Recognition and management of persistent chylomicronemia: A joint expert clinical consensus by the National Lipid Association and the American Society for Preventive Cardiology.

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Purpose of Statement In this consensus statement, we briefly review the metabolism of triglyceride-rich lipoproteins (TRL), the epidemiology of chylomicronemia, and clinical and diagnostic differences between familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS). We also provide the rationale for a new pragmatic diagnostic approach and a paradigm shift in defining adults with persistent chylomicronemia (PC) along with alarm features for risk stratification and recommendations on management options. This expert clinical consensus document was endorsed by the National Lipid Association (NLA) and the American Society for Preventive Cardiology (ASPC). Alt-text: Unlabelled box

Triglyceride-rich lipoproteins: chylomicrons and very-low-density lipoproteins

The metabolism of TRL involves a complex interplay of diverse, key regulatory proteins, cofactors, and enzymes. In the intestine (exogenous pathway), chylomicrons are formed from absorbed dietary fat with apolipoprotein B-48 (apoB-48) as the main structural protein, while in the liver (endogenous pathway), very-low-density lipoproteins (VLDL) are assembled from hepatic TG with apolipoprotein B-100 (apoB-100) [ 1 ]. Microsomal triglyceride transfer protein (MTP) plays a crucial role in both processes. After secretion into the circulation, these TRL rapidly undergo lipolytic depletion of triglycerides (TG) primarily mediated by lipoprotein lipase (LPL), a key enzyme in large TRL metabolism, modulated by a series of regulatory proteins and cofactors [ 1 , 2 ] ( Fig. 1 ). Four proteins are required for LPL activity: i) lipase maturation factor 1 (LMF1) ensures proper folding and secretion of LPL, ii) glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein-1 (GPIHBP1) is crucial for translocating LPL across the capillary endothelium and anchoring it on the luminal surface, iii) apolipoprotein C-II (apoC-II) acts as an essential activator of LPL, and iv) apolipoprotein A-V (apoA-V) serves as a stabilizing cofactor. These five proteins are hereafter called LPL machinery. On the other hand, apolipoprotein C-III (apoC-III) and angiopoietin-like proteins (ANGPTLs), specifically ANGPTL3, ANGPTL4, and ANGPTL8, inhibit LPL activity, thereby reducing lipolysis [ 2 ]. Rare loss-of-function variants affecting genes encoding LPL, apoA-V, apoC-II, LMF1, and GPIHBP1 are pathogenic and can cause chylomicronemia, whereas loss-of-function variants in genes encoding MTP, apoC-III, and ANGPTL3 can result in low TG levels [ 1 , 2 ]. Fig. 1 Triglyceride-rich lipoprotein metabolism. Abbreviations: A5, apolipoprotein A-V; ANGPTL, angiopoietin-like protein; B48, apolipoprotein B-48; B100, apolipoprotein B-100; C2, apolipoprotein C-II; C3, apolipoprotein C-III; CM-remnant, chylomicron remnant; DGAT, diacylglycerol acyltransferase; E, apolipoprotein E; FA, fatty acid; GPIHBP1, glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LMF1, lipid maturation factor 1; LRP1, LDL receptor–related protein 1; MTP, microsomal triglyceride transfer protein; PCSK9, proprotein convertase subtilisin/kexin type 9; TG, triglyceride; VLDL, very-low-density lipoprotein. Created in BioRender. Saadatagah, S. (2025) https://BioRender.com/f90b640 . Fig 1

Hypertriglyceridemia spectrum and identification of patients with chylomicronemia

The distribution of plasma TG in the population is highly skewed to the right ( Fig. 2 ) [ 3 ]. Normal fasting TG levels are typically defined as <150 mg/dL, mild–moderate hypertriglyceridemia (mHTG) as TG levels 150–499 mg/dL, severe hypertriglyceridemia (sHTG) as TG levels ≥500 mg/dL, and extreme hypertriglyceridemia (eHTG) as TG levels ≥1000 mg/dL [ 4 ]. The presence of chylomicrons in the bloodstream is normal in the postprandial state but not after an overnight (10–12 hour) fast [ 5 ]. In a clinical setting, eHTG is commonly considered as an operational definition of chylomicronemia, although chylomicrons may contribute to the pool of circulating TRL in some patients with sHTG [ 6 ]. Fig. 2 The spectrum of triglyceride elevation. The right-skewed bell represents the distribution of fasting triglycerides based on the NHANES data. The box on the top right magnifies the distribution of median TG in those with eHTG. TG ≥1000 mg/dL in more than half of the TG measurements (i.e., median TG ≥1000 mg/dL) is defined as PC. Abbreviations: eHTG, extreme hypertriglyceridemia; FCS, familial chylomicronemia syndrome; mHTG, mild–moderate hypertriglyceridemia; PC, persistent chylomicronemia; sHTG, severe hypertriglyceridemia; TG, triglycerides. Figure adapted from Saadatagah S, et al. J Clin Lipidol. In press [ 11 ]. Fig 2

Fasting chylomicronemia is estimated to affect between 0.1 % and 0.2 % of people in European countries [ 7 , 8 ]. The prevalence could be higher in certain communities in French Canada, the Middle East, South Africa, and Southern Asia because of founder effects, consanguinity, or other factors affecting glycemia and metabolic syndrome at the population level [ 9 , 10 ]. A recent study from the United States showed that among adults ≥20 years old who had participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 and had fasting TG measured, 72.7 % had TG <150 mg/dL, 26.2 % had TG 150–499 mg/dL, 0.9 % had TG 500–999 mg/dL, and 0.20 %, equating to approximately 1 in 500 American adults, had eHTG, defined as TG ≥1000 mg/dL, reflecting chylomicronemia [ 11 ].

