Unmet need of severe hypertriglyceridemia (sHTG)

Treating sHTG is critical to reduce the risk of complications such as acute pancreatitis and atherosclerotic cardiovascular disease. Increased urgency around sHTG is needed to help improve identification of at-risk individuals, discover potential causes, and propose management plans for better patient outcomes.1-3

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Prevalence and causes

Millions of Americans are at risk of life-threatening complications due to severe hypertriglyceridemia (sHTG)1,4

Defining sHTG

sHTG

severe hypertriglyceridemia

sHTG is defined by fasting triglyceride levels 500 mg/dL and above, and characterized by an increased risk of acute pancreatitis (AP), atherosclerotic cardiovascular disease (ASCVD), and other associated morbidities1,5-7

map of north america with the statistic that more than 3 million american adults are estimated to have sHTG

More than 3 million American adults are estimated to have sHTG, although the true prevalence may be even higher4

Current guidelines recommend diagnosing sHTG based on fasting serum triglyceride levels. However, people are in a postprandial state for most of the day. Therefore, a patient's true risk of sHTG and related complications may be greater than what fasting levels may indicate.3,8

sHTG can be caused by a combination of several factors1,9,10

icon of three people representing lifestyle causes of sHTG

Lifestyle (eg, high alcohol intake, poor diet)

icon of pill representing medication causes of sHTG

Medications (eg, antidepressants, oral contraceptives, antiretrovirals)

icon representing physical pain caused by the clinical condition of sHTG

Clinical conditions (eg, diabetes, obesity, HIV, pregnancy)

icon of dna strand representing genetic factors of sHTG

Genetic factors (eg, familial chylomicronemia syndrome, multifactorial chylomicronemia syndrome)

red warning icon

sHTG and its dangers are underappreciated and require urgent action.1,3,5,8,11

Current approach

Existing treatment approaches for addressing severe hypertriglyceridemia (sHTG) are insufficient11-14

Limitations of current approaches

Lifestyle changes

Lifestyle modifications such as diet and exercise have proven to be an unreliable means of lowering triglycerides, as they depend on patient adherence.12

Therapies

Omega-3 fatty acids

American Association of Clinical Endocrinology (AACE) clinical practice guidelines on pharmacologic management of adults with dyslipidemia found insufficient evidence that EPA/EPA+DHA (omega-3 fatty acids) prevent pancreatitis, the main complication associated with sHTG.11

Fibrates and statins

Fibrates and statins are some of the most commonly used lipid-lowering therapies; however, they do not reduce triglyceride (TG) levels sufficiently in all patients with sHTG. According to the American Heart Association (AHA), fibrates lower TG levels by approximately 30%-50%, and statins lower TG levels by approximately 10%-30%.13

Niacin

The AACE clinical practice guideline on pharmacologic management for dyslipidemia does not recommend niacin in adults with sHTG (≥500 mg/dL) due to significant adverse effects.11

GLP-1

Though some patients with sHTG may be receiving treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist for diabetes or weight loss, it's important to note that GLP-1s have been found to increase the risk of gastrointestinal adverse events, including acute pancreatitis.14

red icon of computer with wavelength

Lifestyle modifications and currently available pharmacologic therapies are limited in their ability to sufficiently lower triglyceride levels in patients with sHTG, resulting in continued risk for acute pancreatitis and atherosclerotic cardiovascular disease.1,11-16

Postprandial spikes

Severe hypertriglyceridemia (sHTG) is volatile due to postprandial spikes in triglyceride levels17,18

The risks associated with sHTG are underestimated and life-threatening, as triglycerides—unlike other lipids—can fluctuate greatly between fasting and nonfasting states3,5

visualization of the primary risks associated with sHTG based on TGs greater than 880 mg/dL and TGs greater than 500 mg/dL

The additive effect of multiple meals can cause a substantial postprandial TG peak, with levels elevated for most of the day.8

