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Severe Hypertriglyceridemia: 5 Pearls Segment

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Time Stamps

  • 03:19 Lipoprotein Lipase and Why Triglycerides Fluctuate Fast
  • 05:27 Triglycerides as a Cardiovascular Risk Marker
  • 09:28 Acute Management For Pancreatitis Induced by Triglycerides
  • 14:34 Lifestyle Counseling
  • 17:31 Medications That Lower Triglycerides
  • 25:29 How to Choose the Right Triglyceride Therapy
  • 27:56 Genetic Causes and When to Suspect Familial Disorders

Show Notes

Pearl 1: What is the definition of sHTG and what are the associated risks?

  • Severe hypertriglyceridemia (sHTG) = serum TGs are > 500mg/dL
  • What are chylomicrons and what is the cutoff for chylomicronemia?
    • Chylomicrons = TG rich lipoproteins
      • synthesized in enterocytes after a meal
      • also contain cholesterol and fat-soluble vitamins and are responsible for transporting dietary lipids systemically
    • Chylomicronemia = fasting TG levels > 880 mg/dL (> 10 mmol/L)
  • Should we be checking lipid panels as fasting or non-fasting to assess TGs?
    • Fasting labs
      • TGs can quickly and variably change to reflect intake.
        • Fasting labs make it easier to draw comparisons when starting lifestyle interventions and medications
      • In a fed state, especially after a fatty meal, there will be chylomicrons present.
        • fasting TGs are needed to define chylomicronemia
  • What are the risks associated with sHTG?
    • Inflammation
      • Lipoprotein lipase is primarily what clears circulating TGs in plasma
    • Pancreatitis
      • Patients with sHTG experience pancreatitis at a higher incidence than the general population (14% vs ~0.1 %)
      • Pancreatitis 2/2 to sHTG has been shown to have worse outcomes
      • Prior episodes of acute pancreatitis may lower the TG threshold for recurrent pancreatitis
    • Cardiovascular disease
      • Moderate and severe HTG also increases the risk of cardiovascular disease via the VLDL pathway
        • VLDL: atherogenic in a similar manner as LDL
      • Patients with sHTG also tend to have multiple risk factors for ASCVD:
        • obesity
        • metabolic syndrome
        • hyperglycemia

Pearl 2: Acute Inpatient Interventions for Pancreatitis 2/2 Severe Hypertriglyceridemia

Pearl 3: Metabolic and Lifestyle Factors Are Key to Severe HyperTG

  • What are common causes of high triglycerides?
    • Chronic conditions:
      • Diabetes
      • CKD
      • nephrotic syndrome
      • hypothyroidism
      • Cushing syndrome
      • inflammatory conditions
    • Lifestyle factors:
      • Alcohol
      • diet
      • sedentary lifestyle
    • Disorders of metabolism:
      • overweight/obesity
      • insulin resistance
      • pregnancy
    • Medications:
      • Propofol
      • beta-blockers
      • glucocorticoids
      • anabolic steroids
      • oral estrogens
      • HIV protease inhibitors
      • atypical antipsychotic agents
    • Familial syndromes (rare):
      • autosomal recessive familial chylomicronemia syndrome
      • familial partial lipodystrophy
  • Dietary intervention can reduce TG levels by 20-50%.
    • Very low-fat diet for severe hypertriglyceridemia
      • TG 500-999 mg/dL: 20-25% calories from fat
      • TG ≥1000 mg/dL: 10-15% calories from fat
    • Healthy diet =
      • Include: lean protein, fish, fresh fruits, vegetables, legumes
        • Dietary fiber can also attenuate the triglyceride-raising impact of carbohydrates
      • Avoid: Refined foods with high glycemic index, added sugars, and alcohol
        • Limiting sugar and carbohydrates can effectively reduce TG 10-12%.
          • Total carbohydrate < 50% of daily calories
          • Refined grains < 50% of total daily carbohydrates
          • Limit added sugar
  • Other lifestyle interventions
    • Weight reduction
      • 5-10% weight loss can reduce TG > 20-30%.
    • Physical activity
      • can lead to up to 30% of TG reduction.
        • Resistance training → decrease TG by~6%,
        • regular aerobic training →decreases TG by ~11%.
      • The ACC/AHA guidelines recommend 150 minutes per week of moderate-intensity physical activity or 75 minutes per week of vigorous, high-intensity, aerobic physical activity.
    • Could we better manage comorbidities?