Current approach to classifying chylomicronemia: familial chylomicronemia and multifactorial chylomicronemia syndromes

Over the last century, several different clinical labels have been used to describe eHTG, which are reviewed in detail elsewhere [ 12 ]. The current classification of chylomicronemia differentiates genetically confirmed FCS, caused by biallelic pathogenic variants in genes critical for LPL function, from MCS, which encompasses all other forms arising from a combination of genetic predispositions, environmental influences, and secondary factors [ 13 , 14 ]. Table 1 outlines the key differences between FCS and MCS. Table 1 Current classification of chylomicronemia [ 12 , 15 , 18 , [23] , [24] , [25] ]. Table 1 FCS MCS Population frequency 1–10:1,000,000 1:600 to 1:250 Fasting TG, mg/dL ≥1000 ≥1000 Primarily elevated lipoprotein fractions Chylomicrons Chylomicrons and chylomicron remnants and VLDL and IDL Genetic basis Biallelic monogenic (recessive) Most often polygenic Relevant genetic determinants Biallelic combination of pathogenic variants in LPL or genes encoding proteins required for LPL function ( APOC2, GPIHPB1, APOAV, LMF1 ) Susceptibility may be due to rare variants in genes canonically or peripherally involved in TG metabolism, including heterozygous pathogenic variants in LPL machinery, and/or the accumulation of common, small-effect TG-raising SNPs Role of nongenetic factors May modulate the severity of phenotype, but not its presence Typically modulates the presence and severity of phenotype Age at presentation Most often presents in childhood Most often presents in adulthood apoB-100/LDL-C Low Can be elevated Risk of ASCVD Low Variable, can be high compared to general population BMI Most often normal (can be low) Patients are often overweight or obese Risk of acute pancreatitis Very high, generally higher than in MCS Increased, but generally lower than in FCS Chylomicronemia course Persistent Can be persistent or intermittent Response to fibrates or omega-3 Very little or none Modest to substantial Abbreviations: apoB-100, apolipoprotein B-100; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; FCS, familial chylomicronemia syndrome; IDL, intermediate-density lipoprotein; LPL, lipoprotein lipase; LDL-C, low-density lipoprotein cholesterol; MCS, multifactorial chylomicronemia syndrome; omega-3, marine omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]); SNP, single nucleotide polymorphism; TG, triglycerides; VLDL, very-low-density lipoprotein.

FCS, a rare disease affecting approximately 1 to 10 individuals per 1,000,000 [ 15 , 16 ], is an autosomal recessive disease caused by the biallelic combination of pathogenic variants that impair the lipolytic action of LPL, either defects in LPL or in the genes encoding cofactors and proteins required for LPL processing and function (i.e., LMF1, GPIHBP1, APOC2, and APOA5 ). Disruption of LPL function severely impairs the lipolysis and subsequent clearance of chylomicron and VLDL particles from circulation, leading to extremely elevated TG levels and chylomicronemia. Individuals with FCS often present with symptoms in childhood or adolescence, and have high risk for recurrent acute pancreatitis due to severe refractory chylomicronemia [ [17] , [18] , [19] ]. Nongenetic factors such as insulin resistance, impaired glucose tolerance, diabetes, obesity (particularly visceral adiposity), certain medications, ethanol consumption, and poor dietary habits significantly exacerbate chylomicronemia severity. However, in patients with FCS, strict control of these modifiable factors rarely normalizes TG levels because of the profound underlying genetic impairment of LPL function [ 2 , 16 , 20 ]. Individuals with FCS typically have chylomicronemia and very low levels of LDL-C and do not develop premature cardiovascular disease. Some FCS patients with additional risk factors accumulate atherogenic remnant particles in plasma, which increase the risk of atherosclerotic cardiovascular disease (ASCVD) events [ 21 , 22 ]. A small subgroup of individuals who do not have biallelic pathogenic variants in the LPL machinery exhibit all the clinical phenotypic characteristics of FCS [ 3 , 16 ]. These individuals are sometimes classified as having clinical FCS [ 12 , 19 ].

