really into 3 categories. One would be lifestyle, one would be comorbidities, and one would be medications. Of course, for lifestyle, individuals who have a poor diet, sedentary behavior, too much alcohol, that is all going to be associated with increased triglycerides.

For comorbidities, of course, metabolic syndrome, diabetes, those are going to be the most common if they are not well-treated, and the A1C is elevated, individuals with hypothyroidism, CKD, HIV, chronic inflammation, all associated with hypertriglyceridemia.

Medications, I would group again into 3 buckets. One would be hormones, one would be post-transplant meds, and then finally a group that is basically miscellaneous. Of course, for the hormones, that would include oral estrogens, would include corticosteroids. For individuals who are post-transplant, that is going to include things like cyclosporines, sirolimus. For the miscellaneous category, some of the drugs that we use all the time in cardiology, like beta blockers and thiazide-like diuretics, all important to evaluate.

[00:51:31]

VLDL and Chylomicron Synthesis and LPL-Medicated Lipolysis

We have really 2 major categories of triglyceride-rich lipoproteins. We have the intestinally derived triglyceride-rich lipoproteins. Those are the chylomicrons. It is basically causing fat, containing fat that is received from the diet. That enters into the systemic circulation. The liver, the hepatic-derived triglyceride-rich lipoproteins, which are the VLDLs, are the other triglyceride-rich lipoproteins.

Of course, the major role of these triglyceride-rich lipoproteins are to bring sources of potential energy, triglycerides, which contain a glycerol backbone in 3 fatty acids that are bound to it. Those fatty acids, of course, are a form of potential energy. Basically, you are bringing these triglyceride-rich lipoproteins to the tissues that really need it. That would be skeletal muscle and cardiac muscle, and for storage to adipose tissue.

The capillary beds in those tissues are enriched with an enzyme called lipoprotein lipase, which is basically the enzyme that can catabolize these triglyceride-rich lipoproteins, that cuts off those fatty acids off the glycerol backbone.

Now, those fatty acids can actually now enter the cells, whether you are talking about skeletal muscle, cardiac muscle, and then get into beta oxidation for production of ATP. Or in adipose tissue, you also have lipoprotein lipase on the capillary endothelium there. You clip off those fatty acids, they get shuttled into the fat cells and then they get re-esterified within the fat cell and stored as triglycerides and fat droplets that can be mobilized when energy stores are low.

This system is highly regulated. Here, at the bottom of this figure, you can see LPL, that is lipoprotein lipase that is on the capillary endothelial cells, but it is also regulated by a number of other factors. There are some intrinsic inhibitors and there are some intrinsic activators. This is a finely tuned metabolic machinery.

[00:53:28]

FCS: Impaired Function of LPL Enzyme

As I said, dietary fat causes chylomicron release from the intestine for patients without FCS. In other words, individuals with normal metabolism. Lipoprotein lipase will rapidly hydrolyze those triglycerides and chylomicrons. That LPL activity is essential to prevent chylomicronemia, but mutations in either lipoprotein lipase or one of these other activators will actually be associated with chylomicronemia. In other words, you are not able to catabolize those triglyceride-rich lipoproteins, and chylomicrons accumulate in the circulation.

[00:54:05]

LPL-Independent Pathway of Lipoprotein Metabolism

That is the canonical understanding of triglyceride-rich lipoprotein metabolism. More recently, it has been understood that there are also LPL-independent pathways. There are a number of clearance receptors, the LDL receptor and related receptors, that can actually bind to these triglyceride-rich lipoproteins. These are primarily on the liver, and clear them from the circulation.

[00:54:30]

Metabolism of Triglycerides

Now, it turns out that APOC3, which is now a very important targeted therapy, is an intrinsic inhibitor of lipoprotein lipase activity. In individuals where there is excess of APOC3, and therefore there is an inhibition of lipoprotein lipase, antagonizing APOC3 would be associated with better catabolism of those triglyceride-rich lipoproteins. That would be in the LPL-dependent pathway, but you have to also understand that APOC3 is carried on these triglyceride-rich lipoproteins, and it can actually impede its clearance.

By reducing the amount of APOC3, it might facilitate also the clearance of these triglyceride-rich lipoproteins from the circulation, and that would be through the LPL-independent pathway.

[00:55:16]

Association of APOC3 Loss-of-Function Mutations and CVD-Risk

Now, human genetics is very, very interesting. This is data from just over a decade ago. There were actually 2 genetic studies that were published in the same issue of The New England Journal of Medicine, and basically showed exactly the same results. Here is one of these. These looked at naturally occurring loss-of-function mutations in APOC3 and their impact on triglycerides and cardiovascular disease risk.

Basically, what both of these studies showed is that individuals who had naturally occurring loss-of-function mutations in APOC3 had about a 40% reduction in triglycerides and had approximately a 40% reduction in atherosclerotic cardiovascular disease. This sounds very similar to the PCSK9 story. You will recall that it was naturally occurring loss-of-function mutations in PCSK9 that was found to be associated with lifelong reductions in LDL and fairly significant reductions in ASCVD.

This became a very appealing targeted therapy, especially since there was no other safety issues associated with loss-of-function mutations in PCSK9. We are seeing the same genetic discovery leading to intelligent drug development with this APOC3 pathway as well.

[00:56:30]

Quiz Time

Posttest 1

With that, let us get into another question. Actually, this is a post-test. You have seen this question before, and we will see how we have done in terms of learning this material.