Pearl 4: Triglyceride-Lowering Medications

Pearl 5: Prevalence of Familial Hyperchylomicronemia & When to Send a Genetic Panel

  • Familial chylomicronemia syndrome (FCS):
    • Autosomal recessive disorder
      • Diagnosis is suggested by TG levels > 880 – 1000 mg/dL.
        • fasting and on multiple measurements
      • Gold standard for diagnosis: genetic testing!
        • Can be useful in guiding therapy → particularly novel therapies!
          • NOTE: FCS patients do not tend to respond to traditional TG lowering therapy such as fibrates and omega 3s
      • Prevalence: 1-10 in 1,000,000
    • The implicated genetic mutations include:
      • Lipoprotein lipase (LPL) (most common)
      • Loss of function mutations in apo CII or apo AV
      • Mutations leading to defective or absent GPIHBP1 and LMF1
  • Multifactorial chylomicronemia syndrome (MCS)
  • How to tell FCS vs.MCS?
  • What novel therapy options are there for FCS?

Transcript

Introduction

Dr. Greg Katz: This is to a large extent in your control, and you should feel empowered to treat this with lifestyle adjustments. And everyone’s genetics are a little bit different. And so some people have different thresholds for what you can get away with and what you can’t. And all of those things in life isn’t fair. But for patients, when the triglycerides are really high, to me it’s like a call to action. And if there’s ever a siren call for you should take control of your own health, a very high triglyceride level, it’s just the biggest call to action that you could have from a lipid perspective, that’s not a heart attack. And for some reason, the high triglyceride levels to me is the thing that patients actually respond to in a way that they don’t respond to crazy high LDL levels.

Dr. Shreya Trivedi: That was Dr. Greg Katz, a cardiologist at NYU. Welcome to the CORE IM 5 Pearls podcast, bringing you high-yield evidence-based pearls. I am Dr. Shreya Trivedi, and I am joined by…

Dr. Jimin Hwang: Hi! I’m Jimin Hwang, Chief Resident at UT Southwestern.

Dr. Ananya Gorrai: I’m Ananya Gorrai, a PGY-3 Internal Medicine resident also at UTSW.

Dr. Shreya Trivedi: Awesome. And today we are talking about severe hypertriglyceridemia. This episode was made possible by an independent medical education grant from the National Triglyceride Association. And ive got to say with this episode on severe TG, what i didn’t expect was just how much I’d learn about triglycerides in general and I’ve told countless family members about it since about its a part of the lipid panel most doctors ignore (not that they mean to but we can hyperfocus on the LDL) but a lot of patients are interested in. To get the most out of learning, I saw down at one of my colleagues, Dr. Adam Strauss, who told me about a memorable case to walk us through our pearls

Dr. Adam Strauss: So this is a 59-year-old gentleman with a history of depression, alcohol dependence, and insomnia. And he’d actually had a primary care visit a few days earlier, at which time a lipid panel was checked just for routine monitoring. And then he comes in five days after his appointment, after having had an alcohol binge with triglycerides of about 1600 and abdominal pain, nausea, and vomiting, at which time he was found to have acute pancreatitis. And then from that emergency room, he was initially admitted to the ICU, where he was treated with an insulin drip and had improving symptoms and improving triglyceride level down to 388. And then, upon leaving the ICU was started on a fibrate as well.

Pearl 1 – What is HyperTG? Definition and Risks

Dr. Shreya Trivedi: Oh man, I have so many questions. But of course, the first thing the internist wondered we could have done to prevent this awful complication of elevated triglycerides. And I dug back in this patient’s chart, and he has been seen a few days prior at his PCP and his lipid panel had a TG that came back at about 488 and hadn’t been followed up on… could we have prevented this? And we so we sat down with Dr. Seth Baum, a preventive cardiologist and a clinical lipidologist, Chief Medical Officer of Flourish Research and past President of the American Society for Preventive Cardiology

Dr. Seth Baum: Lipoprotein lipase is what hydrolyzes the triglycerides and lipoprotein lipase is saturated at a triglyceride level of about five or 600.

Dr. Seth Baum: And what that means is if you have a patient sitting around with a triglyceride of four or five, 600, and the patient goes out and eats a terrible meal within minutes, the triglyceride can be well over a thousand, and the risk of pancreatitis will increase as the triglycerides increase.

Dr. Shreya Trivedi: Wow, I did not realize how quickly triglycerides can vary within a few hours of eating French fries or a burger. That is a teaching point that’s definitely stuck with me since learning

Dr. Jimin Hwang: and the other big teaching point is that lipoprotein lipase breaks down triglycerides and saturates at TG around 500. When the TG increases above that 500 threshold, in the most simplest sense, you get all this baddness, chylomicrons in circulation, creating complications.

