Severe Hypertriglyceridemia: A Comprehensive Review of Etiology, Diagnosis, Management, and Epidemiology

Abstract

Severe hypertriglyceridemia (sHTG), characterized by fasting triglyceride (TG) levels ≥500 mg/dL (5.6 mmol/L), represents a profound metabolic derangement that significantly elevates the risk of acute pancreatitis and contributes to atherosclerotic cardiovascular disease (ASCVD) progression. This comprehensive report meticulously examines the intricate facets of sHTG, delving into its diverse etiologies, from rare monogenic disorders to common multifactorial presentations compounded by secondary factors. It expands upon the detailed pathophysiology of triglyceride-rich lipoprotein metabolism, outlining the enzymatic and genetic mechanisms underpinning its dysregulation. The review further elaborates on refined diagnostic criteria, sophisticated risk stratification tools, and an extensive array of management strategies, encompassing both established lifestyle modifications and pharmacological interventions, including conventional therapies and cutting-edge emerging treatments. Moreover, it explores the broader epidemiological landscape, the substantial economic burden, and the profound impact on patient quality of life. By synthesizing the latest research, clinical guidelines, and therapeutic advancements, this report aims to provide a nuanced and exhaustive understanding of sHTG, thereby facilitating enhanced patient care, optimizing clinical outcomes, and identifying critical areas for future research.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Hypertriglyceridemia (HTG), defined as elevated concentrations of triglycerides in the bloodstream, is a pervasive lipid abnormality that affects a significant proportion of the global population. While mild to moderate elevations (150-499 mg/dL or 1.7-5.5 mmol/L) are commonly observed and are often components of the metabolic syndrome, severe hypertriglyceridemia (sHTG) stands as a particularly challenging clinical entity due to its direct association with life-threatening acute pancreatitis and its independent contribution to cardiovascular morbidity and mortality. The Endocrine Society defines sHTG as fasting triglyceride levels ≥1,000 mg/dL (11.3 mmol/L), with very severe hypertriglyceridemia at levels ≥2,000 mg/dL (22.6 mmol/L) [1, 9]. However, other guidelines, such as those from the American Heart Association, often consider levels ≥500 mg/dL as severe, acknowledging a continuous risk gradient for pancreatitis [6].

The complexity of sHTG stems from its heterogeneous etiology, encompassing a spectrum from rare monogenic defects that severely impair triglyceride metabolism to more common polygenic predispositions exacerbated by lifestyle factors and secondary medical conditions. The clinical manifestations can range from asymptomatic elevations detected during routine screening to emergent presentations such as acute pancreatitis, eruptive xanthomas, or lipemia retinalis. Consequently, a thorough understanding of the underlying causes, precise diagnostic approaches, comprehensive risk assessment, and individualized, multi-faceted management strategies is paramount for clinicians and researchers committed to improving patient outcomes.

This report aims to expand upon the foundational understanding of sHTG, providing an in-depth exploration of its mechanisms, clinical implications, and therapeutic avenues. It emphasizes the critical interplay between genetic predispositions, environmental triggers, and co-existing medical conditions, highlighting the need for a holistic and proactive approach to patient care.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Etiology of Severe Hypertriglyceridemia

Severe hypertriglyceridemia is fundamentally a disorder of lipoprotein metabolism, resulting from either excessive production of triglyceride-rich lipoproteins (TRLs) by the liver (very-low-density lipoproteins, VLDL) or, more commonly, impaired clearance of these particles, including chylomicrons and VLDL, from the circulation. This imbalance is orchestrated by a complex interplay of genetic susceptibilities and a myriad of secondary, often modifiable, factors.

2.1 Genetic Factors

Genetic mutations and polymorphisms play a pivotal, often foundational, role in predisposing individuals to sHTG, particularly in its most severe forms. These genetic defects typically impact the enzymes or proteins critical for the synthesis, assembly, or catabolism of TRLs.

2.1.1 Familial Chylomicronemia Syndrome (FCS)

FCS, also known as Type 1 Hyperlipoproteinemia, is a rare, autosomal recessive disorder characterized by a profound impairment in chylomicron clearance, leading to exquisitely high triglyceride levels, often exceeding 1,000-2,000 mg/dL (11.3-22.6 mmol/L) even in childhood [2]. The hallmark of FCS is the virtual absence or severe deficiency of functional lipoprotein lipase (LPL) activity, the rate-limiting enzyme in TRL catabolism. Mutations in several genes can cause FCS:

• Lipoprotein Lipase (LPL) Gene: The most common cause, accounting for approximately 95% of FCS cases. LPL is anchored to the capillary endothelium and hydrolyzes triglycerides within chylomicrons and VLDL, releasing free fatty acids for tissue uptake. Over 200 distinct mutations in the LPL gene have been identified, leading to non-functional or severely reduced LPL protein [2].
• Apolipoprotein C2 (APOC2) Gene: APOC2 acts as a crucial co-factor for LPL activity. Mutations in APOC2 prevent proper LPL activation, mimicking LPL deficiency [2].
• Lipase Maturation Factor 1 (LMF1) Gene: LMF1 is an endoplasmic reticulum protein essential for the correct folding, glycosylation, and secretion of LPL. Mutations in LMF1 lead to LPL deficiency by impairing its maturation and transport to the capillary endothelium [2].
• Glycosylphosphatidylinositol-anchored High-density Lipoprotein-binding Protein 1 (GPIHBP1) Gene: GPIHBP1 is an endothelial cell protein that binds LPL, facilitating its transport from the subendothelial space to the capillary lumen where it can interact with lipoproteins. Mutations in GPIHBP1 disrupt this crucial transport, leading to functional LPL deficiency [2].
• Apolipoprotein A5 (APOA5) Gene: APOA5 plays a critical role in modulating LPL activity and VLDL assembly and catabolism. While mutations in APOA5 are more commonly associated with multifactorial chylomicronemia, homozygous or compound heterozygous mutations can rarely cause a severe FCS phenotype [2].

FCS patients typically present with recurrent acute pancreatitis, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly. Diagnosis often involves genetic testing and, in some specialized centers, measurement of post-heparin LPL activity.