Compared with FCS, MCS is at least three orders of magnitude more common [ 12 ], arising from a combination of genetic predisposition and environmental influences. Although TG levels are elevated in MCS, they are generally lower and more labile than in FCS. MCS may result from a combination of rare loss-of-function variants in genes involved in TG metabolism, including heterozygosity in the canonical genes involved in the LPL machinery, and secondary factors such as visceral adiposity, insulin resistance, impaired glucose tolerance, diabetes, consumption of ethanol, suboptimal dietary composition, and certain medications ( Table 2 ) [ 15 , 24 , 26 ]. These factors can contribute to hypertriglyceridemia by increasing production and/or decreasing clearance of TRL; of note, large VLDL and chylomicrons share a common catabolic pathway via LPL [ 20 , 27 ]. MCS can present at any age, though it typically manifests later than FCS, and is often associated with lower risk for acute pancreatitis than FCS, but MCS sometimes is associated with extreme risk for pancreatitis. However, because of potentially broader perturbations in lipid metabolism, involving the accumulation of VLDL, intermediate-density lipoproteins (IDL), and small dense low-density lipoproteins (LDL), as well as greater prevalence of ASCVD risk factors such as obesity, metabolic syndrome, and diabetes, patients with MCS generally have far higher risk of ASCVD than do patients with FCS [ 20 , 25 , 27 ]. In the absence of genetic testing, clinical diagnosis scoring systems, including the North America FCS Score Calculator and the European FCS Score, have been developed to help differentiate FCS from MCS [ 18 , 19 , 28 ]. These scoring systems use a combination of clinical criteria, lipid profile data, age at onset, family history, response to traditional TG-lowering agents, and presenting symptoms to assess the likelihood of a patient having little or no LPL function, which could be genetically confirmed as FCS, if desired [ 29 ]. Two scores were tested and correlated fairly well with post-heparin LPL activity [ 29 ]. However, these scoring systems are designed to distinguish FCS cases from MCS, not the clinical outcome; whether they will improve the care of people with chylomicronemia needs to be established. Table 2 Causes or triggers of intermittent or persistent chylomicronemia beyond genetic defects in the LPL machinery [ 4 , [30] , [31] , [32] , [33] , [34] ]. Table 2 Categories Examples Hormonal changes Pregnancy, poorly controlled diabetes, central obesity with insulin resistance and metabolic syndrome, hypothyroidism, acromegaly, Cushing syndrome, Lifestyle factors Ethanol consumption, high-fat diet, carbohydrate-rich diet, high fructose intake, sedentary lifestyle, cannabis use Immunological diseases Rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Weber–Christian disease Hematological malignancies Multiple myeloma, lymphoproliferative disorders, paraproteinemia Renal diseases Nephrotic syndrome, chronic kidney disease Medications Oral estrogens, tamoxifen, corticosteroids, androgens, retinoids and retinoid X receptor agonists, some immunosuppressants, anti-HIV agents (protease inhibitors), thiazides, beta blockers, second-generation antipsychotics, SSRIs, valproic acid, propofol, bile-acid sequestrants Other genetic factors Primary partial lipodystrophy, primary generalized lipodystrophy, elevated HTG polygenic scores, dysbetalipoproteinemia (type III; intermittent chylomicronemia may occur), glycerol kinase deficiency (pseudo-HTG), glycogen storage disease (type 1a, G6PC1 mutation) Other conditions Myotonic dystrophy, amyloidosis, HIV infection, secondary lipodystrophy (e.g., due to antiretroviral therapy for HIV), circulating antibodies against LPL or GPIHBP1, epigenetic factors (DNA or histone methylation) Abbreviations: G6PC, Glucose-6-phosphatase catalytic subunit 1; GPIHBP1, glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein-1; HbA1C, hemoglobin A1C; HIV, human immunodeficiency virus; HTG, hypertriglyceridemia; LPL, lipoprotein lipase; SSRIs, selective serotonin reuptake inhibitors.

Risks associated with chylomicronemia

Chylomicronemia is associated with eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, metabolic dysfunction–associated steatotic liver disease (MASLD), abdominal pain, recurrent acute pancreatitis (with onset as early as infancy), and generalized symptoms such as fatigue, dyspnea, and cognitive impairment (“brain fog”) [ 12 , 25 , 35 ]. Severe TG elevation is the third most common cause of acute pancreatitis (after cholelithiasis and excess ethanol consumption), which can lead to temporary or permanent organ dysfunction, pancreatic necrosis, and death in 1 % to 5 % of cases [ 36 ]. Most knowledge regarding pathophysiological mechanisms of acute pancreatitis is derived from animal studies [ 37 ]. The two main mechanistic theories about how extremely elevated TG initiates and/or aggravates acute pancreatitis are (a) increased levels of free fatty acids (FFAs) in the pancreas resulting from hydrolysis of chylomicron TG by pancreatic lipases leading to activation of an inflammatory response and (b) increased blood viscosity due to high levels of chylomicrons resulting in microcirculatory abnormalities [ [38] , [39] , [40] , [41] ]. Chylomicronemia-induced acute pancreatitis is associated with worse clinical outcomes, including longer hospital stays, pancreatic necrosis, persistent organ failure, and higher mortality rates, compared with other causes of acute pancreatitis [ 42 , 43 ]. Mendelian randomization data suggest a causal role of TG elevation in acute pancreatitis, with risk proportional to TG levels [ 37 , 44 ]. After an initial episode of acute pancreatitis, recurrent acute pancreatitis events may occur at lower TG thresholds, and chronic pancreatitis may also occur [ 45 , 46 ]. When eHTG includes the accumulation of lipoproteins in both the exogenous (i.e., chylomicrons and their remnants) and endogenous (i.e., VLDL and IDL) pathways, such as in MCS, affected patients have a greater risk for ASCVD [ 27 ].

Rationale for a new approach to the classification of chylomicronemia

The current approach to categorizing patients with chylomicronemia into FCS and MCS is historically based but has several limitations [ 12 ]. First, only about 0.1 %–1 % of patients with chylomicronemia have FCS; although the rate of pancreatitis is higher in FCS patients, the vast majority of individuals with pancreatitis due to chylomicronemia have MCS, related to its dramatically greater prevalence [ 19 ]. Similar to other complex traits, the genetics of chylomicronemia may be better characterized by combining polygenic and monogenic models. In this framework, a high polygenic TG score could exert a TG-raising effect equal to or greater than that of a monogenic variant [ 47 , 48 ]. This is evident from the understanding that more than one-third of patients with clinical FCS do not carry known biallelic combinations of FCS-causing pathogenic variants [ 19 ]. There is also large variability in TG levels among patients carrying the same FCS variants, emphasizing the importance of other genetic and nongenetic factors in modulating the severity of chylomicronemia [ 49 ]. Additionally, nongenetic causes, such as blocking autoantibodies directed against LPL [ 50 , 51 ] or GPIHBP1 [ 52 ], and complex epigenetic modifications [ 53 ] can cause the FCS phenotype. In addition, genetic testing is not routinely performed in clinical practice and is not always accessible in many parts of the world, particularly in middle- and lower-income countries [ 54 ]. Reliance on genetic testing to differentiate between FCS and MCS may exacerbate existing healthcare disparities. It has been demonstrated that individuals from minority groups and economically disadvantaged backgrounds are less likely to undergo genetic testing, which could limit their access to newer medications as a result of underdiagnosis [ 55 , 56 ]. Moreover, the term “familial” is misleading; patients with FCS usually do not have a family history of chylomicronemia because it is an autosomal recessive disorder, whereas patients with MCS often have a family history of elevated TG [ 2 ].