Dr. Shreya Trivedi: And hopefully we won’t feel comforted if the TG is less than 500, there should still be alarm bells (for multiple reasons), but one is that a fatty meal can make those TGs shoot up 30-50%

Dr. Seth Baum: One of the theories is that there’s such large particles that they can’t make it through the small vessels in the pancreas. They get lodged, they get open, the pancreatic enzymes start auto-digesting because there are areas of clogging, if you will, that’s one belief. It’s not a hundred percent known what that triglyceride induced pancreatitis, what the pathophysiology.

Dr. Shreya Trivedi: I can really picture that. And in particular, it’s TG > 500 that carries a significantly increased risk of pancreatitis. The higher your TG gets, you’re at a higher risk for pancreatitis.

Dr. Jimin Hwang: And if you do have a patient with pancreatitis because of their triglycerides, just know that their risk of organ failure and mortality is higher than other common things that cause pancreatitis. Once someone has had an acute pancreatitis episode, the threshold for recurrent pancreatitis can be reached at even lower TG levels. (it puts them at risk for recurrent episodes.)

Dr. Shreya Trivedi: So that’s the risk of pancreatitis that comes with elevated triglycerides. Let’s shift gears a little bit to talk about another important organ in the body, the heart.

Dr. Jimin Hwang: Yay, my favorite organ! I think people think, of course, triglycerides are associated with a lot of confounders like obesity, metabolic syndrome, and diabetes — things we already know are associated with elevated risk of cardiovascular disease. So how much do triglycerides really matter?

Dr. Shreya Trivedi: So we pressed our disscuants are other direct ways that triglycerides make people more likely to have cardiovascular disease.

Dr. Greg Katz: It’s that when the triglycerides are high, you usually require more LDL particles and more to carry around the cholesterol and the triglycerides through your body. And so it’s atherosclerosis risk through the traditional means. And when triglycerides are high, it usually means that LDL cholesterol is underestimating somebody’s cardiovascular risk related to lipoproteins. Just think particles. You need more particles. You have to carry around all these triglycerides, and so you need more trucks to carry the cholesterol. They’re filled up with all this other stuff.

Dr. Jimin Hwang: So ultimately, with a lot of triglycerides in the body, there needs to be a lot more trucks to carry them, and it’s just like a traffic jam in the blood vessel, causing inflammation.

Dr. Seth Baum: There’s also some evidence that triglycerides can be pro-inflammatory in and of themselves. So even though they’re not part of plaque, right? So when you make a plaque, it’s cholesterol, their triglycerides not in there. Well, triglyceride in the vicinity might be increasing inflammation.

Dr. Jimin Hwang: That inflammation then is the nidus for that lipid-containing junk to build up on the vessel walls! Now, when I counsel patients on the cardiovascular risk, I think I’ll draw up this picture of an inflammatory traffic jam.

Dr. Shreya Trivedi: Okay, to summarize what I took away from thinking about risk of severe hypertriglyceridemia: I was humbled to learn how quickly triglycerides can transiently rise after a fatty meal, and so next time I see triple-digit TGs, especially near the 500 range, I will do much better counseling and management (more on that in pearl 3 and 4). And that risk with elevation of triglycerides, esp over 500mg/dl, is associated with a marked increased risk of acute pancreatitis.

Dr. Jimin Hwang: And it’s not just that 500 threshold we care about, as a budding cardiologist, I do want to emphasize that patients who are sitting at elevated triglyceride level (which some define as >150-175mg/dl) do experience high cardiovascular risk and need our attention.

Pearl 2 – Acute Interventions

Dr. Shreya Trivedi: Now that we know the risks that triglycerides, when do you see a triglyceride level that raises your eyebrows, we learned from our discussants that we should rule out a few things (in addition to genetic which is pearl 5) and see when acute management might be needed

Dr. Ananya Gorrai: We sat down with Dr. Eliot Brinton, an endocrinologist and the president of the Utah Lipid Center in Salt Lake City.

Dr. Eliot Brinton: Hypothyroidism, screened for it, treated if it’s present. Proteinuria nephrotic syndrome is a cause of high triglycerides. Hypercortisolism can be a cause. Systemic glucocorticoids, of course, will cause triglycerides. So if they’re taking prednisone on a daily basis, try to figure out how to deal with that if you can. Anti-psychotic agents can cause both obesity and high triglycerides together. So if somebody’s taking the newer antipsychotic meds, figure out a way to deal with that. If you can maybe refer ’em back to their psychiatrist and see if there’s something you can do.

Dr. Ananya Gorrai: Okay, so we need to rule out thyroid issues, nephrotic range proteinuria, hypercortisolism, like with Cushing’s, is the patient prednisone and dexamethasone or on an antipsychotic agent.