2.1.2 Multifactorial Chylomicronemia Syndrome (MFCS)

MFCS, often referred to as ‘secondary chylomicronemia’ or ‘polygenic hypertriglyceridemia with secondary triggers’, is significantly more common than FCS and represents the etiology for the vast majority of patients presenting with severe hypertriglyceridemia [7]. MFCS results from a complex interplay of multiple common genetic polymorphisms (each with a modest effect) and severe secondary factors that collectively overwhelm the triglyceride clearance capacity. These genetic predispositions might include common variants in the LPL, APOC3, APOA5, CETP (cholesteryl ester transfer protein), and GPD1 (glycerol-3-phosphate dehydrogenase 1) genes, which individually would not cause sHTG, but in combination, create a vulnerable metabolic background [7].

Unlike FCS, MFCS patients usually have detectable, albeit often reduced, LPL activity. The sHTG phenotype in MFCS is typically precipitated or severely exacerbated by secondary causes such as uncontrolled diabetes mellitus, excessive alcohol intake, certain medications, obesity, or hypothyroidism. It is crucial to differentiate MFCS from FCS, as the management strategies, particularly the role of novel therapies, can differ significantly [7].

2.1.3 Other Primary Dyslipidemias Presenting with sHTG

Some other primary dyslipidemias can manifest with sHTG, though typically not to the extreme levels seen in FCS:

• Familial Hypertriglyceridemia: A common, autosomal dominant disorder characterized by moderate to severe HTG (250-1000 mg/dL), often without overt chylomicronemia, but can be exacerbated by secondary factors. It is usually polygenic, involving reduced LPL activity or increased VLDL production.
• Familial Combined Hyperlipidemia: Characterized by elevated cholesterol and/or triglycerides, often variable within the same family. It is also a polygenic disorder, frequently linked to insulin resistance and increased hepatic VLDL and ApoB production.
• Dysbetalipoproteinemia (Type III Hyperlipoproteinemia): A rare genetic disorder primarily caused by mutations in APOE (particularly the APOE2/E2 genotype), which impairs the clearance of chylomicron and VLDL remnants. While cholesterol and triglycerides are elevated, the primary issue is the accumulation of these remnants, which are highly atherogenic. Triglyceride levels can exceed 1000 mg/dL, especially with secondary factors.

2.2 Secondary Causes

Secondary factors are often the critical precipitants or aggravators of sHTG, particularly in individuals with a genetic predisposition. Addressing these factors is a cornerstone of management.

2.2.1 Obesity and Metabolic Syndrome

Excessive adiposity, particularly central or visceral obesity, is tightly linked to insulin resistance, a central feature of the metabolic syndrome. Insulin resistance leads to increased flux of free fatty acids (FFAs) from adipose tissue to the liver, stimulating hepatic triglyceride synthesis and VLDL production. Concurrently, insulin resistance impairs the activity of LPL in peripheral tissues, reducing the clearance of TRLs from the circulation [3]. The vicious cycle of increased production and decreased clearance culminates in elevated triglyceride levels.

2.2.2 Diabetes Mellitus

Both Type 1 and Type 2 Diabetes Mellitus are potent causes of secondary sHTG. The mechanisms differ but converge on common pathways:

• Type 1 Diabetes Mellitus: In cases of poorly controlled Type 1 diabetes, absolute insulin deficiency leads to profound LPL dysfunction. Without adequate insulin, LPL activity is severely diminished, and there is increased lipolysis in adipose tissue, releasing large amounts of FFAs that are then channeled into hepatic VLDL synthesis. Diabetic ketoacidosis is a classic scenario for severe, rapidly developing hypertriglyceridemia.
• Type 2 Diabetes Mellitus: Characterized by insulin resistance and compensatory hyperinsulinemia. While hyperinsulinemia initially maintains LPL activity, chronic insulin resistance in adipose tissue leads to increased FFA delivery to the liver, driving excessive VLDL production. Furthermore, insulin resistance in muscle and adipose tissue reduces glucose uptake and utilization, leading to alternative fuel utilization (fatty acids) and further exacerbating lipid dysregulation [3]. Glycated LPL may also have reduced activity.

2.2.3 Excessive Alcohol Consumption

Alcohol (ethanol) is a well-established cause of hypertriglyceridemia, particularly in genetically predisposed individuals. The metabolic effects of alcohol are multifaceted:

• Increased Hepatic Triglyceride Synthesis: Alcohol metabolism generates excess NADH, which shifts the metabolic balance towards fatty acid synthesis and away from oxidation. This increases the availability of substrates for triglyceride synthesis in the liver.
• Impaired VLDL Secretion: While often increasing VLDL production, severe alcoholic liver disease can sometimes impair the proper secretion of VLDL, leading to intrahepatic lipid accumulation.
• Reduced LPL Activity: Chronic alcohol consumption can directly or indirectly reduce LPL activity, thereby impeding the clearance of TRLs from the circulation [3, 8].

2.2.4 Medications

Numerous pharmacologic agents can significantly elevate triglyceride levels, especially in susceptible individuals:

• Corticosteroids: Induce insulin resistance, increase hepatic VLDL production, and may reduce LPL activity.
• Oral Estrogens (Hormone Replacement Therapy, Oral Contraceptives): Increase hepatic VLDL synthesis and secretion, and can decrease LPL activity, especially in individuals with underlying genetic predispositions. Transdermal estrogens have less impact.
• Beta-blockers (non-cardioselective, e.g., Propranolol): Can inhibit LPL activity and raise triglyceride levels. Cardioselective beta-blockers (e.g., Metoprolol) generally have a lesser effect.
• Thiazide Diuretics: Can induce insulin resistance, reduce glucose tolerance, and elevate triglyceride levels.
• Atypical Antipsychotics (e.g., Olanzapine, Clozapine): Are notorious for causing weight gain, insulin resistance, and profound dyslipidemia, including sHTG, through multiple mechanisms including direct effects on lipid metabolism and adipogenesis.
• Protease Inhibitors (used in HIV therapy): Can cause lipodystrophy, insulin resistance, and increased VLDL production.
• Retinoids (e.g., Isotretinoin): Used for severe acne, can dose-dependently increase triglyceride levels, sometimes significantly, by mechanisms not fully understood but likely involving increased VLDL production and decreased clearance.
• Immunosuppressants (e.g., Cyclosporine, Sirolimus): Can cause dyslipidemia, including HTG, especially in transplant recipients.
• Tamoxifen: A selective estrogen receptor modulator, can have estrogenic effects on hepatic lipid metabolism, increasing VLDL production.