Which of the following best describes the pathophysiology of FCS?

1. FCS is caused by excessive dietary fat intake and can be effectively managed with standard triglyceride-lowering therapies;
2. FCS primarily results from elevated chylomicrons due to genetic defects in APOC3 activity;
3. FCS primarily results from elevated chylomicrons due to genetic defects and lipoprotein lipase activity; or
4. FCS is caused by an overproduction of triglycerides.

You can vote now, and we will see how we have done.

[00:57:24]

          Posttest 1: Rationale

Answer C is correct because FCS is caused by mutations in LPL, leading to impaired hydrolysis of chylomicrons. This results in extreme hypertriglyceridemia, persistent chylomicronemia, and an increased risk of pancreatitis.

[00:57:41]

Team Scores

Man, you are breaking away. I see. What is going on?

[00:57:51]

Patient Perspective

Now, we are going to hear very importantly the patient perspective of FCS.

Scott Reavis: My name is Scott Reavis, and I am a patient living with FCS or familial chylomicronemia syndrome. I was misdiagnosed for 23 years, and it was a long road to finally get a diagnosis. I had many years of pancreatitis flare-ups of hospital stays, at 2 weeks in intensive care at a time. Many of those doctors in the hospital labeled me as an alcoholic because of my triglycerides being just so high. That was part of my misdiagnosis.

I had to tell them, “Look, I do not drink alcohol. I do not even take communion at church, so that I can be able to say that I do not partake in any alcohol”. The misdiagnosis and being labeled as an alcoholic or a pill head, which I was told to my face that I am just in the intensive care looking for pain medicine, that is just not the case.

I cannot believe that the doctors treated me this way. Or as I like to call and tell people, I was abused by these doctors through these 23 years of misdiagnosis. Once I have had the diagnosis, things have changed for me. I have gotten the care that I need. This stereotype of being an alcoholic or a pill head has gone away because I can now say I have FCS, which has been genetically confirmed through a genetic test.

My symptoms during this time presented itself with extremely high triglycerides, pancreatitis flare-ups multiple times a year. I was having eruptive xanthomas, which is the fat coming out of my skin. Those were just some of my symptoms that I experienced during my misdiagnosis.

[01:00:17]

FCS: Fasting Chylomicronemia (TG >880 mg/dL)

Dr Shapiro: Again, talking about fasting chylomicronemia, if you are looking at the most extreme form, generally defined as triglycerides, greater than 880 mg/dL. That can be associated with a variety of different signs and symptoms, some that people may not be as frequently aware of.

[01:00:39]

FCS: Clinical Signs and Symptoms

One of the clues that somebody may actually have FCS is their lack of response to the standard triglyceride lowering drugs. Fibrates, Omega-3s, even statins. There would be limited to no response.

Many of these patients have abdominal pain, even in the absence of acute pancreatitis. They will frequently have mild to severe abdominal pain. Of course, as we have talked about, the most feared complication is acute pancreatitis. Up to 80% of individuals with FCS will experience at least 1 episode of acute pancreatitis with the majority experiencing multiple recurrent episodes. As you have heard about, there are a variety of other additional symptoms, including eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, cognitive impairment, which is often described as a brain fog or other emotional symptoms such as depression, anxiety, and of course, social isolation.

[01:01:13]

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

This basically charts out these various symptoms. Now, frequently, you can see them, but as you can see, people are living with this all the time, daily, difficulty concentrating, brain fog, forgetfulness, impaired judgment, recent memory loss. This is something that plagues people with FCS on a daily basis. We need to look at other symptoms beyond just pancreatitis.

[01:01:59]

FCS: Lack of Lipoprotein Lipase Activity Increases Risk of Pancreatitis

Now, in terms of risk of acute pancreatitis, of course, we draw this arbitrary line in the sand at about triglycerides of greater than 500. That is really where we have told clinicians you need to get people below 500 to reduce the risk of pancreatitis, but it really increases exponentially as triglycerides go up, particularly over 880 or a 1,000.

What this is basically showing is, in individuals on the left in blue with triglyceride levels between 400 and 800, they do have significantly increased risk relative to individuals who have normal triglycerides. But look at what happens when triglycerides go over 800. Specifically, if you are talking about FCS in the far right in green, lipoprotein lipase deficiency, so pathogenic mutations in LPL or the co-factors, you can see how dramatically increased the risk of pancreatitis is because these individuals generally have levels in the thousands, so really high-risk lifetime for acute pancreatitis.

[01:03:05]

Pancreatitis Caused by Severe HTG: Greater Morbidity and Mortality

This is extremely important because all pancreatitis, whether it is from alcohol gallstones, triglycerides, is a very serious condition, but specifically acute pancreatitis related to triglycerides is much more morbid. Actually, fatality rates are considerably higher. You can see here in individuals with hypertriglyceridemia-induced pancreatitis compared to other causes, they have longer hospital stays, more need for intensive care, more pancreatic necrosis, more persistent organ failure. You can see that mortality is almost threefold increased in acute pancreatitis. It is important to actually try to prevent even the first episode of acute pancreatitis because it is such a morbid condition.

[01:03:46]

FCS Leads to Recurrent Abdominal Pain and Acute Pancreatitis

You can see that in these 250 patients with FCS, the majority had a history of recurrent abdominal pain, and about half had a recurrent episode of acute pancreatitis.