As triglycerides surpass 880 mg/dL, chylomicrons become the predominant triglyceride-rich lipoprotein (TRL), resulting in increased risk of acute pancreatitis (AP) and continued atherosclerotic cardiovascular disease (ASCVD) risk.17,19

The primary risks when triglyceride levels reach 500 mg/dL and above are AP and ASCVD, due to the predominance of TRLs such as chylomicrons and very-low-density lipoproteins (VLDL).1

Cred icon of chart

Due to the postprandial increases of triglycerides and the risk associated with escalating levels, it is critical to treat sHTG aggressively and appropriately.1,17,18

Identifying patients with sHTG

To appropriately address severe hypertriglyceridemia (sHTG), prompt patient identification is needed1,20

A patient's risk for serious health complications varies depending on their triglyceride levels and medical history1

Choose a patient journey to explore

portrait of sHTG patient model named Sandra

She experienced her first AP attack. Will there be another?

Sandra
portrait of sHTG patient model named Lawrence

His diabetes and triglycerides were out of control.

Lawrence
Michael profile picture

His cardiologist suspected there was more to his sHTG.

Michael
Maria profile picture

When the standard of care isn't working, it's time to dig deeper.

Maria

Not real patients; actor portrayals and generated models.

portrait of sHTG patient model named Sandra with quote: I want my life back
“I want my life back.”
Not real patient; actor portrayal or generated model.

Sandra, 49

Has severe hypertriglyceridemia (sHTG) with a history of acute pancreatitis (AP)

Not real patient; actor portrayal or generated model.

  • Sandra was diagnosed with sHTG at age 47, when multiple lipid panels revealed elevated triglyceride (TG) levels of 864 mg/dL and 873 mg/dL (fasting)
  • Sandra was prescribed a fibrate, which she stopped taking shortly afterward due to myalgias
  • Sandra experienced her first episode of AP at age 48. She was prescribed an EPA and a statin, to which she adhered, but her TGs remained above 500 mg/dL
  • Sandra has implemented lifestyle changes but is still feeling anxious that she might experience another AP episode if she doesn't get her TG levels under control
“I want my life back.”
  • Sandra was diagnosed with sHTG at age 47, when multiple lipid panels revealed elevated triglyceride (TG) levels of 864 mg/dL and 873 mg/dL (fasting)
  • Sandra was prescribed a fibrate, which she stopped taking shortly afterward due to myalgias
  • Sandra experienced her first episode of AP at age 48. She was prescribed an EPA and a statin, to which she adhered, but her TGs remained above 500 mg/dL
  • Sandra has implemented lifestyle changes but is still feeling anxious that she might experience another AP episode if she doesn't get her TG levels under control
Triglyceride levels of 500-880 mg/dL are associated with an increased risk of AP, especially when there's a history of AP1,17,19,21
Triglycerides 500-880 mg/dL (fasting)
Statins, fibrates, and EPAs do not reduce triglyceride levels sufficiently in all patients with sHTG11,13
Intolerant to fibrates, and TG level not at goal despite statin and EPA therapy
sHTG is commonly associated with comorbidities such as obesity1,9

Overweight with a BMI of 28.9 kg/m2

Once a patient with sHTG has had an episode of AP, the risk for future episodes significantly increases21
History of acute pancreatitis with hospitalization
Is there more that can be done to lower Sandra's TGs and decrease the risk of another AP episode?
portrait of sHTG patient model named Lawrence with quote: I want to turn my health around for my family
“I want to turn my health around for my family.”
Not real patient; actor portrayal or generated model.

Lawrence, 62

Has severe hypertriglyceridemia (sHTG) and type 2 diabetes mellitus (T2DM)

Not real patient; actor portrayal or generated model.