Dr. Shreya Trivedi: Of course, we will have a more exhaustive list of secondary causes to rule out in our show notes, but I’m so glad we mentioned medications because in Adam’s story, there was a medication at play

Dr. Adam Strauss: And then also, actually, he had been started on Seroquel, which can have a role in triglyceride, hypertriglyceridemia-related pancreatitis. So someone did their homework in the ICUI think and realized that that should maybe be stopped.

Dr. Shreya Trivedi: Nice! And then, after rule out organic things that could be elevated risks of triglycerides, now, let’s briefly go over if you have sHTG-related pancreatitis, what acute management you might hear. Ananya, you looked into the management of sHTG pancreatitis, things like insulin drip and plasmapheresis. What did you find?

Dr. Ananya Gorrai: Well, first of all, what we may reflexively do is make the patient NPO. One of our reviewers NPO, can make the TG go down by half in first 24 hours. To hammer it home, we learned in Pearl 1 that TGs can rise quickly … and similarly, they could also fall quickly with just making NPO

Dr. Shreya Trivedi: What about an insulin drip or plasma exchange? Honestly, I’ve never seen it done, but would be good to run through real quick in case it’s mentioned

Dr. Ananya Gorrai: It’s always been a grey area for me, because we looked at there isn’t a clear guidance who you might start an insulin drip or not. The endocrine society practice guidelines do not recommend the routine use of insulin drips in patients with sHTG pancreatitis without diabetes. Of course, if they have diabetes and hyperglycemia it can be offered and if your nursing can do it, insulin can help decrease triglycerides through complicated lipid pathway.

Dr. Shreya Trivedi: What about plasma exchange? Is there a TG level that should reach for it?

Dr. Ananya Gorrai: No it’s not a TG level per se, but when we have a “refractory, severe acute pancreatitis,” so think about patients in shock from their acute pancreatitis who are not getting better, but again, this is all super gray and I’m sure different places will have different practice pattern based on comfort, consultants, and resources. And on top of that, most studies show NO benefit.

Dr. Shreya Trivedi: So if I were to put that all together, it sounds like in the acute management we want to rule out secondary causes and make the patient NPO. When it comes to pancreatitis from TG above 500 or so, you can reach for an insulin drip to more rapidly reduce TGs if they have diabetes, or in severe cases of patients in refractory shock, consider plasma exchange. Some say if they are not getting better, that is when you pull that lever, but what does it mean to not get better, and how long do you wait isn’t clear.

Pearl 3 – Lifestyle Matters – Exercise and Low-fat, Low-carb, High-protein Diet

Dr. Shreya Trivedi: After the immediate things have been addressed, we get to shift our thinking to the long-term management of those triglycerides

Dr. Ananya Gorrai: And of course, before we get into the medications, let’s get into the most important part in my opinion: how we might counsel patients about lifestyle

Dr. Shreya Trivedi: And of course, who better to talk about counseling than Dr. Greg Katz, whose voice you may recognize from our Beyond Journal Club segment

Dr. Greg Katz: I talk to patients, I tell them that your triglycerides are really high, triglycerides are concerning. It’s fat in the bloodstream. It can be toxic to a bunch of organs. Your pancreas is the one that’s most characteristically at risk from it. But it’s also problematic because it tells us about your long-term heart disease risk in some ways, and I then will get into triglycerides are super responsive for most people to the things that we do, how much we move, what we put in our bodies. It’s also really responsive to medications. Ultimately, most people need a combination of medications plus lifestyle interventions to get things under control. And so for this patient, ultimately we gave her a homework assignment for a week of, you need to walk, you can’t have a sip of alcohol, you can’t have any dessert, and you need to bring me a food diary. And we will make adjustment for them.

Dr. Shreya Trivedi: And in talking to him, I just loved his stories of the number of patients he has seen with severe HTG and how zooms in on their lifestyle. For example, recommending over 7 thousand steps

Dr. Greg Katz: And so this was notable because this woman was like, I have my phone on me a hundred percent of the time. And I looked at her step count over the last, I don’t know, month. She averaged 900 to a thousand steps a day. There were plenty of days where triple, triple, it was triple digits, triple, and she hadn’t broken a thousand.

Dr. Ananya Gorrai: Man, there were plenty of days when I might have not even broken a thousand steps when I was studying for STEP. I wonder how my triglycerides were doing back then.

Dr. Greg Katz: And so if you take somebody who does not do any physical activity and you give them the homework of they have to go for a 20-minute walk after every meal that they have, I’ve had quite a few patients who have 50% reductions in their triglyceride levels from doing that. And when you give somebody homework like that, they’re probably going to be a little bit more careful about what they’re eating for their diet and how long that persists, and whether they do it when they don’t have to see me in two or three months.