2.2.5 Other Medical Conditions

Several other systemic diseases can cause or exacerbate sHTG:

• Hypothyroidism: Reduced thyroid hormone levels decrease LPL activity and impair hepatic clearance of TRLs, leading to elevated cholesterol and triglyceride levels. Triglycerides often normalize with thyroid hormone replacement [10].
• Nephrotic Syndrome: Characterized by proteinuria, hypoalbuminemia, and edema. The liver attempts to compensate for reduced oncotic pressure by increasing the synthesis of all lipoproteins, including VLDL, leading to hypertriglyceridemia and hypercholesterolemia.
• Chronic Kidney Disease (CKD): Impaired kidney function leads to a constellation of metabolic derangements, including reduced LPL activity, accumulation of LPL inhibitors, and increased hepatic VLDL production, contributing to dyslipidemia and sHTG.
• Pregnancy: Physiologically, triglyceride levels increase significantly during the second and third trimesters to provide energy for fetal development. However, in women with underlying genetic predispositions, pregnancy can unmask or severely exacerbate hypertriglyceridemia, potentially leading to acute pancreatitis.
• Glycogen Storage Diseases (e.g., Type I): Hepatic glycogenolysis impairment leads to increased fatty acid synthesis and VLDL production, resulting in severe hypertriglyceridemia and often hepatomegaly.
• Autoimmune Diseases: Certain autoimmune conditions, such as systemic lupus erythematosus (SLE) or inflammatory bowel disease (IBD), can be associated with dyslipidemia, often exacerbated by the use of corticosteroids.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Pathophysiology of Hypertriglyceridemia

Understanding the molecular and cellular mechanisms governing triglyceride metabolism is crucial for comprehending the genesis of sHTG. Triglycerides are transported in the blood within lipoprotein particles: chylomicrons (exogenous pathway, from diet) and VLDL (endogenous pathway, synthesized by the liver).

3.1 Overview of Triglyceride-Rich Lipoprotein Metabolism

3.1.1 Exogenous Pathway

Dietary fats are digested and absorbed in the intestine, re-esterified into triglycerides, and packaged with apolipoproteins (primarily ApoB-48) into chylomicrons. These nascent chylomicrons are secreted into the lymphatic system and then enter the systemic circulation. In the capillaries of adipose tissue and muscle, chylomicrons acquire ApoC2 and ApoE from HDL. ApoC2 activates Lipoprotein Lipase (LPL), which hydrolyzes the triglycerides within the chylomicrons, releasing free fatty acids for energy or storage. As triglycerides are removed, chylomicrons shrink, shed ApoC2, and become chylomicron remnants. These remnants are then rapidly cleared by the liver via receptor-mediated endocytosis, primarily involving the LDL receptor-related protein 1 (LRP1) and the heparan sulfate proteoglycan, with ApoE acting as a ligand.

3.1.2 Endogenous Pathway

The liver synthesizes triglycerides from fatty acids (either de novo synthesis from carbohydrates or uptake from circulation) and packages them with ApoB-100 into nascent VLDL particles. These nascent VLDL particles are secreted into the bloodstream. Similar to chylomicrons, VLDL acquires ApoC2 and ApoE from HDL, activating LPL. LPL hydrolyzes VLDL triglycerides, transforming VLDL into VLDL remnants (intermediate-density lipoproteins, IDL). A portion of IDL is taken up by the liver, while the remainder is further processed by hepatic lipase (HL) to form LDL, which is then cleared by the LDL receptor.

3.2 Key Enzymes and Proteins in TRL Metabolism

Dysregulation in the function or quantity of these critical components forms the basis of sHTG:

• Lipoprotein Lipase (LPL): The principal enzyme responsible for hydrolyzing triglycerides in chylomicrons and VLDL. Its activity is modulated by various factors, including insulin, ApoC2 (activator), and ApoC3 (inhibitor). Defective LPL is a direct cause of sHTG [2].
• Apolipoprotein C2 (ApoC2): An essential co-factor that activates LPL. Deficiency leads to functional LPL inactivity [2].
• Apolipoprotein C3 (ApoC3): An inhibitor of LPL activity and also impedes hepatic uptake of TRL remnants. Elevated ApoC3 levels are frequently observed in sHTG and contribute to impaired TRL clearance [7]. Genetic variants in APOC3 that reduce its expression are associated with lower triglyceride levels and reduced ASCVD risk.
• Apolipoprotein A5 (ApoA5): A potent regulator of plasma triglyceride levels. ApoA5 is thought to stimulate LPL activity and enhance the hepatic uptake of TRLs. Variants in APOA5 are strongly associated with hypertriglyceridemia [2].
• GPIHBP1: Facilitates LPL transport to the capillary lumen. Mutations impair LPL function [2].
• LMF1: Essential for LPL maturation and secretion [2].
• Hepatic Lipase (HL): Hydrolyzes triglycerides and phospholipids in IDL and HDL. While primarily affecting HDL and IDL metabolism, its activity can influence the overall TRL clearance.
• Microsomal Triglyceride Transfer Protein (MTP): Essential for the assembly and secretion of ApoB-containing lipoproteins (chylomicrons and VLDL) in the intestine and liver, respectively.

3.3 Mechanisms of Triglyceride Elevation in sHTG

Severe hypertriglyceridemia typically arises from one or a combination of the following mechanisms:

3.3.1 Impaired Clearance of Triglyceride-Rich Lipoproteins (TRLs)

This is the most common and often dominant mechanism in sHTG, especially in FCS and many MFCS cases. It involves reduced LPL activity, which can be due to:

• Genetic defects: As seen in FCS (mutations in LPL, APOC2, LMF1, GPIHBP1).
• Secondary factors: Insulin deficiency/resistance reduces LPL synthesis and activity. High ApoC3 levels inhibit LPL. Chronic kidney disease, hypothyroidism, and certain medications can also directly or indirectly reduce LPL activity.

When LPL activity is compromised, chylomicrons and VLDL accumulate in the circulation, leading to severe hypertriglyceridemia and the characteristic ‘creamy’ layer upon standing of a plasma sample.

3.3.2 Overproduction of VLDL by the Liver

This mechanism is particularly prominent in conditions associated with insulin resistance, such as obesity, metabolic syndrome, and Type 2 diabetes. High levels of circulating free fatty acids, often originating from dysfunctional adipose tissue, are taken up by the liver and preferentially shunted towards triglyceride synthesis. This increased substrate availability, coupled with insulin resistance in the liver, promotes the assembly and excessive secretion of VLDL particles. Chronic alcohol consumption also strongly stimulates hepatic VLDL synthesis [3, 8].