  • Lawrence's endocrinologist started him on metformin and a statin and recommended lifestyle modification
  • With the medications and lifestyle changes, his A1c improved and was at goal; however, his elevated triglycerides (TGs) persisted in the range of 789 mg/dL to 873 mg/dL (fasting)
  • An EPA, and eventually a fibrate, were prescribed to control Lawrence's TG levels. Both were ineffective in lowering his TG levels below 500 mg/dL
  • The endocrinologist had considered treating him with a GLP-1 receptor agonist to help with weight loss but was hesitant due to the increased risk of pancreatitis
  • Lawrence is worried his endocrinologist won't find a treatment to lower his TGs, leaving him at risk for serious health complications
“I want to turn my health around for my family.”
  • Lawrence's endocrinologist started him on metformin and a statin and recommended lifestyle modification
  • With the medications and lifestyle changes, his A1c improved and was at goal; however, his elevated triglycerides (TGs) persisted in the range of 789 mg/dL to 873 mg/dL (fasting)
  • An EPA, and eventually a fibrate, were prescribed to control Lawrence's TG levels. Both were ineffective in lowering his TG levels below 500 mg/dL
  • The endocrinologist had considered treating him with a GLP-1 receptor agonist to help with weight loss but was hesitant due to the increased risk of pancreatitis
  • Lawrence is worried his endocrinologist won't find a treatment to lower his TGs, leaving him at risk for serious health complications
Triglyceride levels of 500-880 mg/dL are associated with an increased risk of ASCVD and AP1,17,19
Triglycerides 500-880 mg/dL (fasting)
Statins, fibrates, and EPAs do not reduce triglyceride levels sufficiently in all patients with sHTG.11,13
TG level not at goal despite statin, fibrate, and EPA therapy
sHTG is commonly associated with comorbidities such as obesity1,9

Obese with a BMI of 31 kg/m2

sHTG is commonly associated with comorbidities such as diabetes1,9
Has controlled T2DM
Is there more that can be done to lower Lawrence's TGs and reduce the risk of a serious health complication?
portrait of sHTG patient model named Michael with quote: I'm tired of living like this. It's time to make a change
“I'm tired of living like this. It's time to make a change.”
Not real patient; actor portrayal or generated model.

Michael, 58

Has severe hypertriglyceridemia (sHTG), hypertension, and coronary artery disease (CAD) and was diagnosed with multifactorial chylomicronemia syndrome

Not real patient; actor portrayal or generated model.

  • Michael was following up with his cardiologist when a repeat lipid panel showed an elevated triglyceride (TG) level of 1512 mg/dL (fasting)
  • Michael was on a statin for his sHTG and CAD. The statin lowered his TG levels by 10%. Concurrent medications included an ACE inhibitor for hypertension, which was well controlled
  • After seeing suboptimal results in TG lowering with a statin, Michael's cardiologist added a fibrate, and eventually an EPA, to his treatment plan, all of which were ineffective in lowering his TGs below 880 mg/dL
  • Michael's cardiologist suspected a genetic cause and used the NAFCS scoring tool to rule out FCS, a monogenic genetic form of sHTG. Michael was finally diagnosed with MCS, a polygenic form of sHTG, commonly seen with comorbid conditions22,23
“I'm tired of living like this. It's time to make a change.”
  • Michael was following up with his cardiologist when a repeat lipid panel showed an elevated triglyceride (TG) level of 1512 mg/dL (fasting)
  • Michael was on a statin for his sHTG and CAD. The statin lowered his TG levels by 10%. Concurrent medications included an ACE inhibitor for hypertension, which was well controlled
  • After seeing suboptimal results in TG lowering with a statin, Michael's cardiologist added a fibrate, and eventually an EPA, to his treatment plan, all of which were ineffective in lowering his TGs below 880 mg/dL
  • Michael's cardiologist suspected a genetic cause and used the NAFCS scoring tool to rule out FCS, a monogenic genetic form of sHTG. Michael was finally diagnosed with MCS, a polygenic form of sHTG, commonly seen with comorbid conditions22,23
Triglyceride levels >880 mg/dL are associated with a significant risk of AP1,17,19
Triglycerides intermittently >880 mg/dL (fasting)
Statins, fibrates, and EPAs do not reduce triglyceride levels sufficiently in all patients with sHTG11,13
TG level not at goal despite statin, fibrate, and EPA therapy
sHTG is commonly associated with comorbidities such as CAD and hypertension1,9
Has CAD with well-controlled hypertension
sHTG is commonly associated with comorbidities such as obesity1,9

