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Bridging the Gap in sHTG and FCS Treatment
Bridging the Gap in sHTG and FCS Treatment With Novel RNA-Based Therapies

Released: May 15, 2025

Expiration: May 14, 2026

Christie M. Ballantyne
Christie M. Ballantyne, MD
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Key Takeaways
  • Severe hypertriglyceridemia can be diagnosed in any patients with fasting triglycerides ≥500 mg/dL, but chylomicronemia should only be considered in those with fasting triglycerides ≥1000 mg/dL.
  • Patients who do not respond to traditional therapy (lifestyle modifications, diabetes management, and discontinuation of problematic medications) should be further evaluated for persistent chylomicronemia and familial chylomicronemia syndrome (FCS).
  • Olezarsen and plozasiran are novel and emerging RNA-based therapies that have demonstrated efficacy and safety in clinical trials for patients with FCS.

Triglycerides are an incredibly confusing area of medicine for both healthcare professionals (HCPs) and patients. The first thing HCPs should clear up when discussing severe hypertriglyceridemia (sHTG) with patients is what it means. sHTG occurs when someone’s fasting triglycerides are ≥500 mg/dL. HCPs may frequently see elevated nonfasting lipids in their patients, so repeating their fasting lipid profile is recommended. This is critical because patients with true sHTG are at increased risk for pancreatitis and adverse cardiovascular events.

There is another group of patients who are at increased risk for pancreatitis: those with chylomicronemia. How do we know someone has chylomicronemia? When fasting triglycerides are ≥1000 mg/dL, lab results will frequently say the patient’s plasma specimen looks like milk because large chylomicron particles that carry triglycerides are present. Patients with chylomicronemia cannot effectively break down the chylomicron particles. Therefore, when HCPs see fasting triglycerides ≥1000 mg/dL, they must understand that there is a greater risk for pancreatitis that continues to grow as triglycerides levels increase.

Current sHTG and FCS Management Strategies
A recent publication found that chylomicronemia is infrequent; 0.1% to 0.2% of US adults have it. Approximately 1% of US adults have fasting triglyceride levels of 500 to 999 mg/dL and 0.2% have levels ≥1000 mg/dL. Of note, severely increased fasting triglycerides levels are seen more commonly in patients who are Hispanic and who have obesity and/or diabetes.

When patients present with either condition, it is critical for HCPs to get a detailed medical history and complete a physical exam. In addition, HCPs should look for secondary factors, including a high-fat or carbohydrate-rich diet, alcohol consumption, comorbid diabetes or obesity, and certain medications. Addressing patients’ lifestyle and medications has a huge impact. That is why it is more important to evaluate and manage these factors when severely elevated triglycerides are present than when cholesterol alone is present. When patients have high fasting triglycerides levels, there is an urgent need for HCPs to treat it quickly.

In general, implementing lifestyle changes, such as a low-fat diet and increased exercise, managing diabetes, discontinuing any medications that increase triglycerides, and initiating fibrates and omega-3 fatty acids will help with getting patients’ fasting triglycerides below 1000 mg/dL. Regardless of the sHTG or chylomicronemia diagnosis, particularly among those who have wild fluctuations, HCPs must work aggressively with these treatment options to lower a patient’s risk for pancreatitis. In terms of cardiovascular disease, adding statins to any prescribed fibrates and/or omega-3 fatty acids will help to address this risk.

This is why getting a complete lipid profile is so important. Although it is okay to measure cholesterol and focus on patients’ low-density lipoprotein cholesterol or ApoB, HCPs may be missing critical needs regarding patients’ triglycerides. A lipid profile that also considers triglyceride levels is going to identify patients with a unique set of problems that must be addressed in a comprehensive manner.

Persistent Chylomicronemia and FCS
It is unfortunate that the traditional treatment methods do not help all patients. It turns out that approximately 1 in every 5500 people have persistent chylomicronemia. With these patients, the risk for pancreatitis goes way up—12.5% of patients with nonpersistent chylomicronemia vs 26% of patient with persistent chylomicronemia experience acute pancreatitis. After trying the traditional management strategies, it is reasonable to consider referral to a lipid specialist. Of note, some patients will have the most severe form: familial chylomicronemia syndrome (FCS). This is a genetic disorder that is biallelic in terms of inheritance, meaning people inherit 2 bad alleles of the causal gene, which causes extremely high levels of triglycerides. And most patients with FCS do not respond to current therapies.

Similar to treating sHTG or chylomicronemia, it is critical to get patients with FCS below a fasting triglyceride level of 500 mg/dL. If they do not respond to traditional therapy, HCPs should consider the diagnosis of FCS, which can be diagnosed using genetic testing or clinical risk scores. HCPs need to take extra steps to help patients with FCS or persistent chylomicronemia, particularly those with recurrent pancreatitis. Some may be eligible for new therapies, while others might become eligible in the future as we get more data.

New and Emerging Treatment Options
What is exciting today is that treatments are now becoming available for patients with persistent chylomicronemia or FCS. This innovation comes from a tremendous amount of research in science, genetics, epidemiology, and discovering new treatment targets. Olezarsen is an APOC-III–directed antisense oligonucleotide that was FDA approved in December 2024 based on the results of the BALANCE study, where treatment with olezarsen reduced the incidence of acute pancreatitis vs placebo in patients with FCS. It should be used in combination with diet to reduce triglycerides in adults with FCS.

There is another investigational therapy, plozasiran, which is a small, interfering RNA agent that targets APOC-III. The phase III PALISADE trial demonstrated its efficacy in significantly reducing triglyceride levels among patients with FCS or persistent chylomicronemia vs placebo. This trial also looked at patients with alarm features and reported a benefit with plozasiran vs placebo in lowering acute pancreatitis incidence (odds ratio: 0.17; P = .03).

Though persistent chylomicronemia and FCS are not common conditions, the risk for pancreatitis is serious because it can be life-threatening. HCPs should always try first-line treatments and refer to a lipid specialist if patients do not respond to these therapies.

What about treatment for patients with sHTG who are not responding to lifestyle interventions and available therapies? Well, this remains a challenge because neither of these newer agents are approved for use in this patient population. But there are now studies looking at benefits with olezarsen or plozasiran for those with sHTG and hopefully we will have those data soon.

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How confident are you in identifying patients that may benefit from emerging RNA-based therapies for FCS? You can get involved in the discussion by answering the polling question and posting a comment below.

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