Dr. Shreya Trivedi: It’s so interesting how powerful giving patients homework can be. I think it just the perspective language that patients need to make change.

Dr. Ananya Gorrai: Another recommendation is to, of course, have a low-fat diet. I found it helpful to talk to Dr. Robert Oh, a clinical professor in family medicine at Stanford. He has ran into to the issue of recommending a low-fat diet to a patient with severe hypertriglyceridemia, but then patients can the mistake of filling their diet with processed carbs.

Dr. Robert Oh: So you can go low-fat, but you have to make sure it’s low saturated fat, and you have to make sure that you have higher protein and not of these refined carbohydrates. You have to cut the sugar out, you have to cut the alcohol off. So most people shy away from low carb for whatever reason, I think got a bad name. But that’s the one. If you look at the studies it’s looked at, there’s a couple of articles in the a AHA that if you look at all the macronutrient composition, the lower carbohydrate, the better. You have a better weight loss, and you have a better with triglyceride profile.

Dr. Ananya Gorrai: So the teaching point here, yes, we recommend a low-fat diet for patients with severe HTG, and its impact also to counsel to avoid a diet that high in simple sugars – the excess carbs are converted by the liver into fatty acids. And of course, those FAs are assembled into TGs and are secreted as VLDL. And if we really wanted to nerd out, we also know that high carb diet also leads to insulin resistance which then reduces triglyceride clearance.

Dr. Shreya Trivedi: Oh man, so much there, to summarize lifestyle counseling. What I took away was counseling patients on how responsive TGs can be to lifestyle, particularly avoiding alcohol, refined carbs, and sugar, to prescribe to patients low-fat diet to those with severe HTG and walking >7K steps of 20 minutes after each meal. Tracking can be helpful and have them come back on the sooner side

Pearl 4 – Triglyceride-Lowering Medications

Dr. Shreya Trivedi: So in addition to counseling about lifestyle, we also have to think about meds (esp first time). I mean for example, Adam’s patient’s TG are still 388 after a few days in the hospital and mostly NPO. And remembering that all it takes it one fatty meal to saturate those lipoprotein lipase above a 500 or so threshold.

Dr. Jimin Hwang: Well before we get into the medications, it will be a solid for “future you” to get a fasting triglyceride level before starting one. Dr Brinton touches a little bit on this.

Dr. Eliot Brinton: I always prefer fasting. And the reason is it has less noise. Triglycerides, fasted or fed, are going to vary by 20 to 30 to 40 to 50%. And if you think about that for a minute, our triglyceride-lowering drugs have efficacy in that same range. So you’ve got a problem with signal-to-noise where the signal and the noise are in the same range. So how can you figure out if somebody is getting better or worse on a given medication if one time you measure them fasting and the next time or if you measure them twice and in one time it is been say six hours, and they had very little fat, or the second time it’s been two hours, and they had a lot of fat. In either case, you’re going to have a huge difference in terms of chylomicrons.

Dr. Jimin Hwang: And yes, different people can have different practices with having patients come back for a fasting or not. It’s an extra bloodstick. Some people want to see what their nonfasting lives at. But when the TG are getting into that severe range, and you are thinking of starting a medication. Getting a fasting one definitely helps to see the impact of that medication without too much noise. I’ve definitely had the temptation to eat some banana chips or some Ben and Jerry’s before getting labs

Dr. Shreya Trivedi: Love all the tips to help future you! So what do we have in terms of meds that are helpful, and by how much

Dr. Jimin Hwang: So there are 3 big ones we are gonna talk about: statins, omega-3s, and fibrates. And let’s start with maybe the most familiar one to a lot of us, most statins

Dr. Eliot Brinton: How do we prevent A-S-C-V-D in our patients with high triglycerides? Well, believe it or not, we’re going to do is use a statin. You go, wait a minute, statins lower LDL. They don’t lower triglycerides. Well, in a person with normal triglycerides, whatever, their percent LDL lowering is about half as good for triglycerides. So you’re using a high-intensity stat. You get a 50 to 60% LDL lowering, you’re going to have a 25 to 30% triglyceride reduction. Well, that’s not, it’s not a big deal. But as you go with higher triglycerides, that two-to-one ratio becomes one-to-one. Now, it doesn’t mean the triglyceride lowering goes down a lot more, but what it means is that you’re going to get as much triglyceride reduction as you do LDL lowering.

