Dr. Zahid Ahmad (UT Southwestern Medical Center): Welcome, everyone. I am Dr. Zahid Ahmad. I am an Endocrinologist who specializes in lipid disorders. I work in Dallas, Texas at UT Southwestern Medical Center, and we have several lipid clinics there, all of which I work at, and see a very high volume of people with both common and very rare lipid disorders.

Today, we are going to talk a lot about high triglycerides.

Disclosures

These are my disclosures.

Learning Objectives

These are our learning objectives. We are going to:

• Identify pathophysiologic mechanisms and diagnostic criteria of severely elevated triglycerides, including Familial Chylomicronemia Syndrome, which is a very rare disease. We are going to talk about it so that we make sure none of the patients get missed;
• Evaluate the risks of severely elevated triglycerides in patients with FCS and the unmet therapeutic need in this population; and
• Assess the latest clinical safety and efficacy data on new and emerging therapies for severe hypertriglyceridemia and Familial Chylomicronemia Syndrome.

Poll 1

We are going to start with some polling questions. Question one. How many people with sHTG, severe hypertriglyceridemia, do you provide care for in a typical week?

1. One to two;
2. Three to five;
3. Six to 10;
4. 11 to 15; or
5. Greater than 15; or
6. Not applicable.

Poll 2

Question two. For those who practice in academic or community settings, please indicate your practice setting:

1. Academic;
2. Community; or
3. Not applicable.

Pretest 1

Now, this is the pre-test. These questions will be repeated at the end for the post-test. So pay attention and make sure you learn these things at least during this talk. Which of the following best explains the pathophysiology of Familial Chylomicronemia Syndrome?

1. Enhanced hepatic uptake of LDL particles;
2. Excess dietary cholesterol absorption in the gut, leading to accumulation of remnant lipoproteins;
3. Increased production of chylomicrons due to uncontrolled hepatic VLDL synthesis; or
4. Impaired clearance of chylomicrons caused by LPL deficiency.

Very good.

Pretest 2

Next question. Which of the following factors differentiates multifactorial severe hypertriglyceridemia from Familial Chylomicronemia Syndrome?

1. Early-onset cardiovascular disease in childhood;
2. Presence of xanthelasmas;
3. Response to lifestyle and traditional pharmacologic interventions; or
4. Triglyceride levels consistently above 500 milligrams per deciliter.

Pretest 3

What is the maximum triglyceride reduction observed in ApoC3 inhibitors in patients with Familial Chylomicronemia Syndrome?

1. 0% to 19%;
2. 20% to 39%;
3. 40% to 59%; or
4. 60% to 80%.

Pretest 4

Question four. I am confident in my ability to recognize the clinical signs and symptoms of severe hypertriglyceridemia, including FCS.

1. Strongly disagree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

Defining Hypertriglyceridemia: Fasting Triglycerides

Okay. Thank you for doing the polling questions and the pre-test questions. We will get started with the talk. First of all, we need to define what we mean by hypertriglyceridemia. In these questions, we just talked about sHTG or severe hypertriglyceridemia. Familial Chylomicronemia Syndrome falls within people who have severe hypertriglyceridemia.

Many of you probably know that a normal triglyceride level is below 150. Mild to moderate hypertriglyceridemia is considered 150 to 499. That is actually not that dangerous per se. The triglycerides themselves do not cause a problem, but these individuals do tend to have higher risk of cardiovascular disease. Then there is people who have severe hypertriglyceridemia, which the cut-off is typically 500 milligrams per deciliter.

Then there are people who are extreme. They are above 1000 milligrams per deciliter. There, we really start worrying about pancreatitis. Really, the 500 cut-off is predictive of who might eventually become extreme and get pancreatitis. So we start worrying at 500 and we really worry at 1,000.

To put this in some perspective of the scope of the problem, the prevalence of triglycerides above 500 is 1.7% of the population. Now, I know that does not always hit you hard, but I live in Dallas and we have this huge arena here called the Dallas Cowboys Stadium or the AT&T Stadium. It houses 105,000 people for a Dallas Cowboys game. If you took everyone in Dallas Fort Worth with triglycerides above 500, you can fill up that stadium. That is how prevalent this this condition is. There are a lot of people walking around with triglycerides above 500.