3.4 Link to Acute Pancreatitis

The most feared acute complication of sHTG is acute pancreatitis. While the exact pathogenesis is not fully understood, several mechanisms are hypothesized to contribute:

• Ischemia: Extremely high concentrations of chylomicrons (and VLDL) can increase the viscosity of pancreatic capillary blood flow, leading to stasis, ischemia, and acidosis within the pancreatic microcirculation. This impaired blood flow and oxygen delivery can damage pancreatic acinar cells.
• Lipolysis and Free Fatty Acid Toxicity: Pancreatic lipase, secreted by the pancreas, can hydrolyze the massive amounts of triglycerides in the capillaries of the pancreas, releasing high local concentrations of free fatty acids (FFAs). These FFAs are directly toxic to pancreatic acinar cells, disrupting cell membranes, inducing mitochondrial damage, and causing inflammation and necrosis [4].
• Inflammation: The high concentration of FFAs within the pancreatic parenchyma can activate inflammatory pathways, leading to the release of pro-inflammatory cytokines, oxidative stress, and further cellular damage, perpetuating the inflammatory cascade characteristic of acute pancreatitis.
• Chylomicron Aggregation: In severe cases, chylomicrons can aggregate within the pancreatic capillaries, forming ‘sludge’ that can obstruct blood flow and further contribute to local ischemia and damage.

The risk of acute pancreatitis increases sharply when triglyceride levels exceed 1,000 mg/dL (11.3 mmol/L) and becomes substantial at levels ≥2,000 mg/dL (22.6 mmol/L) [4].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Diagnostic Criteria and Approach

Accurate diagnosis of sHTG is critical for timely intervention and prevention of severe complications. The diagnostic process involves confirming the elevated triglyceride levels, ruling out secondary causes, and, in selected cases, investigating underlying genetic predispositions.

4.1 Definition and Classification

Hypertriglyceridemia is typically classified based on fasting plasma triglyceride levels:

• Normal: <150 mg/dL (1.7 mmol/L)
• Borderline High: 150-199 mg/dL (1.7-2.2 mmol/L)
• High: 200-499 mg/dL (2.3-5.5 mmol/L)
• Severe Hypertriglyceridemia (sHTG): ≥500 mg/dL (5.6 mmol/L) (American Heart Association classification) [6]
• Very Severe Hypertriglyceridemia: ≥1,000 mg/dL (11.3 mmol/L) (Endocrine Society classification, specifically for pancreatitis risk) [1, 9]
• Extreme Hypertriglyceridemia: ≥2,000 mg/dL (22.6 mmol/L) [1]

These classifications are based on levels measured after a 10-12 hour fast. Non-fasting triglycerides are increasingly recognized for cardiovascular risk assessment, but for diagnosing sHTG and assessing pancreatitis risk, fasting levels are preferred.

4.2 Clinical Presentation

Many patients with sHTG are asymptomatic, with the condition detected during routine lipid screening. However, at higher levels, characteristic signs and symptoms may develop:

• Acute Pancreatitis: The most serious acute complication, presenting with severe upper abdominal pain radiating to the back, nausea, vomiting, fever, and tachycardia. Elevated serum amylase and lipase are diagnostic, but in severe hypertriglyceridemia, these enzymes may be falsely normal or mildly elevated due to assay interference [4].
• Eruptive Xanthomas: Small (1-4 mm), yellowish-red papules with an erythematous base, typically appearing suddenly on extensor surfaces (elbows, knees, buttocks), back, and shoulders. They are painless and resolve as triglyceride levels decrease. Histologically, they represent lipid-laden macrophages in the dermis.
• Lipemia Retinalis: A milky-white appearance of the retinal vessels (arteries and veins) observed on funduscopic examination, indicative of high chylomicron concentrations in the blood. Usually appears when TG levels exceed 2,000-3,000 mg/dL (22.6-33.9 mmol/L) and resolves with treatment.
• Hepatosplenomegaly: Enlargement of the liver and spleen due to the accumulation of lipid-laden macrophages within these organs.
• Abdominal Pain: Chronic, vague abdominal pain can occur even without overt pancreatitis, possibly due to visceral fat accumulation or microvascular changes.
• Neurological Symptoms: Rarely, confusion, memory loss, or peripheral neuropathy have been reported in severe, chronic cases.

4.3 Diagnostic Workup

4.3.1 Initial Assessment

• Fasting Lipid Profile: The cornerstone of diagnosis. Requires a strict 10-12 hour fast. Measurement includes total cholesterol, LDL-C, HDL-C, and triglycerides. Note that in very severe hypertriglyceridemia, LDL-C calculations can be inaccurate, and direct measurement may be necessary [3]. The serum may appear lactescent (milky or turbid) due to high chylomicron and VLDL content.
• Comprehensive Medical History: Crucial to identify genetic predispositions and secondary causes. Inquire about:
  • Family history of hypertriglyceridemia, pancreatitis, or early cardiovascular disease.
  • Dietary habits (fat, sugar, alcohol intake).
  • Medication review (corticosteroids, estrogens, beta-blockers, antipsychotics, etc.).
  • Presence of comorbidities (diabetes, obesity, hypothyroidism, kidney disease, liver disease).
  • Symptoms suggestive of pancreatitis or other complications.
• Physical Examination: Look for eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and signs of metabolic syndrome (e.g., central obesity, acanthosis nigricans).

4.3.2 Ruling Out Secondary Causes

This is a critical step, as managing secondary causes is often the most effective initial approach. Blood tests include:

• Glycated Hemoglobin (HbA1c) and Fasting Glucose: To diagnose or assess control of diabetes mellitus.
• Thyroid-stimulating Hormone (TSH): To rule out hypothyroidism.
• Liver Function Tests (LFTs): To assess for liver disease (e.g., fatty liver, alcoholic liver disease).
• Renal Function Tests (Creatinine, eGFR): To assess for chronic kidney disease.
• Urinalysis/Urine Protein-to-Creatinine Ratio: To screen for nephrotic syndrome.

4.3.3 Advanced Diagnostics (When Primary Genetic Causes are Suspected)

After excluding or controlling secondary causes, if triglyceride levels remain persistently very high (e.g., >1000 mg/dL), especially with a strong family history or early onset, further investigation into primary genetic disorders is warranted.