[01:03:58]

Women May Face Additional Risks: Pregnancy

Now, women face an additional challenge. Christie, we were just talking about this a little while ago, very challenging to take care of women who become pregnant and have severe hypercholesterolemia, specifically FCS, because we know even in individuals with normal metabolism, triglycerides are anticipated to go up fairly substantially over the course of the pregnancy becomes much more difficult. A woman who gets pregnant with FCSA, very challenging condition indeed.

[01:04:27]

Diagnosis is Critical to Care for Patients With FCS

As you heard from the patient, these patients are generally misdiagnosed for a very long time, going from provider to provider until they get the appropriate diagnosis. Of course, that means everything because if you do not have the appropriate diagnosis, you are not getting the appropriate treatment.

Two-thirds of patients with FCS have reported their symptoms being previously misdiagnosed related to something else. As you heard from our patient, they report seeing an average of about 5 healthcare providers before receiving the correct diagnosis of FCS. This of course, is incredibly important so that patients can get the right care.

[01:05:02]

Diagnosis of FCS: European Algorithm

Now, there are a couple of clinical algorithms for facilitating clinical diagnosis of FCS. This is the European algorithm. We have had this for about 5 years. Basically, the suggestion here is if see somebody with persistent chylomicronemia, their triglycerides are always above 880 or above 1,000. You should look at a variety of these criteria to see if they actually meet a clinical diagnosis of FCS.

I would not go through each of the criteria. Suffice it to say, basically, there is different weights that are attributed to different clinical criteria. If you add all these points up and the score is 10 or more, then FCS is very likely. If you are 9, FCS is unlikely. If you are 8 or less, it is considered to be very unlikely.

[01:05:51]

Clinical FCS Score Calculator: North American Algorithm

Now, very recently, within the last couple of months, we have a new clinical algorithm. This is the North American FCS score. Just like its predecessor, it uses a variety of weights, different clinical categories. Here again, if the total score is greater than or equal to 60, that would be compatible with a clinical diagnosis of familial chylomicronemia syndrome. Of course, genetic testing has been available for a long time, but you can make a clinical diagnosis of FCS that you do not necessarily need to get genetic testing.

[01:06:24]

FCS Can Be Clinically Recognized or Diagnosed

At a very practical level, when should you be suspicious of FCS? Because you are not going to remember all of those clinical categories that I just went through on those calculators, but if you see somebody who persistently has triglycerides above 880 or above 1,000 with very minimal to no response to the traditional triglyceride lowering meds, fibroids, omega-3s, statins, maybe niacin, with a history of acute or recurrent pancreatitis, history of abdominal pain, and absent secondary causes, so they are not drinking alcohol, they do not have uncontrolled diabetes, they are not taking some of the medications that we reviewed. These are people that you should be very suspicious, and those are the people that you can actually then go back and use one of these FCS clinical algorithms to see if you can make the diagnosis.

[01:07:12]

Lipid Panel Parameters for Diagnosing FCS

Just looking at the lipid panel, there are things that also would be very consistent with FCS. If we look at the various parameters that you have in a lipid panel, total cholesterol. Well, chylomicrons contain cholesterol. If you have chylomicronemia, you have also high total cholesterol. These patients will typically have low HDL. They are the inverse relationship between HDL, cholesterol, and triglycerides. Of course, triglycerides are persistently elevated, often in the thousands.

LDL cholesterol is often low, but I would recommend actually getting an APOB because the LDL cholesterol in these patients is not going to be accurate. I think APOB can be very helpful in these patients because if it is normal or low, that is again highly suggestive that you are dealing with somebody with FCS.

[01:08:00]

Genetic Load of FCS vs MCS

There is also a very helpful concept of so-called genetic load to differentiate between FCS and a related condition called multifactorial chylomicronemia syndrome. FCS, of course, we are talking about the biallelic pathogenic mutations in LPL or its related co-factors. These are the individuals who are going to have the highest triglycerides and the least response to traditional therapies and the highest risk for acute pancreatitis, recurrent pancreatitis.

But then there is these individuals who may have 1 pathogen of mutation in LPL or one of its co-factors or an accumulation of small effect variants in some of these genes that taken together, can give you high triglycerides but perhaps not quite as high, but can still give you persistent chylomicronemia, can still give you risk of pancreatitis, but not to the same extent as the individual who has true FCS.

[01:08:56]

Cases

I will just end this part of the discussion looking at a couple of cases to see what clues you can use to try to make a differentiation between these 2 conditions.

Case one on the left, this is a 35-year-old woman, 5'3", 120 pounds. BMI is 21. Totally normal. Fasting triglycerides have always been between 2,500 to 3000, normal A1C. We are told that her last blood draw was creamy. She is on fenofibrate, EPA/DHA, niacin. Lifestyle, healthy eater, avoids high fat. She has had 6 hospitalizations since childhood with abdominal pain and pancreatitis. Her gallbladder has been removed. She never or rarely uses alcohol, and she notes skin rash, looks like blistering and comes and goes. This is quite consistent, of course, with FCS.

Case 2, 45-year-old male. 6'1", 250 pounds. BMI of 30. Fasting triglycerides, 942. A1C, 6.5%. Controlled diabetes. Fenofibrate, EPA/DHA, rosuvastatin. Lifestyle. Complaints of stomach pain frequently. Has had 4 episodes of pancreatitis. Alcohol use. Drinks 4 to 5 drinks per day. We have all seen this patient. Every week you are seeing this patient.

This individual, of course, has many secondary factors. There may be some genetic predisposition underlying that, but this is likely more related to secondary factors, not familial chylomicronemia syndrome.