Now the vast majority, 99%, do not have Familial Chylomicronemia Syndrome. We are going to go through how to pick out those patients. Just to give you the scope of the problem, this is actually a huge issue in the population.

Signs and Symptoms of Severe Hypertriglyceridemia

When the triglycerides get really high, especially in the thousands, I mentioned acute recurrent pancreatitis. This is something that unfortunately happens when people's triglycerides get up to the thousands and stay in the thousands. Sometimes they do not get as high and sometimes the patients do not get pancreatitis. They will get abdominal pain instead.

Then there are many physical exam findings. These happen in anyone whose triglycerides get into the thousands, but you can see eruptive xanthomas. On the right side of this slide is a picture of a patient's elbows. You cannot appreciate it here, but there is a skin eruption there. It looks a lot like acne, except the lesions are all the same age. They look like that pus in them. But it is not pus. It is actually triglycerides. The triglycerides erupt in the skin.

You can also get lipemia retinalis. Towards the top of the slide, the top of the human figure here, which you are supposed to see here is a milky appearance of the arteries and the veins in the retina. This is actually pretty easy to see. You just need to look into the eyes with an ophthalmoscope and just visualize any blood vessel, and you will see that it is not red as it usually is. It reflects light back and looks shiny and white.

They also get lipemic plasma. If you draw a blood sample and you let the blood just sit there for a long time, the plasma layer will come up top and you will see that it looks like milk. In the picture here, the plasma layer has been pulled out of that, but it looks like milk.

In fact, what gives milk its milkiness is triglycerides. It is the fat content. Triglycerides are fat. A human plasma can also become milky.

Then they get hepatosplenomegaly. That is because the triglycerides actually stick around and accumulate in the liver.

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

They also report other things. This is mostly reported on surveys of people with very high triglycerides or Familial Chylomicronemia Syndrome, or FCS. Unfortunately, these individuals do take a lot of sick days because they do not feel well much of the time, or they end up in the hospital. A lot of them are unemployed because of their condition. They have cognitive symptoms, as you see here.

In the surveys, people often say they have brain fog or forgetfulness. It is not clear why that would happen. It is also not clear if lowering the triglycerides even helps that. That is something that many of these individuals report. They also can have various different emotional symptoms, which, as we will go into this, you will learn that these individuals, the ones who have Familial Chylomicronemia Syndrome, they cannot eat fat. They just cannot eat fat. If they eat fat, the chance of pancreatitis gets very high.

That actually causes a lot of problems. That essentially means you can almost never go out to eat. Or if you do go out to eat, you have to bring your own food. You cannot go to parties and eat there. You have to be very careful about what you do. So that creates a lot of anxiety and fear about their health. Many of them complained about physical symptoms as well.

FCS: Lack of Lipoprotein Lipase Activity Increases Risk of Pancreatitis

Of course, the most important thing is the risk of pancreatitis. These individuals who have FCS, they lack an enzyme called lipoprotein lipase. We are going to talk about this in a little bit more detail. If you lack this enzyme, you cannot clear triglycerides out of their blood, and they just stay there and then eventually they can inflame the pancreas. It is not exactly clear why triglycerides cause pancreatitis, but it is thought that they probably inflame the pancreas and cause leakage of lipase and amylase, which then further inflames the pancreas and damages it.

If you have FCS or LPL deficiency is the other name for it, the odds ratio of getting pancreatitis is much higher compared to other people with high triglycerides.

The Link Between Triglycerides and Atherosclerosis

Now, I always get asked the question about what about heart disease? That is what everybody's always focused on. That is what many of the cholesterol guidelines have been focused on. Although, most cholesterol guidelines do mention people with high triglycerides and the risk of pancreatitis, it is just not very prominent in the guidelines.

Generally speaking, if you look in an atherosclerotic plaque, there is no triglycerides in it. It is not full of fat. It is full of cholesterol. Cholesterol is a waxy substance. Triglycerides are fat. They are glycerol with three fatty acids on it. That is not present within an atherosclerotic plaque. Triglycerides do not cause atherosclerosis. The people who have high triglycerides, they are the same ones who get the small dense LDL and low HDL. They also tend to have a lot of inflammation and oxidative stress and endothelial dysfunction.