• Apolipoprotein C3 (ApoC3) Levels: Emerging as a useful biomarker. Elevated ApoC3 suggests impaired TRL clearance, which can be due to genetic factors or secondary causes. However, it does not specifically differentiate FCS from MFCS [7].
• Genetic Testing: Indicated for suspected FCS or other monogenic disorders. A panel of genes (e.g., LPL, APOC2, LMF1, GPIHBP1, APOA5, APOE) can be screened. This helps in confirming FCS, differentiating it from MFCS, and informing therapeutic decisions (e.g., eligibility for ApoC3 inhibitors) [2].
• Post-heparin Lipoprotein Lipase Activity: The gold standard for definitively diagnosing LPL deficiency (FCS). Heparin causes the release of LPL from endothelial binding sites into the circulation. Measuring LPL activity in a plasma sample collected after intravenous heparin administration can quantify functional LPL. This test is typically performed in specialized lipidology centers.
• Plasma Lipoprotein Electrophoresis/Ultracentrifugation: Can qualitatively assess the presence of chylomicrons, especially in the fasting state, and characterize other lipoprotein abnormalities (e.g., broad beta band in Type III dyslipidemia).

4.4 Differentiating Primary vs. Secondary sHTG

The diagnostic algorithm for sHTG should prioritize identifying and managing secondary causes. If, despite optimal management of secondary factors and strict lifestyle interventions, triglyceride levels remain severely elevated, a primary genetic cause should be strongly considered. FCS is typically suspected when triglyceride levels are consistently >1,000 mg/dL, with overt chylomicronemia, often since childhood, and a strong family history, especially in the absence of significant secondary factors. MFCS, on the other hand, is diagnosed by exclusion of FCS and by the presence of significant secondary factors in individuals with a genetic predisposition [7].

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Risk Stratification and Complications

Severe hypertriglyceridemia is not merely a laboratory abnormality; it carries significant health risks, both acute and chronic, which necessitate careful stratification and proactive management.

5.1 Acute Pancreatitis

As previously discussed, acute pancreatitis is the most devastating acute complication of sHTG, and its risk increases substantially with rising triglyceride levels. The threshold for significant risk is generally considered to be ≥1,000 mg/dL (11.3 mmol/L), with a sharp increase in incidence above 2,000 mg/dL (22.6 mmol/L) [4, 5].

• Severity of TG-induced AP: Triglyceride-induced acute pancreatitis (TGAP) is often associated with more severe outcomes, including a higher incidence of pancreatic necrosis, systemic inflammatory response syndrome (SIRS), and multiorgan failure, compared to pancreatitis caused by gallstones or alcohol [5]. The pathophysiology involving the local release of toxic free fatty acids is thought to contribute to this severity.
• Recurrence Risk: Patients with sHTG, especially those with underlying genetic predispositions, are at high risk of recurrent episodes of pancreatitis if their triglyceride levels are not effectively controlled. Each episode carries the risk of severe complications and can lead to chronic pancreatitis over time.

5.2 Cardiovascular Disease (ASCVD)

For a long time, the role of triglycerides as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) was debated, largely due to their strong correlation with other risk factors like low HDL-C and small, dense LDL-C. However, accumulating evidence now strongly supports that elevated triglyceride levels, particularly in the postprandial state and in the form of triglyceride-rich lipoprotein remnants (TRLRs), are independently associated with an increased risk of ASCVD [6].

• Atherogenic Remnants: Even at levels below those causing pancreatitis (e.g., 200-499 mg/dL), an accumulation of TRLRs (chylomicron and VLDL remnants) occurs. These remnants are highly atherogenic because they can penetrate the arterial wall, deliver cholesterol to macrophages, and are readily taken up by scavenger receptors, contributing to foam cell formation and plaque development. Unlike native LDL, TRLRs are not efficiently cleared by the classical LDL receptor pathway [6].
• Endothelial Dysfunction: High triglycerides and TRLRs contribute to endothelial dysfunction, impairing the integrity and function of the vascular endothelium, a critical early step in atherogenesis.
• Inflammation and Oxidative Stress: TRLs and their remnants can promote systemic inflammation and oxidative stress, further contributing to plaque initiation and progression.
• Relationship with HDL-C and LDL-C: Hypertriglyceridemia is often accompanied by low HDL-C and a predominance of small, dense LDL-C particles, which are more atherogenic than large, buoyant LDL. This ‘atherogenic dyslipidemia’ constellation significantly amplifies ASCVD risk.
• Recent Evidence: Large epidemiological studies and intervention trials (e.g., REDUCE-IT trial with icosapent ethyl) have demonstrated that reducing triglyceride levels, even in patients with well-controlled LDL-C, can lead to a significant reduction in major adverse cardiovascular events, cementing triglycerides as an independent therapeutic target [4].

5.3 Other Potential Complications

Beyond pancreatitis and ASCVD, sHTG can lead to other complications affecting various organ systems:

• Fatty Liver Disease (Non-alcoholic Fatty Liver Disease – NAFLD): Increased hepatic triglyceride synthesis and accumulation are hallmarks of sHTG and contribute to the development and progression of NAFLD, which can advance to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma.
• Peripheral Neuropathy: While less common, some patients with chronic, severe hypertriglyceridemia have reported symptoms of peripheral neuropathy, possibly due to microvascular damage or direct lipid toxicity to nerve cells.
• Cognitive Dysfunction: Emerging research suggests a potential link between chronic dyslipidemia, including sHTG, and an increased risk of cognitive impairment, although the exact mechanisms are still being investigated.
• Hematological Abnormalities: Very high triglyceride levels can interfere with laboratory assays, leading to spurious results such as pseudohyponatremia (due to volume displacement of the aqueous phase by lipids) and affecting other electrolyte measurements. Extreme lipemia can also increase blood viscosity.
• Vision Changes: Besides lipemia retinalis, chronic severe HTG may be associated with macular edema or retinal vein occlusions, though these are rare.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Management Strategies

Effective management of sHTG requires a comprehensive, individualized approach that prioritizes rapid triglyceride reduction in acute settings and sustained control for long-term prevention of complications. Strategies encompass intensive lifestyle modifications, pharmacological interventions, and, in severe refractory cases, advanced therapies.

