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Severe HTG
Severe Hypertriglyceridemia: Causes, Current Treatments, and Emerging Therapies

Released: February 01, 2024

Michael Miller
Michael Miller, MD, FACC, FAHA
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Key Takeaways
  • Individuals with severe hypertriglyceridemia may be at risk for cardiovascular disease.
  • Treatments for severe hypertriglyceridemia must not only lower triglyceride levels, but also have a favorable effect on parameters of cardiometabolic risk.

Severe hypertriglyceridemia (SHTG) is defined as triglyceride (TG) levels ≥500 mg/dL. Although SHTG is more common than familial chylomicronemia syndrome (FCS), it is still relatively uncommon. Approximately 2.1 million adults in the United States are living with SHTG.

SHTG Diagnosis
Some people living with SHTG may not even know that they have it because, unlike FCS, SHTG is not often associated with pancreatitis. For the most part, SHTG is asymptomatic and is diagnosed based on a routine check of a lipid profile.

Most individuals will not have marked TG elevation unless there is an associated genetic variant, and some of these genes have not yet been characterized. In this regard, there may be 1 or more polymorphisms that promote severely elevated TG levels in affected individuals.

Secondary Causes of SHTG
Although SHTG may be caused by a genetic defect, in most cases we look for secondary causes. Some secondary causes are metabolic related, and some are medication related. It is important for healthcare professionals who have identified a patient with SHTG to first determine whether there are secondary causes that could be effectively treated. Common secondary causes include diabetes, hypothyroidism, metabolic syndrome, and obesity.

During pregnancy, cholesterol and TG levels may increase. In some pregnant women with a genetic predisposition superimposed upon metabolic/inflammatory disorders, TG levels may rise to SHTG.

Medications and/or lifestyle choices also can cause SHTG. Individuals who heavily consume alcohol, especially with meals high in saturated fat, may be at risk of SHTG. Other individuals who are taking oral hormonal contraceptives, β-blockers, and/or newer-generation antipsychotic agents also may be at risk. Again, if there is an underlying genetic component, that may compound the risk of SHTG.

Treating or Modifying Secondary Causes

Treating Underlying Conditions
Now, let us assume that we have identified an individual with SHTG and either a thyroid abnormality or diabetes. Effectively treating these metabolic conditions may significantly reduce and/or normalize TG levels.

Implementing Lifestyle and Dietary Modifications
Beyond identifying and treating secondary causes of SHTG, lifestyle therapy remains a cornerstone of treatment. This includes reducing overall caloric intake for individuals with overweight or obesity. It is also helpful to lower the amount of saturated fat intake and consumption of fried foods.

Increasing one’s intake of omega-3–containing products is also helpful for reducing TGs. This can be accomplished by consuming fatty fishes such as sardines, salmon, herring, and albacore tuna 2-3 times weekly.

Aerobic exercise, such as brisk walking, also can drive down TG levels. Overall, combining lifestyle approaches may result in TG reductions of 30% to 60%. 

Available TG Treatments
Although elevated low-density lipoprotein cholesterol is directly causative in driving cardiovascular disease (CVD) risk, elevated TG levels serve as an excellent biomarker of risk, especially as levels exceed 150 mg/dL (fasting) or are ≥175 mg/dL (nonfasting).

Because CVD risk is increased in individuals with SHTG, why not use medications that not only lower TG levels, but also have demonstrated CVD risk reduction? The traditionally used medicines for TG lowering include niacin, fibrates, and omega-3 fatty acids. We do not use niacin anymore because clinical trials have shown that it does not reduce CVD risk. Similarly, fibrates have failed with respect to lowering CVD risk.

Now, omega-3 fatty acids might work for both TG lowering and reducing CVD risk. Purified eicosapentaenoic acid (eg, icosapent ethyl) is effective in reducing cardiovascular events in patients with TG between 150 and 499 mg/dL. Although the REDUCE-IT study did not evaluate patients with SHTG, icosapent ethyl is a therapeutic consideration and is approved by the FDA for affected patients at these very high levels (ie, TG ≥500 mg/dL).

Guideline Recommendations
Based on the 2021 American College of Cardiology Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients with Persistent Hypertriglyceridemia, when you have a patient 20 years of age and older with SHTG, the first objective is to rule out secondary causes and address them when they exist. Next is to help your patients optimize their diet and exercise practices. If a patient’s glycemic control should be improved upon (via lifestyle and medications if indicated) or if TG remains persistently elevated, the guidelines recommend starting a fibrate or prescription-strength omega-3 fatty acid.

Newer Fibrate Data
After this guideline was published, a study of nearly 10,500 patients (high-risk patients with diabetes) who received pemafibrate demonstrated no reduction in cardiovascular events vs placebo. Consequently, the guideline recommendation to add a fibrate is on less solid ground, and therefore we have tended not to use this class of agents.

Emerging Therapies for SHTG
Currently, we do not have TG-lowering therapies that are proven to reduce CVD risk in people with TG 500-1000 mg/dL. However, several new therapies are being tested in patients with SHTG.

ANGPTL3 Inhibitors
One therapeutic class is the ANGPTL3 inhibitors. Drugs in this class reduce TG by upregulation of lipoprotein lipase. Evinacumab is the drug in this class currently being studied for reducing TG levels in individuals with SHTG. Although this therapy is approved by the FDA to treat patients 5 years of age and older with homozygous familial hypercholesterolemia, it is not yet approved for patients with SHTG.

Antisense Oligonucleotides
Another class of injectable agents being studied is the antisense oligonucleotides. These agents markedly reduce TG levels by approximately 70% to 80%.

Volanesorsen is an antisense oligonucleotide designed to inhibit apolipoprotein C-III (APOC3 inhibitor). By inhibiting APOC3, its inhibitory effect on lipoprotein lipase is offset, thereby allowing activation of lipoprotein lipase and subsequent TG lowering. Volanesorsen is approved by the European Medicines Agency to treat FCS, but it is not approved in the United States because there was an unintended adverse event of thrombocytopenia and related bleeding. So, although volanesorsen is quite effective in lowering TG in patients with FCS, it is unlikely to gain FDA approval.

Fortunately, a second-generation agent in this class (olezarsen) is being studied in phase III trials of individuals with FCS or SHTG. To date, phase II data are very encouraging. Moreover, olezarsen does not cause thrombocytopenia based on N-acetyl-galactosamine conjugation. With moderately elevated HTG, olezarsen reduces TG levels by approximately 60%. We await phase III data and the potential filing of a New Drug Application with the FDA later this year.

Conclusion
SHTG poses an increased risk of CVD at TG levels from 500-800 mg/dL, whereas higher levels raise the risk of pancreatitis. Treatment of the underlying metabolic disorder, coupled with lifestyle therapy and effective and new TG-lowering therapies, is ushering in a new era for treating our high-risk patients with SHTG.

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