Dr. Jimin Hwang: So in general with statins, we can expect patients to drop their triglycerides by 10-30% but at higher triglyceride level, we can have an even greater degree reduction

Dr. Shreya Trivedi: Awesome, and just to say it out loud. And to this point, the 2018 AHA/ACC cholesterol management guidelines recommend patients start a statin if they are 40–75 years old with persistent moderate (so fasting TG >175-499 mg/dl) or severe HTG (≥500 mg/dL) and elevated ASCVD risk ≥7.5% 10-year risk ASCVD the other added benefit to starting a statin in these patient is that statins as we all know reduces/reduces cardiovascular risk.

Dr. Ananya Gorrai: Let’s dive into other options since a lot of these patients with triglycerides in the triple digits might need more than just a statin, and so the other options are fenofibrate

Dr. Greg Katz: Fenofibrate is probably the medication that has the largest evidence base that it lowers triglyceride levels, and anecdotally, it just seems really effective at lowering triglyceride levels.

Dr. Ananya Gorrai: And if we look at the evidence, you can actually expect a 30-50% reduction in triglycerides when you start a fenofibrate. (There was even real-world data median reductions in TG with fenofibrate of up to 60%). And some side effects to consider with fibrate therapy are a slightly increased risk for myopathy, cholelithiasis, and venous thrombosis

Dr. Shreya Trivedi: Now tell me about omega-3s. I mean my dad takes fish oil supplements because of some random WhatsApp video he was sent. Sounds like maybe it’s helping?

Dr. Greg Katz: Omega fatty acids also do a really good job of lowering triglyceride levels. It’s related to how they impact lipoprotein lipase, and that’s a very easy, and if you look at the whole premise behind reduce it, which was the trial adding VASCEPA to standard of care, lipid-lowering therapy, was that it helped to clear the triglycerides and it helped to treat these patients who had residual triglycerides

Dr. Robert Oh: So, reduce it was pretty large trial. These are patients with type two diabetes or other cardiovascular risk factors, and they already were on a statin, which is super important to understand. And they had triglyceride levels above 150. So that was the inclusion criteria. And so these are high-risk patients already on a statin, and their triglyceride levels are up. And then they offered them in randomized fashion, four grams of icosapent-ethyl or Vascepa.The number needed to treat was 111. So one person, 111 person treated to have one cardio or mortality benefit, which is pretty decent. It’s decent numbers considering they’re already on a statin already.

Dr. Ananya Gorrai: So that’s huge finding, that omega 3 supplements had a 25% reduction in major cardiovascular events. And for those who like numbers, these omega-3s, we can expect a 20% triglyceride reduction when you get to doses of 3-4g of EPA per day.

Dr. Jimin Hwang: One association to possibly keep in mind is that they did find increased rates of hosp for atrial fibrillation in the omega-3 group. This might be something to watch out for, especially in patients who may have poor cardiac substrate.

Dr. Ananya Gorrai: That is definitely something to be cautious about. I am also wondering if patients (or Shreya’s your dads) OTC fish oil is that sufficient? Or should we transition them to a prescription strength (if it is available and affordable, of course).

Dr. Eliot Brinton: So what about the dietary supplement Omega-3? It’s cheap, it’s easy. It’s there in the grocery store. Pick up a giant bottle of it and start taking it. Well, there are several problems. Number one, they tend to have a lot of saturated fat. Number two, they tend to be oxidized. Number three, they basically always have a lot of D-H-A. So you’re digging the hole deeper. So please tell your patients, please never recommend dietary supplement Omega-3, and please tell your patients if they’re taking ’em to stop because it’s not helping them.

Dr. Shreya Trivedi: So those omega-3 supplements that patient over the counter can have variable amounts of EPA and DHA, and for context, what was used in the REDUCE-IT trial was VASCEPA, which is prescription omega-3 and just purified EPA, and no DHA

Dr. Ananya Gorrai: I do want to point out that there is some very recent evidence supporting a combination of EPA/DHA [1.6 g of EPA and 0.8 g of DHA – docosahexaenoic acid] in CV risk reduction – specifically for patients on hemodialysis. In the RCT, the fish oil group had significantly lower rates of cardiovascular events than placebo [HR 0.57]. And just hot off the press recently, there a RCT showing that prescription strength omega-3s in patients on dialysis reduced MACE significantly by 43%. So reducing in MACE might not be specific to TG and may be there other ways omega-3s are reducing CV events.

Dr. Shreya Trivedi: Interestingly that was a combo prescription with 2:1 EPA and DHA so maybe EPA has to be more to be effective but i think the takeaway either way is when ur doing your med rec, make sure its no something patients are buying off shelves (the dose of EPA/DHA is highly variable) and we are prescribing an omega-3 that is high in EPA

Dr. Ananya Gorrai: Also, just to say out loud. You might have learned about Niacin in triglyceride treatment, but it’s not in our toolkit, even for severe TG. No one can tolerate it with the terrible flushing it gave and liver injury. No cardiovascular benefit also.