Given the well-established causal relationship between chylomicronemia and pancreatitis, which is similar to the causal relationship between LDL cholesterol (LDL-C) and ASCVD, we can draw an analogy to support the rationale for an updated clinical approach to the classification of chylomicronemia. Familial hypercholesterolemia (FH) is recognized as a monogenic cause of markedly elevated LDL-C, primarily associated with mutations in LDLR, APOB, PCSK9, or LDLRAP1 . However, most individuals (>90–95 %) with severe hypercholesterolemia (i.e., LDL- C ≥ 190 mg/dL) do not have a positive genetic test, and LDL-C levels vary markedly among patients with the same gene variant [ 47 , 48 ]. Although a genetic diagnosis of FH is valuable for purposes such as cascade family screening, management is tailored based on the extent of LDL-C elevation and risk of complications, particularly ASCVD [ 57 , 58 ].

By analogy, a similar paradigm can be applied to the classification and management of chylomicronemia, with a focus on the magnitude and duration of TG elevation and the risk of complications, particularly pancreatitis. Focusing exclusively on the rare subgroup of genetically confirmed FCS patients for novel therapies inadequately addresses the broader clinical challenge among the 1000-fold more prevalent group of patients with MCS, among whom the majority of cases of acute pancreatitis and other morbidities of chylomicronemia occur. A broader strategy emphasizing risk reduction and effective management, regardless of the genetic basis, is essential to meet the needs of all high-risk patients with chylomicronemia. Therefore, we propose the term “persistent chylomicronemia” to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition, and recommend treatment strategies based on the severity of TG elevation and the risk of complications, particularly pancreatitis.

Temporal patterns of triglyceride: spectrum of chylomicronemia burden

The lability of plasma TG levels makes it challenging for any classification based on temporal patterns of TG levels [ 11 , 59 ]. Chylomicronemia severity and frequency could be considered across a spectrum ranging from a single occurrence in a lifetime to persisting in every measurement. Infrequent and sporadic episodes of chylomicronemia are usually caused by secondary factors that occur episodically, such as high ethanol intake or a temporary increase in dietary fat intake, in the context of a genetic predisposition. Whether TG levels normalize between these episodes of chylomicronemia depends on underlying metabolic conditions and aggravating factors affecting the metabolism of TRL. More frequent and persistent episodes of eHTG suggest a stronger genetic influence and/or more enduring uncontrolled secondary factors, such as uncontrolled diabetes, adverse dietary habits, or ethanol intake [ 2 , 3 , [12] , [13] , [14] ].

It is suggested that the term “persistent” in PC should not be considered in its literal sense, as occasional decreases in TG below the chylomicronemia threshold of 1000 mg/dL do not exclude PC. For instance, the TG level in genetically confirmed FCS patients in the Balance trial ranged from 334 to 6898 mg/dL [ 60 ]. Therefore, the appropriate cut point for defining PC is unclear. The classification for treatment could include an estimation of risk of complications, particularly pancreatitis, noting that such risk increases markedly when severe PC is present [ 25 ].

In a recent study in 1,294,044 individuals from a large healthcare network across three US states (Minnesota, Florida, and Alabama), 5618 (0.43 %) patients had at least one episode of chylomicronemia [ 11 ]. The investigators aimed to define pancreatitis risk based on the proportion of TG levels measuring ≥1000 mg/dL out of the total number of TG measurements, using cutoffs of 50 %, 75 %, and 83 %. Among individuals with chylomicronemia who had multiple TG measurements, 8.8 %, 1.6 %, and 0.7 % met the respective cutoffs. In comparison, the overall occurrence of pancreatitis increased only slightly across these cutoffs, rising from 28 % to 29 % to 30 % [ 11 ]. To put the numbers in perspective, among 775,019 individuals with maximum TG <150 mg/dL, 1.3 % had a diagnosis of acute pancreatitis, compared with 12.5 % of individuals with nonpersistent chylomicronemia (less than half of TG measurements ≥1000 mg/dL) [ 11 ]. Therefore, investigators defined PC as TG levels ≥1000 mg/dL in more than half of multiple measurements. Using this definition, only 8.8 % of patients with chylomicronemia (1:5500 in the general US population) met this operational definition of PC. Younger age, Hispanic ethnicity, history of pancreatitis, and higher TG levels were predictors of PC [ 11 ].

Persistent chylomicronemia and its subtypes

Considering PC as a category encompassing patients with a wide range of risk for complications, we suggest classification of PC into four subtypes. These subtypes can help guide tailored management recommendations based on the severity of the phenotype and associated risk of pancreatitis ( Fig. 3 ). The first and most severe subtype comprises individuals with genetically documented FCS. The second includes patients with clinical FCS, who also have severe chylomicronemia with a high likelihood of FCS based on the available scoring systems but either have not had genetic testing or lack a classic biallelic monogenic deficit [ 18 , 19 , 28 ]. Given the ultra-rare prevalence of FCS (both genetic and clinical), most patients with PC will be in subtypes 3 and 4 (collectively, refractory MCS) [ 15 , 16 , 27 ]. The third subtype is “PC with alarm features” and consists of individuals with chylomicronemia on at least three occasions with at least one alarm feature: (a) history of recurrent acute pancreatitis not caused by cholelithiasis or ethanol, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) pancreatitis in childhood, (d) family history of hypertriglyceridemia-induced pancreatitis, (e) post-heparin LPL activity <20 % of normal value (not widely available in the clinical setting). Fig. 3 Proposed algorithm to diagnose and manage PC. Patients with genetic FCS, clinical FCS, and PC with alarm features have very high and similar risk of pancreatitis. Abbreviations: eHTG, extreme hypertriglyceridemia (TG ≥1000 mg/dL); FA, fatty acid; FCS, familial chylomicronemia syndrome; MCS, multifactorial chylomicronemia syndrome; PC, persistent chylomicronemia; TG, triglycerides. * Three measurements ≥ 1000 mg/dL over 6–12 weeks. ** Alarm features: recurrent acute pancreatitis not caused by ethanol or cholelithiasis, recurrent hospitalizations for severe abdominal pain without another identified cause, childhood pancreatitis, family history of hypertriglyceridemia-induced pancreatitis, and/or post-heparin LPL activity <20 % of normal value. *** TG ≥1000 mg/dL in more than half of measurements without alarm features listed above. Fig 3