[01:10:25]

Patients Can Benefit From Multidisciplinary Care

I will just conclude by saying that these patients are extremely challenging. Generally, to be successful in treating them, they require the help from a multidisciplinary team, including endocrinologists, cardiologists, lipid specialists, gastroenterologists, pancreatolologist. Actually, I would say dieticians. Dieticians are key to this team because they need to be counseled on very low fat diet, very strict diet to reduce that chylomicronemia.

Christie, I will turn it over to you to talk about some of the clinical trial data.

[01:10:59]

Analyzing New Data on Novel RNA-Based Therapies for sHTG and FCS

Dr Christie Ballantyne (Baylor College of Medicine): Thank you, Michael. It has been a long day for everybody, but I get to do the exciting part. I have been taking care of patients in lipid clinics for a long time, and it has been so challenging to have people who have multiple of pancreatitis. Basically, you try the drugs, they do not work and it is extremely frustrating for these individuals with it.

We have now, for the first time, an approved therapy. I will go through the history on that, but it is really exciting to see, in my career, where you understand the molecular basis. By doing that, actually come up with a treatment. It is great to diagnose something, but if you cannot treat it, where does that go? A little bit of how neurology used to be. They could make these tremendous diagnoses, but then afterwards you say, well, nothing we can do about it. Now, we can do something about it.

[01:11:58]

Selecting Optimal Medical Therapy

Very exciting in terms of this. Now, what we are focusing on tonight is this pancreatitis risk, but there is this also issue of triglycerides and cardiovascular disease.

[01:12:10]

Patient Populations and Considerations

This is the algorithm that was published by my colleague, Salim Virani was part of this ACC Consensus. We are focusing on this part of severe high triglycerides that is over 500. One of the things that was talked about, the first thing is when you see a high triglyceride, the history and physical is very important more than cholesterol because lifestyle plays such an important role in triglycerides.

Why would that be? Well, he explained what are triglycerides for. It is the way you transport fatty acids. They are for energy metabolism. When you see a patient who has a very high triglyceride, first thing I always say when we get to energy metabolism, what is there an epidemic within this country? Obesity.

Somebody comes in and says, I have got high glucose, I got high triglycerides. The first question is I usually say is what did you weigh in high school or college? Then where did you gain the weight? I will have someone actually stand and say, make your stomach muscles as tight as you can, press on their abdomen. I say, I can feel your muscles right below the skin. Where is the fat? It is inside. It is wrapped around the organs. What ends up happening, what does that fat do? Releases fatty acids to the liver. You make more triglycerides and the pancreas is back there.

We say, listen, you have a problem with your energy metabolism, your glucose and your triglycerides. If you want to improve your energy metabolism, what can you do? Well, carbohydrates and fats. What else can you do? Burn more energy. This is the loss of thermodynamics. Lifestyle makes a huge difference. Cholesterol is harder, but this is one where we talk about lifestyle. It is a fundamental aspect. This is also pharmacotherapy, ruling out secondary causes for this.

[01:14:17]

For Patients Aged ≥ 20 Yr With sHTG

Now, what we are really focusing on more tonight is triglyceride over 1,000. He already went over this issue. You always look for diabetes, alcohol, other types of secondary factors because those can make a huge difference in terms of some of the patients.

Now, for the people who have biallelic FCS, when it is genetic, unfortunately, it does not make much difference.

[01:14:43]

Common Medication Therapies for sHTG

You can try all these things with it. What do we use? Well, these are our therapies for triglycerides. Fibrates, they are pretty effective for triglyceride reductions in most people, up to 50%. Omega-3 fatty acids. You have got statins which do not give as much, but they are beneficial.

Niacin does, but it raises glucose and has not been shown to be reduce events on top of statins. You can use it sometimes for very high triglycerides if it is MCS. For FCS, it does not do anything. We have data, some of these for cardiovascular event reduction. Statins, we know work. EPA, we do not have studies.

Generic. Mix Omega-3 ethyl esters are perfectly fine in terms of triglycerides. EPA is not better than the generic Omega-3 ethyl esters for triglyceride reduction. It is superior for cardiovascular event reduction.

[01:15:40]

Tailored and Stringent Diets for Patients With FCS Are Critical

This is one of the things that comes up, the diet is very restrictive for FCS. You are talking about 15, 20 grams of fat per day. It is really hard to do that. What ends up happening is somebody goes to a party or they are with their kids, they are doing something. It is very, very easy to exceed that. Unfortunately, it is unforgiving. You can end up with pancreatitis, just with a couple of bad meals with it.

These are the other things in terms of MCS is going to be more of the carbohydrates. Alcohol is going to be bad for everybody. You can use a medium chain triglycerides because they do not make chylomicrons with that.

The main thing is you need to have very careful follow up. Let us go back to our patient.

[01:16:35]

Patient Perspective

Scott Reavis: How does FCS impact my daily life? I left my corporate management job and started working for myself, just for the simple fact that I needed the flexibility of attending multiple doctor's appointments a week, 12 hours a month in my doctor's office for IV infusions, additional hospital visits and whatnot. I had to have that flexibility, so I left my corporate job that was a very well paying corporate job. I had great health insurance benefits to quit all of that and move into go into business for myself.