If you do see someone with high triglycerides, pay attention to their risk factors for ASCVD and treat them accordingly.

VLDL and Chylomicron Synthesis and LPL-Mediated Lipolysis

Now here we are going to spend a minute on physiology, and I will try to make this as simple as I can. We have two sources of cholesterol and triglycerides. One is what we ingest, the fat that we ingest. The other is what the liver makes and packages into very low density lipoprotein or VLDL. We all learn this in medical school. We all forget about it because it is not always that useful on a daily basis. In this case, it actually does help understand the conditions.

Wherever the triglycerides come from, they are all acted basically by one enzyme called lipoprotein lipase. This enzyme is ubiquitous in the circulation throughout the body. It is actually most prevalent in the heart because the heart uses fat for energy or fatty acids for energy. Lipoprotein lipase breaks down the triglycerides so that you can bring them into different places, like skeletal muscle or adipose tissue or even cardiac muscle. Then they could be used for energy or stored for energy.

If you have a problem with lipoprotein lipase, then you are in trouble because you cannot get the triglycerides out. People with FCS, they typically have mutations in lipoprotein lipase. The average person who has high triglycerides does not have a mutation, but they saturate lipoprotein lipase.

Another thing you learned in biology in high school was that all enzymes have saturation points. Lipoprotein lipase has a saturation point that probably starts around 500 milligrams per deciliter. Once your triglycerides hit 500, which they can by gaining weight or letting your diabetes get uncontrolled, or in some people drinking a lot of alcohol. Once you hit that point, the triglycerides just get worse and worse because you are saturating the enzyme that clears them.

You may also remember that enzymes have things that inhibit them and activate them. Lipoprotein lipase is activated by things like insulin or heparin. It is inactivated by these proteins that are shown in this diagram, ApoC3 and ANGPTL3.

Now we are showing these on purpose because some of the new drugs are inhibitors of ApoC3. They are inhibiting an inhibitor which then activates the enzyme. We will go over this a little bit more later. The important thing to remember is lipoprotein lipase in the patient with FCS is dysfunctional. Then the average patient with high triglycerides, it is saturated.

FCS: Impaired Function of LPL Enzyme

This is a little bit more about the impaired function of lipoprotein lipase. You take in fat in your diet, it gets packaged into chylomicrons and if you do not have FCS, it very quickly gets hydrolyzed and the triglycerides and cholesterol get removed and get taken up into circulation. You need this lipoprotein lipase activity. It is essential.

As we talked about before, mutations in lipoprotein lipase or the related factors cause decreased activity and increased chylomicrons. So you can eat fat and it will just stay in your blood. It is a huge problem.

There is a list of genes. It is not just a lipoprotein lipase gene. There are some other genes too that are at the bottom of the screen here on the left. These all are related to lipoprotein lipase. They are all in the same pathway. They basically affect the function of lipoprotein lipase.

Differential Diagnosis of Severe Hypertriglyceridemia

Let us take a step back. Let us say you see someone with severe hypertriglyceridemia. The triglycerides are 700. What do you do?

Step one is take a good history. Make sure you find out what their past medical history is. Also find out about their medications. Do a good exam and look at their body fat distribution, and I will explain why in a second. Make sure to test at least the core set of labs like the A1C, the glucose, a metabolic panel, TSH, and urine for at least microalbumin.

All of this is to look for secondary or associated causes that associate with high triglycerides. All of these causes tend to cause the liver to overproduce VLDL, which eventually saturates your lipoprotein lipase. You will see 98% of people, in fact, have a secondary cause. The majority of those people have what we refer to as polygenic hypertriglyceridemia or Multifactorial Chylomicronemia Syndrome, or MCS. So not FCS, but MCS.

There is a subset of people who have lipodystrophies. These are conditions where people are born without subcutaneous fat, and that is why it is important to do a body fat examination. Just take a look at their arms and legs and maybe their abdomen. These individuals with lipodystrophy often have muscular arms and legs. Some are even professional bodybuilders. They also tend to have veins popping out and sometimes they have a six pack of abs. I mean, they can really look like a very fit person, but in fact they have the worst metabolic conditions, including high triglycerides.