Overweight with a BMI of 29 kg/m2

Could a genetic component be complicating the management of your sHTG patient?
portrait of sHTG patient model named Maria with quote: It's frustrating when medication doesn't work and the doctor isn't sure why
“It's frustrating when medication doesn't work and the doctor isn't sure why.”
Not real patient; actor portrayal or generated model.

Maria, 53

Has severe hypertriglyceridemia (sHTG)

Not real patient; actor portrayal or generated model.

  • Maria had a lipid panel as part of her routine physical exam with her primary care doctor. It showed an elevated triglyceride (TG) level of 863 mg/dL (fasting). Repeat lipid panels showed consistent results
  • After seeing that Maria's TGs were above 500 mg/dL, her doctor prescribed an EPA and lifestyle modifications. The EPA only slightly reduced her TG level, which remained above 500 mg/dL
  • Her doctor then prescribed a statin, and eventually a fibrate, both of which failed to lower her TG levels below 500 mg/dL
“It's frustrating when medication doesn't work and the doctor isn't sure why.”
  • Maria had a lipid panel as part of her routine physical exam with her primary care doctor. It showed an elevated triglyceride (TG) level of 863 mg/dL (fasting). Repeat lipid panels showed consistent results
  • After seeing that Maria's TGs were above 500 mg/dL, her doctor prescribed an EPA and lifestyle modifications. The EPA only slightly reduced her TG level, which remained above 500 mg/dL
  • Her doctor then prescribed a statin, and eventually a fibrate, both of which failed to lower her TG levels below 500 mg/dL
Triglyceride levels >500 mg/dL are associated with an increased risk of AP and ASCVD1,17,19
Triglycerides consistently >500 mg/dL (fasting)
Statins, fibrates, and EPAs do not reduce triglyceride levels sufficiently in all patients with sHTG11,13
TG level not at goal despite statin, fibrate, and EPA therapy
sHTG is commonly associated with comorbidities such as obesity1,9

Overweight with a BMI of 26 kg/m2

Could Maria's limited response to the standard of care warrant a referral to a lipid specialist?

A1c=glycated hemoglobin; ACE inhibitor=angiotensin-converting enzyme inhibitor; AP=acute pancreatitis; ASCVD=atherosclerotic cardiovascular disease; BMI=body mass index; CVD=cardiovascular disease; EPA=eicosapentaenoic acid; FCS=familial chylomicronemia syndrome; GLP-1 receptor agonist=glucagon-like peptide-1 (GLP-1) agonist; MCS=multifactorial chylomicronemia syndrome; NAFCS scoring tool=North American Familial Chylomicronemia Syndrome scoring tool.