Now, I have to pay for my own health insurance, which is really expensive. The impact of daily life for me and my family has been great, has just out the roof crazy. Because another thing is my diet, which is extremely restrictive. I eat under 10 grams of fat a day. Just to put it in perspective, a tablespoon of ranch salad dressing has 12 grams of fat. If I eat a tablespoon of ranch, I am done for the day. I cannot eat anything else. That calculations and having to be super aware of everything that I put in my mouth. There is that hidden fat as well, that things that should not have fat in them sometimes do.

With FCS, fat is fat. Good fat such as avocados, salmon, tuna, you would think that that is good, but fat is fat and it has to be accounted for in a FCS diet. I have to be super vigilant with my diet. If I am not, then I get a pancreatitis flare up and I am in the hospital in intensive care for a couple weeks, and then at home recovering. That is very important. The diet is very important.

The lack of treatment up until this point, I know that there is a new treatment. I have not been approved yet to get the new treatment. We are in the process, which is another frustration just to get in. I had to wait for months to get into my doctor, and now insurance is being difficult, so we are having to fight it out with insurance to get it approved.

This new therapy has been out for a while now, but I have not been able to take part of it yet because of the red tape and the bureaucracy behind this. It is very frustrating because I know that great things are happening, but I have not been able to participate in those yet.

Thank you so much for the opportunity to come and to share with you about my misdiagnosis, diagnosis, and living with FCS. I am excited for the new treatments that are coming down the pipeline and how these treatments may improve the quality of my life and also the lives of my friends living with FCS.

[01:20:07]

Novel and Emerging Therapies for FCS

Dr Ballantyne: All right. There is hope. In fact, we have an approved therapy, the first of these targets. What has been incredible is once you identify a genetic loss of function variant from what was mentioned, people who had APOC3, PCSK9, we did this. You can have a couple of strategies, monoclonal antibodies, but you can also target messenger RNA. You can do this with antisense oligonucleotides.

The first generation was volanesorsen. Second generation, it is really almost third is olezarsen. There was an improvement just like the same way the initial monoclonals were mirroring and then chimeric and fully human. There has been an improvement by having this targeting to the liver. The dosage was reduced by 90%. Some changes in terms of the backbone.

Now, this is a once-a-month therapy that was approved in December of 2024 for basically patients with FCS to reduce triglycerides. Plozasiran is a small interfering RNA, so targeting, once again messenger RNA for degradation, a little different mechanism. This has also been submitted to the FDA.

[01:21:29]

APPROACH Trial: Volanesorsen for sHTG in FCS

Volanesorsen was the first one, highly effective, but you were giving dosing on a frequent basis. It turned out you were using a larger dosage and you had some patients who had reductions in platelets. This was effective but had more side effects, more injection site reactions. We go back to the drawing boards and develop a better therapy, given once a month, less frequent administrations, lower dosages.

[01:22:08]

BALANCE: Olezarsen in Patients With FCS

This was the data. You can see 80 milligrams. This is in patients with FCS. Olezarsen, 80 milligrams is the approved dosage reducing the triglycerides by, if we take a look from baseline of 40%, but if you look at the placebo subtracted, it is about 60%, 70% reduction at some time points.

In addition to that, there was a reduction in regards numerically to the acute pancreatitis episodes. It was really exciting news to see this study and we thought we would see this because basically, we saw this with volanesorsen. What we did not see here were problems with platelets. You do not have the thrombocytopenia. We have not been seeing that. Also, it is fewer injection site reactions. An improvement in the technology and the delivery system. We have a better safer therapy, which was highly effective, recently approved.

[01:23:13]

PALISADE: Plozasiran in Patients With FCS

This is a drug that is still in the pipeline, has not been approved. This is plozasiran, but targets the same molecule, APOC3. It is an sRNA, reduces triglycerides. Once again, if you look at the placebo adjusted, it is about 70% to 80%, and reduced time to first acute pancreatitis episode. Consistent data, that this is an excellent target.

[01:23:46]

Bridge-TIMI 73a: Olezarsen for HTG in Patients With High Cardiovascular Risk

You can effectively lower triglycerides by targeting APOC3, and most importantly for these patients, you can prevent pancreatitis. Really exciting news for people who have this.

Now, if we go back to, what about the other patients? You mentioned 500 to 1,000 cardiovascular potential. This was data with olezarsen in high cardiovascular risk patients. Once again, that is focused on the 80 milligrams. You can see getting triglycerides. Mentioning to this, optimal level of 100. These were people with mixed hyperlipidemia for the most part. There were some people with severe hypertriglyceridemia who went into the trial.

What you saw is in this study, reductions in APOC3, triglycerides. What we look at in people who have mixed dyslipidemias is something called remnant cholesterol. That is the cholesterol that is atherogenic beyond what is in the LDL, low-density lipoproteins. APOB went down, and also an increase in the levels of HDL cholesterol.

Something that was very promising in regards to the potential for benefit in patients who have high risk for cardiovascular disease.

[01:25:05]

Ongoing Phase III Trials for Olezarsen in sHTG

There is ongoing studies, including a trial which is doing CT angiography to look at the progression of atherosclerosis in these individuals. These studies are well underway. We should be having information later this year. We are looking forward to further information also in patients who have severe high triglycerides, not just FCS over 500.

It is a robust program, lots of information. One of the nice things is when you see all of these phase III studies, the patient exposure is much larger than the smaller rare FCS studies. I am an investigator. Mike is investigating on these studies too. We have not seen any new safety signals. That is very encouraging in terms of understanding more long-term safety in larger numbers.