Dysbetalipoproteinemia is another very rare disease that needs a second hit, an associated condition where the triglycerides get high. Now, about 2% of people will have no associated conditions. They are born with high triglycerides. That is the ones we are focused on today because there is new treatment options for these individuals. That is the ones who have what we call Familial Chylomicronemia Syndrome or FCS.

Primary and Secondary Causes of Hypertriglyceridemia

Now, when you are looking for secondary causes, when you are taking a good history, these are the things we are thinking about, on the right of the slide, the secondary causes. The left is the primary causes, which is FCS, but the right is the more common things. By far the most common thing is type 2 diabetes.

For many people, when their blood sugar goes up, their triglycerides also go up. Other things that contribute to obesity, metabolic syndrome, there is other medical conditions like kidney disease, HIV, third trimester of pregnancy, Cushing's syndrome. Alcohol is another one. There are people who drink alcohol and their triglycerides just get sky high. Similarly with estrogen, there are women who take birth control or women who take hormone replacement and their triglycerides get sky high.

Retinoids. People who take tretinoin or isotretinoin for acne. The dermatologists are actually pretty good about monitoring their lipids because they know some of them get high triglycerides. Interestingly, if that happens, those people tend to get diabetes later in life too.

There is a long list of medications that can raise triglycerides too. It is very important to go through these, because if you miss this, the triglycerides will just stay high. The vast majority of people who have polygenic or Multifactorial Chylomicronemia Syndrome, you can fix their triglycerides if you can address these conditions.

Differential Diagnosis: FCS vs MCS

Now the main question becomes, how do we distinguish between people who have the pure genetic condition of FCS, which is the middle column here in this table, versus those who have the more common polygenic or Multifactorial Chylomicronemia Syndrome, which is the right column?

As you might expect, it is a genetic condition, so the age of onset is pediatric. The triglyceride levels are persistently high. These individuals’ triglycerides just never come down. You can tell by the ratio of triglycerides to cholesterol as well. That ratio is usually typically very high. Meaning if the triglycerides are 8,000 and, yes, 8,000 is a common number in these individuals, the cholesterol would be 800, as opposed to MCS, where it is something more like if the triglycerides are 5,000, the cholesterol will be much higher, like 1,000. That is because of the particles that carry these. In FCS, it is mostly chylomicrons and MCS is mostly VLDL.

ApoB-100 can be a test that can help you distinguish between the two conditions. Then another characteristic thing. These individuals with FCS do not respond to treatment, at least the traditional treatments. Usually, we use fibrates and omega-3s in people with very high triglycerides. If they have MCS, if they have the polygenic version, they do typically respond. But if they have FCS, they hardly ever respond.

As you might expect, because the triglycerides just always stay extremely high, the lifetime pancreatitis risk is extremely high. It is something like 65% to 90% of people with FCS get pancreatitis, whereas 20% to 40% of MCS patients get pancreatitis. We have even seen a six-month-old with triglycerides of 6,000 who had FCS and had pancreatitis.

Now, very interestingly, what happens to your risk of cardiovascular disease if your triglycerides have been very high since you were born? Actually, they do not get cardiovascular disease because of the triglycerides. It is a pretty fascinating thing. If they do get cardiovascular disease, it is a case report. I mean, for the most part, their issue is not cardiovascular disease. It is pancreatitis as opposed to MCS who typically have things like diabetes and hypertension and other medical conditions that do raise their risk of cardiovascular disease.

Genetic Load of FCS vs MCS

Now, in terms of genetics, I would not go into too much detail here, but FCS is what we call a monogenic condition. Essentially, you get one mutation or biallelic homozygous type of mutations, and you get the condition, you get the disease. Whereas MCS runs a little different.

Usually, they do not have any mutations at all. You cannot find anything. Many times you can detect that it is polygenic, but for the most part, it is very hard to tell that.

Clinical FCS Score Calculator: North American Algorithm

We talked a little bit about differentiating FCS and MCS or polygenic hypertriglyceridemia. There is actually a calculator. In the chat, the link to the calculator is there or will be there soon. You can put in many of the things we talked about and it will calculate a score. This is a North American score. There is also a European one.

Anyway, we like to do our own thing in North America. We do not like to rely on the European stuff. If you look at the score and the score is high, there is a very good chance that your patient has FCS.