These features were used for enrollment into a recent clinical trial and identified a subset of individuals with PC who have a high risk of pancreatitis comparable to that in FCS patients [ 60 , 61 ] (further detail provided in the next section). While subtypes 1–3 are considered very high risk, the fourth subtype, “PC with no alarm features,” is still considered high risk and consists of individuals with recurrent TG ≥1000 mg/dL in more than half of multiple measurements after making lifestyle modifications and receiving medical interventions [ 11 ]. As discussed earlier, the risk of pancreatitis in these patients is higher than in patients with isolated or intermittent chylomicronemia but lower than the risk in FCS [ 11 ]. The prevalence of PC using the aforementioned definitions is 1 in 5500 in the United States, which meets the definition of a rare disease (affecting fewer than 200,000 people in the country) according to the Rare Diseases Act of 2002 [ 62 ].

Approach to assessment and treatment of persistent chylomicronemia

Once chylomicronemia (TG ≥1000 mg/dL) is identified, healthcare professionals should identify secondary factors that may contribute to elevated TG levels, such as poorly controlled diabetes, obesity, metabolic syndrome, ethanol intake, suboptimal dietary habits, inactivity, and TG-raising medications (see Table 2 ) [ 13 ].

Lifestyle measures

Briefly, lifestyle modification should be initiated as a foundational approach to manage eHTG (chylomicronemia), including a diet very low in fat (<10–15 % daily caloric intake), reduction in simple/refined carbohydrates, avoidance of high fructose intake, avoidance of ethanol intake, exercising regularly (while not specific to these patients, ≥150 min of moderate-intensity physical activity or ≥75 min of vigorous-intensity physical activity is recommended per week for overall cardiovascular health) [ 63 ], and regulating and maintaining a healthy weight in patients with overweight or obesity [ 13 ]. Referral to a dietitian expert in low-fat diet should be considered. The role of lifestyle modification and details on the consumption of essential fatty acids and use of medium-chain TG to allow a small amount of fat intake without aggravating chylomicronemia have been reviewed elsewhere [ 13 ].

Conventional triglyceride-lowering medications

Together with lifestyle interventions, first-line TG-lowering agents, including fibrates and marine omega-3 fatty acids, should be prescribed and their effectiveness evaluated [ 64 ]. Fibrates are modulators of peroxisome proliferator–activated receptor α (PPARα), and their effect is mainly related to LPL upregulation, resulting in minimal TG lowering in individuals with no LPL activity [ 65 ]. Prescription marine omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid, not linolenic acid) reduce TG synthesis in the liver, resulting in reduced secretion of VLDL, and have a small effect on LPL upregulation and chylomicron clearance in the exogenous pathway [ 64 , 66 , 67 ]. Any omega-3 intake (e.g., 2 g twice daily) must be considered as part of the individual's daily fat limit [ 16 , 68 ]. Both these medication classes are more effective when endogenous pathways and VLDL accumulation contribute significantly to elevated TG and LPL activity is present [ 13 , 69 , 70 ]. Statins are indicated to reduce any excess cardiovascular risk and may modestly lower TG levels in patients who do not have FCS [ 4 ]. Orlistat (an intestinal lipase inhibitor), which reduces intestinal fat absorption and thus chylomicron TG content by about one-third [ 71 , 72 ], and niacin, which reduces hepatic TG secretion [ 73 ], may also be considered. Although glucagon-like peptide 1 (GLP1) receptor agonists have not traditionally been considered TG-lowering medications, they are increasingly utilized in clinical practice for patients with diabetes and/or obesity, given their beneficial effects on TG reduction. Despite cautionary labels regarding the potential risk of pancreatitis, more recent data from large placebo-controlled randomized trials of treatment with GLP1 receptor agonists have not demonstrated an increased risk of pancreatitis compared with placebo [ [74] , [75] , [76] ].

Referral to a lipid expert and multidisciplinary lipid clinic

If eHTG (chylomicronemia) persists after addressing secondary causes, implementing lifestyle modifications, and trying fibrate therapy and possibly one or more of the other TG-lowering agents, a diagnosis of PC should be considered. In such cases, the patient may benefit from referral to an expert in lipidology for further evaluation and treatment. Assessment of available serial TG measurements to document the frequency and severity of chylomicronemia episodes is needed to establish the presence of PC and its subclassification. Assessing the risk of pancreatitis, particularly in individuals with a history of pancreatitis, is crucial to determine the necessity for additional therapeutic interventions beyond conventional medications [ 45 , 46 ]. The presence of “alarm” features (particularly prior history of acute pancreatitis) should be evaluated to estimate the risk of future pancreatitis. Genetic testing may be performed to characterize the etiology and subtype of PC, and FCS scoring algorithms can be used to determine the likelihood of clinical FCS.