[01:26:06]

SHASTA-2: Plozasiran in Patients With sHTG

That is the ASO story. What about the sRNA story? This is plozasiran. Once again, now this is phase II data, but showing reductions in triglycerides. These are people with over 500. HDL goes up. You will see this, C3 goes down. Now, when you have very high triglycerides, LDL tends to increase. But what happens has been shown with both of these, it changes the particle. The particles are larger LDL particles. You reduce small, dense LDL more with these therapies.

[01:26:37]

Quiz Time

Okay. Quiz time.

[01:26:38]

Posttest 2

The PALISADE trial evaluated the efficacy of plozasiran in patients with FCS. Based on the trial results compared with placebo, plozasiran demonstrated significant reduction in:

1. Acute abdominal pain;
2. Fasting triglycerides and acute abdominal pain;
3. Fasting triglycerides in time to acute pancreatitis episode;
4. Time to acute pancreatitis episode only.

[01:27:19]

          Posttest 2: Rationale

C is correct because you reduced triglycerides significantly and also you reduce times of pancreatitis episode.

Dr Shapiro: Did you give them the answers?

Dr Ballantyne: I do not know what is going on. I did go to all the tables with teal. I said, you are on my team and I expect everybody to get the answers right. I got to admit it. It is not that I am competitive, I just want to encourage learning.

Posttest 3

A 35-year-old woman with FCS presents with persistent severe hypertriglyceridemia, over 1,500 mg/dL, despite strict adherence to a very low fat diet. She has a history of recurrent pancreatitis, reports significant challenges in maintaining triglyceride control. Which of the following therapies would be the most appropriate to help lower her triglyceride levels and reduce her risk for pancreatitis?

1. Evinacumab;
2. Fibrates;
3. Icosapent ethyl;
4. Olezarsen.

[01:28:42]

          Posttest3: Rationale

D is correct. Olezarsen is an ASO therapy that targets APOC3. Indicated to reduce triglycerides in patients with FCS, and recently approved in December 2024. Now available.

[01:29:00]

Test Scores

Still ahead. I do not know what is going on there.

Just to give you some encouragement with this. The patient was talking about his experience and he had not gotten approved. I was part of the trial for this agent, for FCS, and there is a program to help get patients approved. My particular patient, there was a little bit of a struggle with the approval process, but she has gotten approved and is now starting this therapy.

She is a nurse who is never been able to control her triglycerides. Usually, runs around 4,000. Many episodes of pancreatitis. For her, it is a fantastic improvement and it is exciting about that. Let me get back here.

[01:29:57]

Turn-and-Talk

Turn and talk. Turn to your neighbor and discuss the following. What are your current perceptions of the presented data for each agent? Which of your anticipated challenges around integration of these normal therapies into practice? If you want to talk about who is going to win the basketball tournament, that is okay also. We will give a little pause for that.

Turn and talk. Are you all finished? All right, let us keep going. It is late.

[01:30:29]

Faculty Response: Implications of clinical trial results and regulatory decisions on day-to-day clinical Practice

Implications of clinical trial results on day-to-day clinical practice.

Dr Shapiro: I think that you alluded to this earlier, which is we have never seen anything like this before for these patients with persistent chylomicronemia , FCS. The standard therapies do not work. Now, actually, as you showed with the clinical trial data, highly effective therapies that not only lower the triglycerides, but actually reduce acute pancreatitis. It is really an amazing triumph.

Dr Ballantyne: This is one of these things where it is pretty exciting. If you take a look at it, when we started off, we could not treat heterozygous FH very well. Now, we have this therapy, we can even treat homozygous FH. One of your choices was evinacumab. It targets ANGPTL3. We have that therapy.

Now, we have a therapy for FCS. There were 2 things that we were unable to treat, and now we have therapies to treat them.

Now, one of the things that I think in terms of clinical practice we pointed out is genetic testing is one way to document FCS, and it is actually widely available. Genetic testing, many companies do this. It is not that expensive. I think there is actually a program, if I am not mistaken, to help defray the cost of genetic testing, which is available, but you can also use the clinical scoring systems.

There are 2 of those available, and those are data that should be available in all of your patients. You can order an APOB, but you can also do it without an APOB for it. You can make a clinical diagnosis just the same way you can make a clinical diagnosis for familial hypercholesterolemia , heterozygote or homozygote. We have a joint publication today. Michael is the President of ASPC. I am President of National Lipid Association.

Basically, the first thing you look for is persistent chylomicronemia. If someone’s triglycerides stay over 1,000 after lifestyle, after you have gone through drug changes, secondary factors, after you have tried a fibrate, there is something serious going on. We looked at this in the Mayo Clinic, 1.2 million of people who had serial labs. It is a pretty rare condition, let us say about 1 in 5,500. 26% of those people had pancreatitis.

Just persistent chylomicronemia alone is a very important condition to recognize, requires intensive therapy.

Now, the FCS studies, for example, in balance, in 1 year, guess how many people had pancreatitis? With 30% of the people in 1 year had pancreatitis. That was the same thing for PALISADE, for genetically biallelic.

Just think about a cardiac trial where you had 30% of the people having an MI in prevention. That is an extremely high rate of pancreatitis. That is the extreme. The other thing is that if someone has had 1 episode of pancreatitis and they have persistent chylomicronemia, at least in my consideration, for example, with micro infarction, if someone has had a micro infarction and their LDL is 250, I do not really think I need genetic testing to tell me I should do something about that.