Genetic Testing Recommendations

How often do you do genetic testing? Most of the time it is not really recommended. Because most cases are polygenic or multifactorial, the genetic testing is not that useful. It is like diabetes. It runs in families, but it is not typically that useful because diabetes is also polygenic. If you suspect FCS, then genetic testing becomes a gold standard.

What I do is if I am suspicious of FCS or lipodystrophy or the other genetic condition, dysbetalipoproteinemia, or the patients is very nice and asked for it, or they are very curious, then I will order genetic testing. It is commercially available now. It is not that hard to get. Most of the time, the patients that see me, we can justify it with their insurance or their insurance covers the cost.

If insurance does not cover the cost, many of the genetic testing companies do have some out-of-pocket fee of a few hundred dollars that covers the basic cost of the test.

I would recommend that someone who is familiar with genetic testing for triglycerides ordered this test, because the results are very confusing. It does take somebody with a little experience to interpret it and explain it to patients.

The Pivotal Role of Primary Care in sHTG 

What is the role of a primary care doctor, which I am really privileged to be talking to a bunch of primary care doctors today. What is your role in these patients?

You are the first line essentially and you help recognize the patients early. On average, a patient with FCS sees five different specialties before they end up with a lipid specialist who diagnoses their condition. These people show up with persistently high triglycerides and they do not get referred to a specialist in time, and then they suffer with pancreatitis over and over until they finally find someone who understands the condition and can counsel them on their diet, which we will talk about in a second, as well as get them on some of these new medications that we are going to talk about in a second.

Poll 3

Here is a polling question. This 32-year-old woman with a BMI of 22 presents with recurrent abdominal pain and a history of acute pancreatitis. She has no history of diabetes, alcohol use or hypothyroidism, so no secondary causes. Her triglycerides have been over 1,500 in multiple fasting tests, despite being on a low-fat diet and fibrate therapy. Her ApoB is very low and her plasma appears milky after refrigeration. What would your next step be for this patient? Would you:

1. Order a coronary artery calcium score to assess ASCVD risk;
2. Order a fasting insulin and A1C to evaluate for insulin resistance;
3. Start high-dose prescription omega-3 fatty acids and repeat lipids in four to eight weeks; or
4. Refer to a specialist and consider genetic testing.

It looks like most people got this right. Yes, at this point, this patient should be referred to a specialist. Genetic testing should be done. Beyond that, there are new treatments that we are going to talk about that can be ordered for a patient like this.

Poll 4

Question four. I am familiar with the latest clinical trial evidence on novel RNA-based therapies for severe hypertriglyceridemia and FCS.

1. Strongly disagree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

Okay. Very good. I am glad there are a few people who agree. For you, probably the next few slides will probably be a lot of review, but for everyone else I am going to introduce you and try not to overwhelm you with some of these new drugs.

Treatment of TG ≥500 mg/dL

Starting off, this is the general way that we treat triglycerides above 500. I went into some detail about secondary causes. That is really important. We really need to spend some time making sure that we address any secondary causes. Otherwise the triglycerides may not come down.

When the triglycerides are especially above 1,000, we implement a very low-fat diet. If it is FCS or MCS, it does not matter, because in either case, your lipoprotein lipase is not working. In the case of polygenic or Multifactorial Chylomicronemia Syndrome, the lipoprotein lipase is saturated. To give it a chance to catch up, you really have to cut out fat in the diet. If they are diabetic, optimize glycemic control or whatever secondary issues that you identify, optimize those.

Then most of the time, we give fenofibrate and prescription omega-3s. You can also use gemfibrozil, but you have to be a bit careful with statins if you do that together.

The idea with these drugs is that they do lower triglycerides somewhat and we assume that reduces the risk of pancreatitis.

Then in the Multifactorial Chylomicronemia Syndrome patients, think about statins. Nearly all the patients are at a higher risk of atherosclerotic cardiovascular disease.

Mechanisms of Action for Novel Triglyceride-Lowering Agents

Let us talk about some of the novel triglyceride lowering drugs. This is again the diagram showing that the two main sources of triglycerides are fat ingestion from the intestine that gets packaged into chylomicrons. The other one is large VLDL on the left in the liver.