Beyond conventional treatment: apolipoprotein C-III inhibitors

ApoC-III is a glycoprotein that inhibits LPL and hepatic lipase activity and interacts with apolipoprotein E (apoE). Inhibition or decreased production of apoC-III can dramatically reduce TG through both LPL-dependent and -independent mechanisms, including increased hepatic clearance of TRL, reduced VLDL secretion, and reduced intestinal lipid absorption of dietary TG [ 77 , 78 ]. Two medications in this class are olezarsen (an antisense oligonucleotide targeting apoC-III) and plozasiran (a small interfering RNA [siRNA] targeting apoC-III).

Two pivotal trials investigated the effects of olezarsen and plozasiran on TG lowering and pancreatitis risk in adult patients with chylomicronemia. In the Balance trial, 66 “genetic FCS” patients were randomized to receive either placebo or olezarsen. Notably, olezarsen markedly reduced mean TG levels, −43 % (95 % confidence interval −69 to −18; P < 0.001) in the 80-mg monthly arm and −22 % (−47 to 3; P = 0.08, not statistically significant) in the 50-mg monthly arm, and reduced the risk of pancreatitis (a secondary endpoint) by 88 % (rate ratio 0.12; 95 % confidence interval 0.02 to 0.66) [ 60 ]. The PALISADE trial investigated the ability of plozasiran to reduce TG and pancreatitis risk in patients with chylomicronemia. In this trial, patients were initially enrolled based on a genetic diagnosis of biallelic FCS, but subsequently, at the suggestion of regulatory authorities, the inclusion criteria were broadened to include patients with very-high-risk PC defined as a documented history of fasting TG levels >1000 mg/dL on at least 3 occasions with “alarm” features that included (a) history of recurrent episodes of acute pancreatitis; (b) recurrent hospitalizations for severe abdominal pain; (c) childhood pancreatitis; (d) family history of hypertriglyceridemia-induced pancreatitis; (e) positive genetic testing or post-heparin LPL activity <20 %. Accordingly, 75 patients were included, 58 % with FCS and 42 % with PC and “alarm” features but without biallelic pathogenic variants in genes causative of FCS. In this trial, plozasiran led to reductions in median TG levels, −80 % (−90 to −61) in the 25-mg every 3 months arm and −78 % (−88 to −49) in the 50-mg every 3 months arm, and reduced pancreatitis risk by 83 % (odds ratio 0.17; 95 % confidence interval 0.03 to 0.94) after 10 months of treatment. The observed benefits were irrespective of genotype (i.e., FCS vs non-FCS) [ 61 ].

The clinical criteria in the latter phase of recruitment for PALISADE were useful to identify a subset of individuals with PC who had a very high frequency of prior pancreatitis (89 % of the study population) and also during the 1-year duration of the clinical trial (20 % incidence in the placebo arm) [ 61 ]. These frequencies are comparable to those among genetically confirmed FCS patients in the Balance trial (71 % and 30 %, respectively) [ 60 ]. Therefore, patients enrolled in these trials represented the most severe PC cases and highlighted the importance of treatment with apo-CIII inhibitors to minimize the risk of acute pancreatitis and its sequelae.

In the clinical setting, TG should be measured after implementation of lifestyle management and first-line pharmacotherapy, and individuals with three measurements ≥1000 mg/dL over 6–12 weeks, as well as any of the alarm features, meet the criteria for PC and should be considered at very high risk for complications. Although no trial has been specifically designed for patients with “clinical FCS,” particularly with “alarm” features, the PALISADE trial can be regarded as the most relevant source of information about effects of treatment with anti–apoC-III therapies in these patients (see Fig. 3 ).

Olezarsen was approved by the US Food and Drug Administration to reduce TG in patients with FCS in December 2024, and the data reviewed here and elsewhere suggest that patients with clinical FCS and PC with “alarm” features may also benefit from treatment with this agent. The New Drug Application for plozasiran for the same indication was accepted in January 2025, and the Prescription Drug User Fee Act review deadline is in November 2025. Both medications are currently being studied for a broader spectrum of patients with TG elevation, including sHTG, intermittent chylomicronemia, and less severe forms of PC [ 61 , [79] , [80] , [81] ]. Data are lacking on the use of these medications in nonadult patients with these conditions.

Management of patients with persistent chylomicronemia and no alarm features: subtype 4

PC patients without “alarm” features, classified as PC subtype 4, have lower risk of pancreatitis compared to subtypes 1–3, but have high risk of pancreatitis, particularly patients with a single prior episode of pancreatitis. Many patients with chylomicronemia are not effectively treated, allowing its persistence and elevated risk of pancreatitis. Identifying patients with PC subtype 4 with no “alarm” features who are at high risk of pancreatitis can provide an opportunity for earlier intervention that may improve outcomes. Although no data from clinical trials are available to guide individualized treatment in this group, the observational data described above demonstrated a high occurrence (26 %) of potentially preventable TG-induced pancreatitis in patients with PC subtype 4 [ 11 ]. Therefore, these patients need to be offered intensive lifestyle modifications, treatment of causes of secondary hypertriglyceridemia, treatment with conventional TG-lowering medications including combination therapy if needed, and frequent TG monitoring, as well as patient education about the risks and symptoms and signs of pancreatitis [ 82 ]. Efforts should be made to identify individuals at greatest risk of pancreatitis within this group (e.g., those with a history of pancreatitis, positive genetic testing for heterozygous pathogenic variants in genes involved in TG metabolism or high polygenic score for TG, or TG >2000 mg/dL) [ 26 , 44 ] and to consider additional treatment in these patients. Additionally, abdominal pain episodes in these patients should be carefully evaluated for pancreatitis. This can be done by measuring TG levels at the time of abdominal pain and plasma amylase and/or lipase levels and imaging the pancreas (using ultrasound and/or computed tomography) as clinically indicated. Recurrent episodes of pancreatitis or abdominal pain with no other etiology will reclassify these patients to higher risk categories (i.e., PC with alarm features). Ultimately, patient–clinician discussions should involve shared decision-making to explore the possible use of newer treatment options for managing PC, recognizing the limitations of approval criteria from the FDA and other regulatory agencies (see Fig. 3 ).