Hopefully, as we gather more data, we might make this a little bit easier for clinicians in terms of this concept of patient who has had persistent problem is at very high risk. Right now, the studies were focused on FCS for the initial indication, but there is a lot more trials in the pipeline, which we will be looking at severe high triglycerides, which will include the people I am talking about. Michael, any other points?

Dr Shapiro: I think the only other thing is, one of the parts of this question is what do we anticipate as being the challenges? I think you heard it from the patient himself, which is just getting the diagnosis established, being suspicious, finding patients who would be eligible for this therapy to get on therapy, which can dramatically change their life.

Dr Ballantyne: This is going to be one. It is the same thing with PCSK9 inhibitors. I got to say that the experience for my patient, even though she had genetically documented biallelic FCS, who was initially rejected, but then with a 30-minute phone call, luckily by my fellow, not by me, I was fortunate to be able to have that. It was basically resolved and talking through the case and here is this direction.

Now, the reason why I am saying it is not as bad as PCSK9s because you do not have as many patients. In your practice, you are only going to have a few FCS patients. It may take a little extra work, but you can get a lifesaving potentially drug for those patients with some perseverance. It is frustrating dealing with payers insurance. They do have a program to make it easier for you. This guy had some trouble with it.

We have talked about some of this beforehand. It is not the simplest thing in the world, but it is their resources available to help you with it and it is doable with it. Do we have more?

[01:36:37]

Bonus Round

Bonus round. All right.

Dr Shapiro: We need it.

[01:36:40]

Poll 3

Dr Ballantyne: Which triglyceride level serves as they cut up for suspected FCS?

1. 550;
2. 690;
3. 880;
4. 2,000 mg/dL.

Okay, 880. That is the European, is 10 millimoles . You say, why 880? 10 millimoles is a round number. They would tell us why 1,000. It is a round number. Some of these are somewhat arbitrary. It is easy to remember, 10 millimoles or 1000. What can we say?

[01:37:30]

Poll 4

Poll 4. Which of the following factors differentiates multifactorial severe hypercholesterolemia from FCS?

1. Early-onset cardiovascular disease in childhood;
2. Presence of xanthelasmas;
3. Response to lifestyle and traditional pharmacological interventions; and
4. Triglyceride levels consistently greater than 1,750.

Which one of those is the best answer? Okay. C, response to lifestyle and traditional pharmacological therapies.

[01:38:16]

Test Scores

Dr Shapiro: I think I am catching up here, Christie.

Dr Ballantyne: Yeah, you are catching up some. That means everybody got that one right. Good.

[01:38:23]

Poll 5

Okay. Poll 5. What is the maximum recommendation fat intake per day for a patient with FCS? The whole day.

1. 20 milligrams;
2. 30 milligrams;
3. 40 milligrams;
4. 50 milligrams;

Dr Shapiro: That should be grams.

Dr Ballantyne: It is grams, sorry. Not milligram. That is really restrictive. 20 grams is the correct answer. All right.

[01:39:07]

Test Scores

Okay. Pancreas protectors are lagging behind. Was that the last question?

[01:39:26]

Poll 6

Okay. Poll 6. Which of the following is the most common complications for patients with FCS?

1. Accelerated ASCVD in young adults;
2. Increased risk of stroke;
3. Nephrotic syndrome;
4. Recurrent pancreatitis.

Recurrent pancreatitis. I think everybody is getting them all right now. Let us see. The scores keep going up a whole lot.

[01:39:51]

Final Leaderboard Standings

Final leaderboard standings. Now, I was told that the people on the winning team were going to get a new car. Wait a second. It is a used Tesla. Anything else?

[01:40:19]

Q&A

Question and answer session. Was there online questions?

Dr Shapiro: Yeah, we have some questions that we can start off with, probably from the home audience and some people writing in here. Christie, one of the questions is, why does the hypertriglyceridemia cause cognitive dysfunction? Why do these people describe brain fog as one of their symptoms?

Dr Ballantyne: I think that may end up being this hyper viscosity, really does affect circulation. The other one is people get headaches sometimes. Once upon a time as medical students, we were taught to do retinal exams and look in their eyes, but you can actually see what is called lipemia retinalis. Instead of a typical reddish color, you will see this creamy. That just shows you that is the circulation in the eye and the brain.

It is slower, and I think that probably has what to do with it, but it is something where a lot of these people have complaints, brain fog, and sometimes they will have headaches also related to this.

Dr Shapiro: Yeah. One of the questions that I see here quite a few times variance of it is why do not the traditional triglyceride lowering drugs work in this condition? It really just has to do with the fact that these drugs work through the LPL system. It is actually a bit like homozygous FH. The standard teaching has been in HoFH, that there is no LDL receptor, no LDL receptor activity, which is actually not completely true. Most patients will have at least some minimal residual LDL receptor activity. It is worthwhile giving some of the standard drugs.

Turns out to be the case also for FCS where some individuals will have some residual LPL activity. You may see some effect of the standard drugs fibrates, omega-3s, statins, but it is usually quite modest, and certainly not sufficient to treat them. But the real reason that these drugs are not working is because they work through the LPL, you have defective LPL.

Dr Ballantyne: The surprising thing, this was one of the situations where, for example, we know that ANGPTL3 also enhances lipoprotein and interferes with lipid and lipase. Basically, an inhibitor to ANGPTL3 lowers triglycerides quite well, but does not work for FCS. That is why I had it. This was the surprising thing. It was the same way that evinacumab ends up, no LDL receptors, but your lower LDL.