They are all acted upon by lipoprotein lipase. These new drugs inhibit the inhibitors of lipoprotein lipase. You will see ANGPTL3, but really what we are going to talk about is ApoC3. The ANGPTL3 story has not panned out yet. We are still waiting to see if that pans out.

For ApoC3, there is three drugs here. The first one is volanesorsen, which did not really work out. Olezarsen and plozasiran are actually now in the market. Both are inhibitors of ApoC3. We are going to go into some detail about these drugs or the efficacy of these drugs.

Management of FCS: Prevent Pancreatitis by Reducing Triglycerides

Our goal has always been to prevent pancreatitis by reducing triglycerides. The vast majority of these patients, even now, even with these new drugs, they have to be on a lifelong very low-fat diet, and it is very hard to adhere to.

When we diagnose FCS in children, they do a little bit better because they start the diet as a child. Then as an adult, it just makes sense for them to stay on the same diet. They understand it. But in adults, it is a bit harder to get them to cut out all the fat. As I mentioned, it is very hard to go out to eat or anything like that.

To give you a sense, these individuals can have no more than the equivalent of two tablespoons of olive oil in a day. In terms of medications, the traditional agents, fibrates, statins, omega-3s do not work. Olezarsen and plozasiran are two new drugs. Olezarsen is ApoC3 mRNA inhibitor, and plozasiran is a small interfering RNA. Both are FDA-approved for FCS.

In kids, they often present with failure to thrive. In babies, it is actually not that hard to manage because there is a special formula. We have to get it from the Netherlands, but it is a very low-fat formula that has some medium chain triglycerides, which actually do not cause your blood triglyceride levels to go up. That becomes the main source of fat for the babies who have this condition.

Pregnancy. If someone has FCS and they are pregnant, it can be very high risk and many times the women get pancreatitis in the third trimester. We sometimes have to use TPE or therapeutic plasma exchange in these women.

BALANCE: Olezarsen in Patients With FCS

Let us go a little bit into the actual drugs, olezarsen and plozasiran. This is olezarsen data with FCS patients. On the left side is the efficacy of lowering triglycerides. With the highest dose of olezarsen, you get between 40% and 50% reduction in triglycerides. That is actually very meaningful. Before, we had nothing that reduced these individuals’ triglycerides and now we have something.

On the right is actually the more important thing. It reduced the incidence of pancreatitis. The top two lines here, the orange and the blue are people who got olezarsen in different doses. Regardless, though, they got far fewer pancreatitis episodes than the grey line here. Each step down here is a pancreatitis episode.

BALANCE: Safety

Safety-wise, olezarsen is quite safe. The only thing that was imbalanced was injection site reactions. You will see platelet count as something that is of a special interest. That is because the previous generation of this drug, which was called volanesorsen, caused a decrease in platelet count, but does not seem like a huge problem with olezarsen.

PALISADE: Plozasiran in Patients With FCS

This is the other drug, plozasiran. The previous drug olezarsen is given as a once a month subcutaneous injection. It comes in an autoinjector pen. Plozasiran is given once every three months in a syringe and vial type of situation. It is just once every three months. It also lowers triglycerides. This is the maximum lowering of triglycerides in FCS patients that we have seen.

Plozasiran lowers triglycerides 60% to 80%. On the left side, you see that. On the right side, again, people who get the drug get less pancreatitis because their triglycerides are lower. The orange is the people who got the drug in the pooled cohort. The grey is the people who did not. Again, each step down as an episode of pancreatitis. If you got the drug, you are far less likely to get pancreatitis.

PALISADE: Safety

Safety-wise, there were some safety issues, but nothing particularly serious. Maybe a small change in platelet counts, maybe some differences in nausea and headaches and some increase in ALT, but nothing that occurred above 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. I am going to quickly just blow through some data for MCS because the drugs, although right now they are approved for the rare genetic condition, FCS, olezarsen is actually at the FDA being evaluated now for the routine patient with severe hypertriglyceridemia, just anyone with triglycerides above 500.

You can see again, it works for those patients. It lowers the triglycerides and all the other lipoproteins that you want lowered.