Multidisciplinary care

Optimal care for all patients with PC necessitates the collaboration of a multidisciplinary team, including lipidologists, dietitians, primary care health professionals, diabetologists, pancreatologists (especially in patients with a history of recurrent pancreatitis), and cardiologists if there is elevated risk of ASCVD. Additionally, psychologists, counselors, nurses, social workers, pharmacists, and patient support groups are helpful for personalized care, addressing social factors contributing to and resulting from PC, and improving health-related quality of life. Healthcare professionals in private or small group practices may have difficulty accessing this necessary team of providers, but referral to specialized clinics may help overcome barriers to team-based care. Women with PC need special advice concerning contraception and management during pregnancy in collaboration with their gynecologist or obstetrician and primary care clinician; aggravation of chylomicronemia with hormonal contraception and during pregnancy is associated with increased risk of pancreatitis.

Other emerging therapies

ANGPTL3 inhibitors

Evinacumab (a monoclonal antibody), zodasiran (siRNA), and solbinsiran (siRNA) are ANGPTL3 inhibitors that can treat a large spectrum of lipid disorders, from severe refractory hypercholesterolemia to chylomicronemia [ 83 , 84 ]. However, their effect on TG reduction is LPL-dependent, and patients with no or very low LPL activity, as in FCS, do not achieve significant TG lowering in response to treatment with ANGPTL3 inhibitors, despite substantial decreases in circulating apoC-III [ [83] , [84] , [85] , [86] ]. The efficacy of these agents has been assessed in patients with mixed dyslipidemia, mHTG, sHTG, and eHTG, demonstrating up to 82 % TG reductions, but none are currently in ongoing development for the treatment of chylomicronemia. Evinacumab is FDA-approved for LDL-C lowering only in patients with homozygous FH [ 83 , 85 , [87] , [88] , [89] ]. Other ANGPTL3, ANGPTL3/8, or ANGPTL4 inhibitors are in development and might be useful in subgroups of patients with PC having residual LPL bioavailability.

FGF21 analogs

Fibroblast growth factor 21 (FGF21) is a peptide hormone secreted by the liver, adipose tissue, skeletal muscles, and pancreas that affects energy expenditure and metabolism. Pegozafermin is an FGF21 analog, for which initial studies showed ∼60 % TG reduction across a wide range of hypertriglyceridemia, as well as multiple other metabolic benefits, including improved markers of insulin resistance, weight loss, and improvement of hepatic steatosis [ [90] , [91] , [92] ]. An ongoing phase 3 trial of pegozafermin is enrolling patients with sHTG without genetically proven FCS ( NCT05852431 ).

Summary and conclusions

Until very recently, there were no effective treatments for patients with severe forms of chylomicronemia besides lifestyle modifications and conventional TG-lowering medications, and these generally had extremely limited efficacy. The current diagnostic approach for chylomicronemia is focused on genotypic categorization of patients into FCS and MCS, but an update in the approach is needed. Nevertheless, our current understanding of chylomicronemia management now extends beyond purely genetic classifications, emphasizing phenotype severity and associated risks to guide more precise therapeutic interventions. We have described in detail the rationale for proposing the term persistent chylomicronemia (PC), defined as TG above 1000 mg/dL in more than half of the measurements, which identifies adult patients with chylomicronemia with a high disease burden and high risk of pancreatitis. While further research is needed to refine and better characterize the definition of PC, the current proposal is a template for transitioning the classification of chylomicronemia from genetic criteria to more pragmatic and clinically focused criteria. We introduced “alarm” features, which include (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) post-heparin LPL activity <20 % of normal value, which can identify PC cases with very high risk of pancreatitis comparable to the risk in patients with FCS. The recent clinical availability of the first apoC-III inhibitor, olezarsen, has greatly improved our ability to treat PC, with a second agent potentially becoming available in late 2025. Although the current FDA approval of olezarsen is for treatment of patients with FCS, expanded indications beyond the current approval criteria should be further evaluated for very-high-risk PC such as individuals with alarm features.

Future direction

Considering that pancreatitis is the most severe complication of chylomicronemia, further research is warranted to identify the clinical, environmental, and host factors, including genetic predisposition and imaging characteristics, associated with increased risk of pancreatitis. These findings should be derived from large, diverse populations worldwide, encompassing various ethnic, racial, and socioeconomic backgrounds. By adopting this personalized approach, we can define treatment thresholds for each patient based on individual characteristics and risk profile. Our proposed approach, which aligns with the general principles for improving the quality of healthcare, provides a strategy to make available safe, effective, patient-centered, timely, efficient, and equitable care for all patients with PC [ 93 ].

Declaration of interest statement

SS, ML, MN, and DB have no relationships with industry.

VN has been site investigator for a study sponsored by Ionis and has received stock options from Insera Therapeutics and a research grant from Roche Laboratories.

IJK has received grant/research support from Amgen and Kaneka.

PBD has received grant/research support and/or served as a consultant for Esperion, Ionis, New Amsterdam, Regeneron, and Retrophin.

EDM has served as a consultant for Amgen, Arrowhead, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Life Science, Esperion, Ionis, Eli Lilly, Medtronic, Merck, New Amsterdam, Novartis, Novo Nordisk, and Zoll.