Here, you can have basically close to zero LPL activity, with your lower triglycerides because of this second. You show this second pathway. Frankly, we did not really know for sure that that existed until these drugs were targeting APOC3.

Dr Shapiro: Here is a related question, a very good question, I think. In these individuals who have established a diagnosis of FCS and you get them on olezarsen, and they may be on some of the standard drugs, you are going to keep them on those drugs in addition to the ASO.

Dr Ballantyne: If they have had some response. One thing, first of all, is let us go back in terms of medical treatment, includes diet. In the trials, these people were maintaining diet. If we take a look at their triglyceride levels, they were reduced, but they were not going to less than 500, they are going down to less than 1,000 sometimes. I would make sure that you encourage people to maintain a low fat diet, and maybe they can be a little looser than the strict 15 grams today, but you do not want somebody going out.

We do a lot of postprandial studies with our group over the years at Baylor College of Medicine. You mentioned that you go up 25, but if you give someone who has got metabolic syndrome, if they have a triglycine of 200, 300, you give them a big fat load, they may go up to 600.

Now, the way you can also really jack that up is if you have alcohol. In Houston, every Friday night, people do some experimental studies where they go out and they have Mexican food with margaritas and beers, and get the chips and the queso and the refried beans and the tacos. That is a huge fat in alcohol load. Somebody can jack up their triglycerides. Just because you have this drug, does not mean you can go out and binge like that. You still need to be healthy, but you will stay out of the hospital for pancreatitis.

If someone had some response to the fibrate, I would continue with it. Most of the people we see, they get zero response.

Dr Shapiro: Here is an interesting question. They say FCS is primarily associated with pancreatitis. Is there evidence linking it to increase cardiovascular risk, similar to severe hypertriglyceridemia?

I would say that in the FCS patients, typically you are going to see normal to low APOB, which of course is the principal driver as ASCVD. In true FCS, we do not believe that the cardiovascular risk is elevated, but in multifactorial, then of course, high-risk than those individuals.

Dr Ballantyne: I think there is this issue, going back, if someone has FCS and also diabetes, then there may be some increase in risk, but a lot of it is correlated to the diabetes with it.

Dr Shapiro: If a cardiologist encounters a patient with severe fasting hypertriglyceridemia, when should they suspect FCS and what are the immediate steps that should be taken in terms of diagnosis, management, and/or referral?

Dr Ballantyne: The first thing that ends up happening if you have severely elevated triglycerides is, I usually talk to the patient, say, “Listen, you are at high risk for pancreatitis. We are going to have to do something. I am going to put on a challenge. You are going to go on a very low fat diet”.

If someone is really worried about and they are motivated, if you are going on a clear liquid diet for 24 hours with zero fat intake, you can dramatically lower triglycerides. In the past, I would hospitalize people sometimes, put them on NPO, IV fluids, triglycerides go down dramatically. You can do that as an outpatient, but then I want to say is, “Look, if you will also just be really strict, and if we will start exercising and walking, no alcohol, you can prove that and we are going to repeat it in 3 days. You can show someone the impact of lifestyle”.

I believe in starting fibrates early. [Inaudible] wait to get the triglycerides down. You may not be changing things acutely because the effect is going to be more after you lower it, but go ahead. I put someone right away on a fibrate, rule out secondary cause. If they have got diabetes, you got to control that. All the secondary cause that you have to immediately evaluate when you see severe high triglycerides.

The response to treatment is the big tip off. We said we looked at this recently the same, we did this joint publication. There are 2 papers out in JCL that were online today for High Triglyceride Day, but 92% of the people who have chylomicronemia end up not being persistent.

Most people, as you said, have MCS. Now, they are still high risk. Those people need intensive treatment. In fact, I think many of them may end up needing more than what we have available, but they do not have FCS, so they still need to be treated intensively. They are still high-risk because their risk for pancreatitis was 12%. It went 26%, but it is still a big increase with it. The response to treatment is your biggest tip off.

Now, the other one that does come up, it is really useful, is if they do not respond to treatment, and this could be cardiology, internal medicine, family practice, referral to a lipidologist is a good idea because we are used to seeing these types of patients and we can get the genetic testing, the nutritional consults, diet, and everything else.

Dr Shapiro: Great. That is all the questions we have from online. Any other questions from the audience? Congratulations to the Teal Team, Dr Ballantyne's team was a great competition. Christie, any closing thoughts?

Dr Ballantyne: We are going to have a party for my team afterwards. It is one of these things where it is just clinical. We practice medicine and we went into research and the research is really slow. So many things fail in research, but it is really exciting when something works for it. It is a slow process. It takes a long time with it, but it is very gratifying.

When I was in medical school, everything was going to be monoclonal antibodies, and it turns out it was not so easy because they were doing the chimeric. You had immuno-ratchets and chimeric and then humanized, and finally fully human.

About 20 years after medical school, I had lymphoma and I got a monoclonal antibody. I was in a clinical trial also for something else, and I was a Stage 3B lymphoma. I am here today doing well. I have been a beneficiary of clinical research. I have participated in clinical research as a patient, and it is really exciting when we see people having this terrible disorder that we can treat.

My take-home is slow process. This drug is very expensive. At some point in the future, it will be generic. Statins used to be expensive. We have these great hypertension drugs that are all generic. The system works. It is painful sometimes to get there, but it is good for patient care and it is just exciting to see that science and research absolutely does pay off. It works.