Dr. Shreya Trivedi: Okay, so it sounds like we really have statins, fenofibrate, and omega-3s, but how do we choose? Is it the side effects?

Dr. Jimin Hwang: So we really pressed our discussants on this. And honestly, most of them said start with the medication you’re most comfortable with.

Dr. Ananya Gorrai: Another way to think about it, if you rapidly lower, like you worried someone might be at risk for TG-induced pancreatitis, especially with TG > 500, reach for fenofibrates and omega3; they can rapidly lower their triglycerides, and in patients with severe TG, can give as high as 50% reduction.

Dr. Shreya Trivedi: Even the ADA, the American Diabetes Association, has an explicit recommendation for fasting TG ≥500 mg/dL, pharmacologic therapy specifically to lower TG (a fibrate or high-dose omega-3 fatty acid) is warranted to reduce pancreatitis risk.

Dr. Ananya Gorrai: And there is also Statins, which has a less impressive TG lowering footprint in terms of % reduction, but also lower ASCVD, as do omega-3.

Dr. Jimin Hwang: And so we talked about importance of meds. Once our patients are on these medications, the other question in clinic is when to bring the patient back and what to check-in on during these visits?

Dr. Seth Baum: I can bring them back more frequently, more rapidly. So four to six weeks, let’s say. So that’s what I would do. So you’re looking for frankly dramatic changes in those comorbidities. Is the patient doing something to lose weight? Has the patient started exercising? Is the diet better? Has the patient cut back on alcohol? Any medications that they were on that increased triglycerides, have they been changed? Things like that. So you’re looking to see that there’s been a significant change that would ultimately lead to a sustained reduction in triglycerides, not just the blood tests that you’re repeating.

Dr. Ananya Gorrai: That was good spaced repetition to what we talked about earlier in the podcast about all things that contribute to that TG level.

Dr. Shreya Trivedi: so to summarize the 3 typical meds to treat TG: it’s an art on which ones to start and how many do you start at once depending on how high the TG is and how motivated the pt may be with lifestyle but the ones that give us ASCVD reduction: Statins and Omega 3s (the EPA kind at doses as high as 3-4g/day). And the ones that rapidly lower those triglycerides, especially when they are really high, are the fibrates and the omega-3s.

Pearl 5 – When to Send a Genetic Panel & Prevalence

Dr. Shreya Trivedi: Most cases with high triglycerides are associated with factors we talked about, such as diabetes, alcohol use, and metabolic syndrome. But Greg did mention everyone also has different genetics at play.

Dr. Jimin Hwang: The reason to watch out for genetic syndromes at play is because the treatment is completely different. There are two big buckets: We call FCS for familial chylomicronemia syndrome. The other form is MCS – the metabolic form – we call mixed chylomicronemia syndrome. Dr. Seth Baum and Dr. Eliot Brinton takes us through this beautifully.

Dr. Seth Baum: In FCS, first of all, it’s an ultra-rare disorder. It’s present somewhere between one and let’s say 10 people per million. The two FCS has certain classic patterns of presentation, classic findings. They are not necessary though to make the diagnosis. So you could be off on one or two of these things and still have FCS. So it’s a monogenic disorder. There are five genes that are typically involved mutations. So one mutation from mom, one from dad.

Dr. Eliot Brinton: It is most often a defect in the lipoprotein lipase gene LPL that reduces its activity. In fact, generally, these people have zero to 20% of normal lipoprotein lipase activity. So FCS means what? You generally have chylomicronemia since you were very young, it often presents in neonates or young children or preteens or teenagers.

Dr. Jimin Hwang: Yes. People with FCS have a genetically determined, low activity of lipoprotein lipase. When you don’t have as much lipoprotein lipase, you lose your ability to break down chylomicrons as well. So patients with FCS present with sky-high triglycerides that are persistent regardless of fasting.

Dr. Seth Baum: If you do genetics on a patient and the patient does not have the evidence of those mutations, it does not mean that the patient doesn’t have FCS, right? If you find them, the patient has it. If you don’t find them, you still have to consider the diagnosis.

Dr. Jimin Hwang: So, turns out genetic tests miss a certain number of people who behave like FCS, but do not have a detectable mutation in our genetic panels.

Dr. Shreya Trivedi: yes hold that thought.. and then there is also MCS and those just to be clear these technically patients with a fasting TG >880 since thats whats been observed as the point where chylomicron develop in the blood

Dr. Greg Katz: For every single case of those, there’s probably 500 of it’s just metabolic syndrome and it’s just elevated triglycerides related to an imbalance between somebody’s lifestyle and what their genetics want their lifestyle to be.