References

  1. Virani SS, Morris PB, Agarwala A, et al. 2021 ACC expert consensus decision pathway on the management of ASCVD risk reduction in patients with persistent hypertriglyceridemia: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2021;78(9):960-993.
  2. Arca M, Veronesi C, D'Erasmo L, et al. Association of hypertriglyceridemia with all-cause mortality and atherosclerotic cardiovascular events in a low-risk Italian population: the TG-REAL retrospective cohort analysis. J Am Heart Assoc. 2020;9(19):e015801.
  3. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2(8):655-666.
  4. Data on file. sHTG prevalence. Ionis Pharmaceuticals; 2024.
  5. Gurevitz C, Chen L, Muntner P, Rosenson RS. Hypertriglyceridemia and multiorgan disease among U.S. adults. JACC Adv. 2024;3(5):100932.
  6. Kessler AS, Aggio D, Howard EM, et al. A qualitative study to explore the patient experience of hypertriglyceridemia-related acute pancreatitis. J Clin Lipidol. Published online April 10, 2025.
  7. Kessler AS, Zhang C, McStocker S, et al. Study-start characteristics of individuals with severe hypertriglyceridemia (sHTG) in an app-based home-reported outcomes study evaluating disease burden and treatment patterns. Abstract accepted for presentation at: PancreasFest; July 24-25, 2025; Pittsburgh, PA.
  8. Keirns BH, Sciarrillo CM, Koemel NA, Emerson SR. Fasting, non-fasting and postprandial triglycerides for screening cardiometabolic risk. J Nutr Sci. 2021;10:e75.
  9. Hegele RA, Ahmad Z, Ashraf A, et al. Development and validation of clinical criteria to identify familial chylomicronemia syndrome (FCS) in North America. J Clin Lipidol. 2025;19(1)(online-only supplementary material):83-94.
  10. Hegele RA, Ahmad Z, Ashraf A, et al. Development and validation of clinical criteria to identify familial chylomicronemia syndrome (FCS) in North America. J Clin Lipidol. 2025;19(1):83-94.
  11. Patel SB, Wyne KL, Afreen S, et al. American Association of Clinical Endocrinology clinical practice guideline on pharmacologic management of adults with dyslipidemia. Endocr Pract. 2025;31(2):236-262.
  12. Santos-Baez LS, Ginsberg HN. Hypertriglyceridemia—causes, significance, and approaches to therapy. Front Endocrinol (Lausanne). 2020;11:616.
  13. Skulas-Ray AC, Wilson PWF, Harris WS, et al. Omega-3 fatty acids for the management of hypertriglyceridemia: a science advisory from the American Heart Association. Circulation. 2019;140(12):e673-e691.
  14. Aldhaleei WA, Abegaz TM, Bhagavathula AS. Glucagon-like peptide-1 receptor agonists associated gastrointestinal adverse events: a cross-sectional analysis of the National Institutes of Health All of Us Cohort. Pharmaceuticals (Basel). 2024;17(2):199.
  15. Fung MA, Frohlich JJ. Common problems in the management of hypertriglyceridemia. CMAJ. 2002;167(11):1261-1266.
  16. Shemesh E, Zafrir B. Hypertriglyceridemia-related pancreatitis in patients with type 2 diabetes: links and risks. Diabetes Metab Syndr Obes. 2019;12:2041-2052.
  17. Rashid N, Sharma PP, Scott RD, Lin KJ, Toth PP. Severe hypertriglyceridemia and factors associated with acute pancreatitis in an integrated health care system. J Clin Lipidol. 2016;10(4):880-890.
  18. D'Erasmo L, Di Costanzo A, Cassandra F, et al. Spectrum of mutations and long-term clinical outcomes in genetic chylomicronemia syndromes. Arterioscler Thromb Vasc Biol. 2019;39(12):2531-2541.
  19. Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia: its etiology, effects and treatment. CMAJ. 2007;176(8):1113-1120.
  20. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. 2019;139(25):e1046-e1081.
  21. Sanchez RJ, Ge W, Wei W, Ponda MP, Rosenson RS. The association of triglyceride levels with the incidence of initial and recurrent acute pancreatitis. Lipids Health Dis. 2021;20(1):72.
  22. Pallazola VA, Sajja A, Derenbecker R, et al. Prevalence of familial chylomicronemia syndrome in a quaternary care center. Eur J Prev Cardiol. 2020;27(19):2276-2278.
  23. Paquette M, Bernard S. The evolving story of multifactorial chylomicronemia syndrome. Front Cardiovasc Med. 2022;9:886266.