6.1 Acute Management (for Very Severe sHTG ≥1,000 mg/dL, especially with Pancreatitis or Symptoms)

In cases of acute pancreatitis or when triglyceride levels exceed 1,000-2,000 mg/dL, immediate and aggressive triglyceride reduction is paramount to prevent or mitigate organ damage.

6.1.1 Intravenous Insulin Infusion

• Mechanism: Insulin is a potent stimulator of LPL activity and suppresses hepatic VLDL production. In patients with insulin deficiency (e.g., Type 1 diabetes) or severe insulin resistance, continuous intravenous insulin infusion can dramatically lower triglyceride levels [1].
• Protocol: Typically initiated with a continuous infusion (e.g., 0.1-0.3 U/kg/hr) with concurrent dextrose infusion to prevent hypoglycemia. Blood glucose and potassium levels must be meticulously monitored.
• Indications: First-line therapy for severe HTG-induced pancreatitis, particularly in patients with diabetes or severe insulin resistance. Its efficacy is rapid, often reducing TG levels by 50% within 24-48 hours.

6.1.2 Heparin

• Mechanism: Intravenous unfractionated heparin causes a rapid release of LPL from its endothelial binding sites into the circulation, leading to a transient surge in plasma LPL activity and triglyceride hydrolysis. However, repeated doses of heparin can deplete the LPL pool, potentially reducing its effectiveness over time [1].
• Caution: Heparin is generally not recommended as a primary treatment for sHTG, especially without concurrent insulin, due to its transient effect and the potential for LPL depletion, which could paradoxically worsen HTG if continued. Furthermore, the release of high concentrations of free fatty acids (from TG hydrolysis) is thought to contribute to pancreatic damage.

6.1.3 Plasmapheresis/Apheresis

• Mechanism: Therapeutic plasma exchange (plasmapheresis) involves removing the patient’s plasma, which contains high concentrations of chylomicrons and VLDL, and replacing it with donor plasma or albumin. This provides the fastest and most direct method for reducing circulating triglycerides [1].
• Indications: Reserved for life-threatening situations where very rapid triglyceride reduction is required, such as severe or worsening acute pancreatitis, or when triglyceride levels are extremely high (>2,000 mg/dL) and not responding quickly to insulin therapy. It is also considered in pregnant women with sHTG who develop pancreatitis due to concerns about fetal safety with other pharmacotherapies.

6.2 Chronic Management

Long-term management focuses on sustained triglyceride reduction to prevent recurrent pancreatitis and mitigate cardiovascular risk. This involves intensive lifestyle modifications, pharmacological agents, and addressing any underlying secondary causes.

6.2.1 Lifestyle Modifications

These are the cornerstone of chronic sHTG management and should be implemented universally.

• Dietary Changes:
  • Very Low-Fat Diet: For patients with chylomicronemia (especially FCS or severe MFCS), a diet extremely low in total fat (<10-15% of total calories, or <20g/day) is critical to minimize chylomicron formation. Medium-chain triglycerides (MCTs) can be used as a fat source as they are absorbed directly into the portal circulation and do not form chylomicrons [1].
  • Restriction of Simple Sugars and Refined Carbohydrates: Fructose and sucrose contribute significantly to hepatic de novo lipogenesis and VLDL production. Limiting these is essential, especially in patients with insulin resistance [1].
  • High Fiber Intake: Soluble fiber can help reduce cholesterol absorption and indirectly influence triglyceride levels.
  • Lean Protein Sources: Incorporate adequate lean protein to maintain satiety and muscle mass.
• Weight Management: Achieving and maintaining a healthy body weight (BMI 18.5-24.9 kg/m²) is crucial, particularly for individuals with obesity and metabolic syndrome. Weight loss reduces adipose tissue FFA flux to the liver, improves insulin sensitivity, and decreases hepatic VLDL production [3]. Bariatric surgery can be highly effective for sustained weight loss and significant lipid improvement in appropriate candidates.
• Physical Activity: Regular aerobic exercise (e.g., 150-300 minutes of moderate-intensity or 75-150 minutes of vigorous-intensity physical activity per week) improves insulin sensitivity, increases LPL activity, and promotes fatty acid oxidation, all contributing to triglyceride reduction and overall cardiovascular health [1].
• Alcohol Cessation/Strict Limitation: Complete abstinence from alcohol is strongly recommended for all patients with sHTG, especially those with a history of pancreatitis or genetic predisposition, due to its potent stimulatory effect on hepatic VLDL synthesis [3, 8].
• Smoking Cessation: While not directly affecting triglyceride levels, smoking cessation is vital for overall cardiovascular risk reduction, as sHTG patients are already at elevated risk.

6.2.2 Pharmacological Interventions

Pharmacotherapy is usually initiated when lifestyle modifications alone are insufficient to achieve target triglyceride levels, particularly when levels remain >500 mg/dL or >200 mg/dL in high-risk ASCVD patients.