Dr. Shreya Trivedi: Makes me wonder, in the clinic when we’re evaluating patients with severely high triglycerides (that is over 880), when would we suspect FCS vs. MCS?

Dr. Seth Baum: So phenotype always trumps genotype. Okay? So that’s one thing you think about. You look at the individual and there are certain things you’re going to look for. What’s the age of onset? Well, when I was 30 years old, I was told I had a very high triglyceride. So it’s young, it’s not terribly young, but it’s young. That favors FCS over MCS patient’s. Body habits. Is the patient overweight or obese? If the patient’s overweight or obese favors, M-C-S-F-C-S typically thinner. you look at whether or not the patient has any secondary causes of severe diabetes would be the typical one. Metabolic syndrome, central obesity, other underlying rheumatologic disorders or medications that might cause it. Hormonal medications, atypical antipsychotics. So you go through this list and you go, does the patient have any of these features? You ask about things like abdominal discomfort. Do you have periodic abdominal discomfort because that could be a sign that there’s a low grade pancreatitis, if you will, or are there cognitive disorders? Do you feel like you’re in a foggy state frequently? Do you miss a lot of work? Those favor FCS, what were prior triglyceride levels if you have access to them, if they were all over a thousand and the patient doesn’t have any of these other causes that would be associated with MCSU, really looking at an FCS patient. What about response to triglyceride lowering therapeutics? So you say, have you ever been given a fibrate or have a statin for triglyceride lowering or omega fatty acids? Yeah, I have. They didn’t work at all start favoring FCS over MCS. They’re variable in MCS though, so you still might have a poor response.

Dr. Jimin Hwang: These are important clues that can help us identify patients with FCS. This brings us to an important question: why do we want to identify FCS? The presence of FCS has significant implications for treatment. FCS tends to not respond well to traditional lipid-lowering therapies, because often these therapies require a working lipoprotein lipase. For a very long time, patients with FCS didn’t have much therapeutic options except for a lifelong very low-fat diet. But lo and behold! we have had some good news.

Dr. Eliot Brinton: December of 2024, finally, the FDA approved the first drug for FCS, and that’s Olezarsen. It’s an antisense oligonucleotide that blocks a OC three production. In FCS, you get only a 50% triglyceride lowering. Well, that’s a miracle for an FCS patient because there they have so few treatment options, and that’s enough to reduce pancreatitis by roughly 80 to 90%, and that is amazing.

Dr. Shreya Trivedi: That is amazing for these patients with FCS, so now have Olezarsen and Plozasiran. And that makes me think of another relevant question: if we have a patient that comes in for TG >500, do you send off genetic testing?

Dr. Eliot Brinton: One other thing I will say, I do not bother to genotype patients who have persistent cardio micro anemia and or either the clinical functional FCS or what would ultimately be proven to be genotypic FCS. Why? Because the label does not require it. FDA does not require this for use of these very expensive AOC three drugs and a majority of patients who have what looks like typical FCS have this clinical or functional FCS and not genotypic. So in a majority of cases, you will quote prove yourself wrong by failing to genotype them as FCS.

Dr. Jimin Hwang: So, for the most part, our discussants had mixed practices for sending off genotyping. Some say it can get expensive for patients. Dr. Baum did say he will send genetic testing for FCS if the phenotype fits because it may have implications for familial screening.

Dr. Shreya Trivedi: And we will leave with one final word from Dr. Seth Baum

Closing

Dr. Seth Baum: I would say that I think we need to look at triglycerides differently nowadays, that we need to have in the SHTG population, we need to have a sense of urgency. Where previously we didn’t have that. And it’s for a couple of reasons. One, it’s for the acute pancreatitis risk and especially in view of the saturation of lipoprotein lipase at triglycerides of around 500. These people are at much higher risk than you think they are for acute pancreatitis. And the other is A-S-C-V-D. I mean, it’s still the leading cause of death in the United States. And I think anything we can do to diminish the risk would be valuable. So that would be it. Pay attention, take it seriously, and do what you can to reduce it to reduce.

Dr. Shreya Trivedi: So that wraps up our episode on severe hypertriglyceridemia. And if you got any value from this podcast, our ask is to please share this with at least one other colleague that could also use a nice aha moment.

Dr. Jimin Hwang: Thank you to our peer reviewers, Dr. Zahid Ahmad and Dr. Michael Shapiro. Thank you to Dr. Nabil Sweiss for the accompanying graphic.

Dr. Ananya Gorrai: And as always, we love hearing feedback, so please email us at [email protected] opinions expressed our own and do not represent the opinions of any affiliated institutions. Thank you. Take care.

References

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