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

The previous slide was in patients with triglycerides baseline around 250. This is people with triglycerides baseline around 800. In either case, the drugs work really well. I mean in these patients, honestly it gets their triglycerides down to pretty much normal. On the right side is some pancreatitis curves. Here the step up is a pancreatitis event. You will notice that there is far fewer step-ups in people who took the drug.

CORE-TIMI 72a/b: Lipid Outcomes at 6 Mo

This is similar data. Triglyceride lowering is 60% to 70%. So it is pretty impressive. You also, as you expect, you lower ApoC3 because it is inhibitor lower remnant cholesterol, non-HDL, ApoB goes down a touch. LDL can go up. It is not much, but it can go up. That happens with almost any drug that lowers triglycerides.

SHASTA-2: Plozasiran in Patients With sHTG

This is the other drug plozasiran, the once every three month injection. Similarly, the triglyceride reduction is 60% to 80%. The HDL goes up, the ApoC3 goes up. The LDL again does go up, but you are still talking pretty low numbers, 60% to 80% for the most part.

Importance of Multidisciplinary Care

Again, what is the role of the primary care doctor in all of this? The role is a very important one because it is the front line. It is the early identification and referral to specialists so that these individuals, both who have FCS and the more common severe hypertriglyceridemia from MCS, that they actually see the people who understand the condition and can get on the right therapy as soon as possible before they have pancreatitis.

They do typically need to see someone who is a lipid specialist, which are often endocrinologists, cardiologists. Some primary care doctors are also lipid specialists. If you are looking for lipid specialists, you can look at a few websites. The National Lipid Association has a list. So does the Family Heart Foundation. They have a list of lipid specialists. You can actually search on Family Heart Foundation by zip code.

These patients also need to see a dietician. They need a primary care doctor to be their quarterback. They need pancreatologists and gastroenterologists. Thanks to many patient advocacy groups, they have now support. There is a lot of peer support for these individuals and it helps. We talk to these patients all the time and they need that peer support.

Poll 5

Polling question. A patient is diagnosed with FCS. Which of the following therapies would be the most appropriate to lower triglyceride levels and reduce the risk of pancreatitis? Is it:

1. Evinacumab;
2. Icosapent ethyl;
3. Olezarsen; or
4. Omega-3 fatty acids.

This is outstanding. Everybody got this exactly right. Yes. Olezarsen. If this patient has FCS, it is the only thing that would work.

Summary and Key Points

Quick summary before we get to the post-test questions. Patients with severe hyperthyroxinemia and FCS have a high disease burden due to recurrent pancreatitis, morbidity and poor quality of life. Primary care plays a key role in screening patients early and managing care. You should suspect FCS when somebody has persistently high triglycerides above 1,000. They have early onset of symptoms, recurrent pancreatitis and poor response to therapy.

Lifestyle changes are essential in FCS management, so these individuals need to be on an extremely low-fat diet. The standard treatments like fibrates and omega-3s are inadequate. Refer patients to a specialist if the triglycerides are above 500 persistently or you suspect FCS. We have these new RNA-based agents that show strong triglyceride lowering potential in both just the routine severe hypertriglyceridemia cases and FCS.

Posttest 1

Now on to the post-test. Which of the following best explains the pathophysiology of FCS?

1. Enhanced hepatic uptake of LDL particles;
2. Excess dietary cholesterol absorption in the gut leading to accumulation of remnant lipoproteins;
3. Increased production of chylomicrons due to uncontrolled hepatic VLDL synthesis; or
4. Impaired clearance of chylomicrons caused by LPL deficiency.

It looks like almost everyone got this question right. This is LPL deficiency. Yes. The only thing about VLDL is that that does go up in secondary when you have secondary causes of high triglycerides, but not if it is FCS.

Posttest 2

Which of the following factors differentiates multifactorial severe hypertriglyceridemia from Familial Chylomicronemia Syndrome? Just one choice.

1. Early-onset cardiovascular disease in childhood;
2. Presence of xanthelasmas;
3. Response to lifestyle and traditional pharmacologic intervention; or
4. Triglyceride levels consistently above 500 milligrams per deciliter.

Good. The majority of people got this right. Let us check actually.