• Fibrates (e.g., Fenofibrate, Gemfibrozil):
  • Mechanism of Action: Fibrates are peroxisome proliferator-activated receptor alpha (PPAR-α) agonists. Activation of PPAR-α leads to:
    • Increased expression and activity of LPL.
    • Reduced synthesis of ApoC3 (an LPL inhibitor).
    • Increased hepatic fatty acid oxidation.
    • Decreased hepatic VLDL synthesis and secretion. These combined actions result in a significant reduction (20-50%) in triglyceride levels [1].
  • Efficacy: Fibrates are generally considered first-line pharmacological agents for reducing triglyceride levels, especially to prevent recurrent pancreatitis in patients with sHTG. They also modestly increase HDL-C and may reduce small, dense LDL-C.
  • Side Effects: Common side effects include gastrointestinal upset, myopathy (increased risk when combined with statins, especially gemfibrozil), and cholelithiasis. They can also transiently increase creatinine and liver enzymes. Fenofibrate is generally preferred over gemfibrozil due to its more favorable safety profile, particularly in combination with statins [1].
• Omega-3 Fatty Acids (n-3 PUFAs):
  • Mechanism of Action: Prescription-grade omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce hepatic VLDL and triglyceride synthesis, enhance fatty acid oxidation, and may reduce ApoC3 production. Icosapent ethyl, a highly purified EPA ethyl ester, is particularly well-studied [1].
  • Efficacy: At high doses (e.g., 4g/day), n-3 PUFAs can reduce triglyceride levels by 20-50%. The REDUCE-IT trial famously demonstrated that icosapent ethyl significantly reduced cardiovascular events (by 25%) in high-risk patients with elevated triglycerides (135-499 mg/dL) despite statin therapy, irrespective of baseline LDL-C, suggesting a benefit beyond lipid lowering [4].
  • Dosing: Typically 2-4g daily in divided doses. Prescription formulations are preferred over supplements due to purity, concentration, and regulated content. Icosapent ethyl is specifically indicated for ASCVD risk reduction in patients with elevated triglycerides on statin therapy.
  • Side Effects: Minor gastrointestinal upset, fishy aftertaste. High doses can prolong bleeding time (though rarely clinically significant) and may increase the risk of atrial fibrillation, particularly with mixed EPA/DHA formulations.
• Statins:
  • Mechanism of Action: HMG-CoA reductase inhibitors, primarily reducing hepatic cholesterol synthesis, which in turn upregulates LDL receptors and reduces LDL-C. They also have a modest triglyceride-lowering effect (5-20%) by reducing hepatic VLDL secretion [1].
  • Efficacy: While not primary agents for sHTG, statins are crucial for ASCVD risk reduction and should be used in patients with sHTG who also have elevated LDL-C or other ASCVD risk factors. They are often used in combination with fibrates or omega-3s.
  • Side Effects: Myalgia, myopathy, elevated liver enzymes, new-onset diabetes. Close monitoring is required, especially in combination with fibrates.
• Nicotinic Acid (Niacin):
  • Mechanism of Action: Niacin reduces hepatic VLDL secretion by inhibiting lipolysis in adipose tissue, thereby decreasing FFA flux to the liver, and by directly inhibiting diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in triglyceride synthesis [1]. It also significantly increases HDL-C.
  • Efficacy: Can reduce triglycerides by 20-50% and raise HDL-C by 15-35%.
  • Side Effects: Its use has significantly declined due to bothersome side effects, particularly flushing (prostaglandin-mediated), hepatotoxicity, and worsening of glucose control. Large clinical trials failed to show an additional cardiovascular benefit when added to statins, and some even suggested harm in certain populations, leading to reduced recommendations for its use.

6.2.3 Emerging and Advanced Therapies

For patients with severe or refractory sHTG, particularly those with FCS or high risk of pancreatitis despite conventional therapies, novel agents targeting specific metabolic pathways have emerged.

• Volanesorsen:
  • Mechanism of Action: Volanesorsen is an antisense oligonucleotide that inhibits the production of apolipoprotein C3 (ApoC3) by binding to its messenger RNA, leading to its degradation. Reduced ApoC3 levels decrease the inhibition of LPL and enhance the hepatic uptake of TRL remnants, thereby profoundly lowering triglyceride levels [2, 7].
  • Indications: Approved for the treatment of familial chylomicronemia syndrome (FCS), which is caused by a primary genetic defect leading to severely impaired LPL function. It is administered via subcutaneous injection.
  • Efficacy: Clinical trials have shown significant and sustained reductions in triglyceride levels (up to 70-80%) in FCS patients.
  • Side Effects: Main concerns include thrombocytopenia (requiring regular platelet monitoring) and hepatotoxicity (elevation of liver enzymes), as well as injection site reactions. These side effects necessitate careful patient selection and monitoring.
• Evinacumab:
  • Mechanism of Action: Evinacumab is a fully human monoclonal antibody that inhibits angiopoietin-like 3 (ANGPTL3). ANGPTL3 is a circulating protein that inhibits both LPL and endothelial lipase (EL). By inhibiting ANGPTL3, evinacumab restores the activity of these lipases, leading to enhanced catabolism of triglyceride-rich lipoproteins [7].
  • Indications: Approved for homozygous familial hypercholesterolemia (HoFH) and under investigation for other severe forms of refractory hypertriglyceridemia. It is administered via intravenous infusion.
  • Efficacy: Shows robust reductions in both triglycerides and LDL-C, particularly effective even in patients with severely impaired LPL function.
  • Side Effects: Generally well-tolerated; infusion-related reactions, nasopharyngitis, and influenza-like illness have been reported.
• Pemafibrate:
  • Mechanism of Action: Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator (SPPARM). It is a more potent and selective agonist of PPAR-α than traditional fibrates, potentially offering improved efficacy and safety profiles [7].
  • Efficacy: Clinical trials have demonstrated significant triglyceride lowering and HDL-C increase, with a promising safety profile. It is approved in Japan and other countries and is undergoing further investigation in large cardiovascular outcomes trials.
• Other Potential Targets: Research continues into other targets, including DGAT1 inhibitors (for intestinal triglyceride absorption) and MTP inhibitors (e.g., Lomitapide, approved for HoFH, but limited by severe GI side effects due to broad inhibition of ApoB-lipoprotein assembly).

6.2.4 Management of Secondary Causes

Crucial for both acute and chronic management, addressing secondary causes often yields the most significant and immediate impact on triglyceride levels:

• Optimal Diabetes Control: Tight glycemic control (HbA1c <7%) through diet, exercise, and appropriate medications (e.g., metformin, GLP-1 receptor agonists, SGLT2 inhibitors) is paramount to improve insulin sensitivity and reduce hepatic VLDL production. Insulin may be necessary in severe cases.
• Thyroid Hormone Replacement: For hypothyroidism, levothyroxine replacement to achieve euthyroid status will typically normalize triglyceride levels.
• Medication Review and Adjustment: Discontinue or switch medications known to elevate triglycerides whenever possible. If essential, choose alternatives with less metabolic impact or aggressively manage the resulting dyslipidemia.
• Management of Renal/Liver Disease: Optimize treatment for underlying kidney or liver conditions.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Epidemiological and Economic Impact

Severe hypertriglyceridemia, while less common than mild-to-moderate HTG, represents a substantial public health concern due to its potential for acute, life-threatening events and its contribution to chronic diseases.

7.1 Prevalence and Demographics

• Overall Prevalence: The prevalence of sHTG (defined as TG ≥500 mg/dL) in the U.S. population is estimated to be approximately 1.7-2% [6, 11]. This figure is higher in certain populations, particularly those with a high prevalence of obesity, metabolic syndrome, and Type 2 diabetes.
• Age and Sex: Rates of HTG tend to be higher in men than women and generally increase with age, peaking in individuals between 50 and 70 years old [11]. However, some genetic forms (like FCS) manifest in childhood or early adulthood.
• Ethnicity: There can be ethnic variations in the prevalence of HTG, often reflecting underlying genetic predispositions and lifestyle factors. For example, some Native American and Hispanic populations have a higher prevalence of insulin resistance and associated dyslipidemias.
• Geographic Variation: Prevalence varies globally, influenced by dietary patterns, genetic backgrounds, and access to healthcare and diagnostic screening.

7.2 Healthcare Burden and Economic Impact

The economic burden of sHTG is considerable, stemming from both direct healthcare costs and indirect costs associated with morbidity and mortality.

7.2.1 Direct Healthcare Costs

• Hospitalizations for Acute Pancreatitis: This is the most significant acute cost driver. TGAP often requires prolonged hospital stays, intensive care unit (ICU) admissions, and can involve expensive interventions such as plasmapheresis. Recurrent episodes further amplify these costs [5].
• Cardiovascular Events: Costs associated with managing myocardial infarctions, strokes, and other ASCVD complications are substantial, including emergency care, revascularization procedures, long-term medications, and rehabilitation.
• Outpatient Care: Regular physician visits, laboratory monitoring (lipid panels, liver/renal function, electrolytes, platelet counts for specific therapies), and prescription medications (fibrates, omega-3s, statins, novel agents) contribute to ongoing costs.
• Management of Comorbidities: Costs related to treating associated conditions like diabetes, fatty liver disease, and obesity indirectly add to the sHTG burden.
• Diagnostic Procedures: Genetic testing and specialized lipid assays, though not routine, add to diagnostic expenses in selected cases.

7.2.2 Indirect Costs

• Productivity Losses: Patients experiencing severe acute pancreatitis or chronic cardiovascular disease may face reduced work productivity, absenteeism, or premature disability, leading to lost wages and decreased economic output.
• Premature Mortality: Complications of sHTG, particularly severe pancreatitis and ASCVD, can lead to premature death, representing a significant societal loss.
• Diminished Quality of Life (QoL): Chronic sHTG and its associated complications can severely impact a patient’s QoL, leading to physical discomfort (e.g., chronic abdominal pain, xanthomas), dietary restrictions, psychological stress, and fear of recurrent events. This QoL burden is difficult to quantify economically but has profound personal and societal implications.

Overall, the epidemiological data underscores sHTG as a prevalent condition with serious clinical consequences, imposing a significant and growing financial strain on healthcare systems worldwide. The rising global prevalence of obesity, metabolic syndrome, and diabetes suggests that the burden of sHTG is likely to continue to increase in the coming decades, making effective management strategies even more critical.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Future Directions and Research Gaps

Despite significant advancements, several areas in the understanding and management of sHTG warrant further investigation and innovation.

• Personalized Medicine Approaches: While genetic testing for FCS is established, more widespread and cost-effective genetic screening for polygenic risk factors in MFCS could enable earlier identification of high-risk individuals and guide more personalized therapeutic strategies.
• Novel Therapeutic Targets: Continued research into new molecular targets beyond LPL activation and ApoC3 inhibition is needed to offer more diverse treatment options, particularly for patients refractory to current therapies or those with specific genetic profiles.
  • Targeting diacylglycerol acyltransferase (DGAT) isoforms involved in triglyceride synthesis.
  • Modulators of adipose tissue lipolysis and fatty acid efflux.
  • Agents influencing ANGPTL3 and ANGPTL4 pathways.
• Improved Diagnostic Tools and Biomarkers: Development of non-invasive, accessible biomarkers that can accurately identify patients at high risk of pancreatitis or cardiovascular events, beyond just triglyceride levels, would be invaluable. This includes better characterization of TRL remnants and their atherogenicity.
• Long-Term Outcomes Research for Emerging Therapies: While novel agents like volanesorsen and evinacumab show promising short-term efficacy, long-term data on their safety, cardiovascular outcomes, and overall cost-effectiveness are essential.
• Public Health Interventions: Greater emphasis on population-level strategies for lifestyle modification, including diet and physical activity, is crucial to address the underlying drivers of metabolic syndrome and HTG. This includes policy changes to promote healthier food environments.
• Understanding Gut Microbiome Interactions: Emerging evidence suggests a role of the gut microbiome in modulating lipid metabolism and potentially contributing to hypertriglyceridemia. Further research could open new therapeutic avenues targeting the microbiome.
• Cognitive and Neurological Impact: More robust studies are needed to fully elucidate the relationship between chronic sHTG and cognitive dysfunction or peripheral neuropathy, and whether effective lipid lowering can mitigate these risks.
• Standardization of Management Guidelines: While guidelines exist, there is still some variability in definitions and therapeutic algorithms across different professional societies. Harmonization and consolidation of evidence-based guidelines, particularly for the diagnosis and management of rare genetic forms, would benefit clinical practice.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

9. Conclusion

Severe hypertriglyceridemia is a multifactorial and clinically significant metabolic disorder demanding meticulous attention. Its etiology spans a spectrum from rare monogenic defects, such as Familial Chylomicronemia Syndrome, to more common polygenic predispositions profoundly influenced by lifestyle, secondary medical conditions, and medications. The pathophysiological mechanisms invariably involve an imbalance between the production and clearance of triglyceride-rich lipoproteins, leading to an accumulation of chylomicrons and VLDL in the circulation. This accumulation poses immediate and grave risks, most notably acute pancreatitis, and contributes independently to the long-term burden of atherosclerotic cardiovascular disease.

Effective management necessitates a comprehensive, tiered approach. In acute, very severe cases, rapid triglyceride reduction via intravenous insulin or plasmapheresis is often life-saving. For chronic management, intensive lifestyle modifications, focusing on a very low-fat diet, weight management, physical activity, and strict alcohol avoidance, form the foundational pillar. Pharmacological interventions, including fibrates and prescription omega-3 fatty acids, are crucial for sustained control. Furthermore, the advent of targeted therapies like volanesorsen and evinacumab offers unprecedented hope for patients with severe refractory forms, particularly those with rare genetic disorders.

Early detection, precise diagnostic differentiation of primary versus secondary causes, comprehensive risk assessment, and individualized treatment plans are paramount to mitigate the substantial health implications and improve patient outcomes. The significant epidemiological prevalence and economic burden of sHTG highlight the ongoing need for continued research into novel therapeutic targets, refined diagnostic biomarkers, and integrated public health strategies to combat this complex and impactful lipid disorder.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

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