Posttest 2: Rationale  

Yes. The response to lifestyle and traditional pharmacologic interventions was actually the correct answer. Because this is a distinguishing thing between FCS and MCS or severe hypertriglyceridemia, I know many people answered D. This is a bit of a tricky question. Both conditions can have triglycerides above 500. With FCS, FCS is consistently above 1000. 500 is actually low for a patient with FCS, but it is this response to lifestyle and traditional pharmacologic interventions that really helps in a lot of ways, distinguish just the routine case of severe hypertriglyceridemia from FCS.

If you have a patient who does not respond to fibrates and omega-3s and low-fat diet or weight loss, then think about FCS.

Posttest 3

What is the maximum triglyceride reduction observed with ApoC3 inhibitors in patients with FCS?

1. 0% to 19%;
2. 20% to 39%;
3. 40% to 59%; or
4. 60% to 80%.

While you are doing this, please do feel free to put questions in the Q&A. I will get to them in just a few minutes.

This is great. Everybody got this exactly right. Yes. 60% to 80% with the second drug I talked about plozasiran.

Posttest 4

I am confident in my ability to recognize the clinical signs and symptoms of severe hypertriglyceridemia, including FCS.

1. Strongly disagree;
2. Disagree;
3. Neither agree nor disagree;
4. Agree; or
5. Strongly agree.

Okay, we shifted the curve. It is all shifted to agree or strongly agree. Great.

Q&A 

Now we will do the question and answer session. There is a few questions in the chat or in the Q&A that I will answer right now. Please again, feel free to put anything there. I will answer them in the order that they came in until we run out of time, at least.

If patients are on these new FCS drugs, can they eat more dietary fat?

Good question. They cannot. It would be amazing if they could. That is still something we are trying to figure out. In the studies of these drugs, the patients were instructed to stay on a low-fat diet. In practice, myself and others who prescribed these drugs have noticed that the patients can eat their way past the drug. If they start eating a lot more fat, their triglycerides go back up even when they take the drug.

That is a good question. I wish we had something that could really prevent them from doing that, but that has not happened yet.

David Changyu asked, can poor dietary choices such as processed foods and high fructose cause high levels of triglycerides?

Yes, absolutely. Although the main factors are what things stimulate the liver to make more triglycerides. Yes, processed foods and high fructose foods have been linked to creating more triglycerides de novo in the liver. Even worse, people who eat that tend to eat hypercaloric diets and have excess adiposity and have more fat, and fat is triglycerides. The more fat you accumulate, the more you are going to get in your circulation. That is a thing that does happen.

To pontificate a little bit on your question. Another issue we have nowadays is keto or carnivore diets. There are many people who can do a keto or carnivore diet and they lose a lot of weight and some of them, their triglycerides come down, but not all of them. If they have MCS, a lot of times their triglycerides get sky high and especially if they have FCS, it is almost guaranteed that their triglycerides are just going to get sky high.

There are a few questions that Tammi asked. Would RNA-based therapies be used alone or in addition to other medications?

In the clinical trials, they were mostly used in addition to other medications. We do use them in addition. If the other medications do not work, you could consider stopping them.

Then, what steps should a primary care provider take when severe hypertriglyceridemia is found? For example, order specific labs, recheck triglyceride levels, ask about family history.

Yes, it is a good question. If the triglycerides were non-fasting, I would definitely get it checked fasting. Family history sometimes is helpful, but the genetics of FCS and MCS are complicated, so it does not always give you a lot of clues.

The other steps are make sure you figure out any secondary issues associated with high triglycerides. So obesity, diabetes, medications. I did not mention steroids, but a lot of people will take steroids and do not tell you or they get steroids for joint pain or other things they do not tell you, etc., or estrogen and alcohol.

I do get a lot of referrals for very high triglycerides and people forget to ask the patient if they drink alcohol or they are unaware that alcohol in some people can raise triglycerides. I can usually convince those patients to stop their alcohol. Not always. Many of them are pretty addicted, but sometimes I can get them to stop. If you do, their triglycerides and cholesterol comes down to normal.

When should PCPs consider referring a patient with severe hypertriglyceridemia for genetic testing?

We talked about this at length. If they meet some of those conditions that are consistent with FCS. So their triglycerides stay high, they do not respond to therapy. They tell you something like, “My triglycerides have been high since I was a child.” Those are people who you really should get to a specialist as soon as you can, not just for genetic testing, but also for treatment.