MDS has received grant/research support (through his institution) from Amgen, Arrowhead, Boehringer Ingelheim, 89Bio, Esperion, Novartis, Ionis, Merck, New Amsterdam, and Cleerly. He has participated in Scientific Advisory Boards with Amgen, Arrowhead, Ionis, Novartis, New Amsterdam, Tourmaline, and Merck. He has served as a consultant for Ionis, Novartis, Regeneron, Aidoc, Shanghai Pharma Biotherapeutics, Novo Nordisk, Arrowhead, and Tourmaline.

GFW has received research support or consulting fees from Amgen, Arrowhead, Novartis, Novo Nordisk, Silence Therapeutics, Esperion, Sanofi, CSL Sequirus.

DG has received grant/research support (through his institution) for contracted research or consulting fees from Amgen, Arrowhead, 89Bio, Eli Lilly, Ionis, Merck, New Amsterdam, Novartis, Regeneron, Sanofi, Ultragenyx, and Verve.

CMB has received grant/research support (through his institution) from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic, NIH, AHA, ADA (all paid to institution, not individual) and consulting fees from 89Bio, Abbott Diagnostics, Amarin, Amgen, Arrowhead, Astra Zeneca, Denka Seiken, Eli Lilly, Esperion, Genentech, Illumina, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic.

Funding statement

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. SS is supported by the National Institutes of Health [grant number NIH/NHLBI T32 HL139425]; ML is supported by Centre Intersectoriel en Santé Durable, Université du Québec à Chicoutimi; IJK is funded by the National Institutes of Health [grant numbers U01 HG11710 and U01 HG06379]; and EDM is supported by the American Heart Association [grant number 946222] and the Amatao Fund for Women's Cardiovascular Health research at Johns Hopkins University.

Use of AI and AI-assisted technologies statement

AI has not been used in the writing process.

Ethical statement

The work described has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki), and the manuscript is in line with the Recommendations for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals.

CRediT authorship contribution statement

Seyedmohammad Saadatagah: Writing – original draft. Miriam Larouche: Writing – original draft. Mohammadreza Naderian: Writing – review & editing. Vijay Nambi: Writing – review & editing. Diane Brisson: Writing – review & editing. Iftikhar J. Kullo: Writing – review & editing. P Barton Duell: Writing – review & editing. Erin D. Michos: Writing – review & editing. Michael D. Shapiro: Writing – review & editing. Gerald F. Watts: Writing – review & editing. Daniel Gaudet: Writing – original draft. Christie M. Ballantyne: Writing – original draft.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Nambi reports a relationship with Ionis Pharmaceuticals Inc that includes:. Nambi reports a relationship with Insera Therapeutics that includes: equity or stocks. Nambi reports a relationship with Roche Laboratories that includes: funding grants. Kullo reports a relationship with Amgen that includes: funding grants. Kullo reports a relationship with Kaneka that includes: funding grants. Duell reports a relationship with Esperion that includes: consulting or advisory and funding grants. Duell reports a relationship with Ionis Pharmaceuticals Inc that includes: consulting or advisory and funding grants. Duell reports a relationship with New Amsterdam that includes: consulting or advisory and funding grants. Duell reports a relationship with Regeneron that includes: consulting or advisory and funding grants. Duell reports a relationship with Retrophin that includes: consulting or advisory and funding grants. Michos reports a relationship with Amgen that includes: consulting or advisory. Michos reports a relationship with Arrowhead Pharmaceuticals Inc that includes: consulting or advisory. Michos reports a relationship with AstraZeneca that includes: consulting or advisory. Michos reports a relationship with Bayer that includes: consulting or advisory. Michos reports a relationship with Boehringer Ingelheim that includes: consulting or advisory. Michos reports a relationship with Edwards Life Science that includes: consulting or advisory. Michos reports a relationship with Esperion that includes: consulting or advisory. Michos reports a relationship with Ionis Pharmaceuticals Inc that includes: consulting or advisory. Michos reports a relationship with Eli Lilly that includes: consulting or advisory. Michos reports a relationship with Medtronic that includes: consulting or advisory. Michos reports a relationship with Merck that includes: consulting or advisory. Michos reports a relationship with New Amsterdam that includes: consulting or advisory. Michos reports a relationship with Novartis that includes: consulting or advisory. Michos reports a relationship with Novo Nordisk that includes: consulting or advisory. Michos reports a relationship with Zoll that includes: consulting or advisory. Shapiro reports a relationship with Amgen that includes: board membership and funding grants. Shapiro reports a relationship with Arrowhead Pharmaceuticals Inc that includes: board membership and funding grants. Shapiro reports a relationship with Boehringer Ingelheim that includes: funding grants. Shapiro reports a relationship with 89Bio that includes: funding grants. Shapiro reports a relationship with Esperion that includes: funding grants. Shapiro reports a relationship with Novartis that includes: board membership, consulting or advisory, and funding grants. Shapiro reports a relationship with Ionis Pharmaceuticals Inc that includes: board membership, consulting or advisory, and funding grants. Shapiro reports a relationship with Merck that includes: board membership and funding grants. Shapiro reports a relationship with New Amsterdam that includes: board membership and funding grants. Shapiro reports a relationship with Cleerly that includes: funding grants. Shapiro reports a relationship with Regeneron that includes: consulting or advisory. Shapiro reports a relationship with Tourmaline that includes: board membership and consulting or advisory. Shapiro reports a relationship with Aidoc that includes: consulting or advisory. Shapiro reports a relationship with Shanghai Pharma Biotherapeutics that includes: consulting or advisory. Watts reports a relationship with Amgen that includes: consulting or advisory and funding grants. Watts reports a relationship with Arrowhead Pharmaceuticals Inc that includes: consulting or advisory and funding grants. Watts reports a relationship with Novartis that includes: consulting or advisory and funding grants. Watts reports a relationship with Novo Nordisk that includes: consulting or advisory and funding grants. Watts reports a relationship with Silence Therapeutics that includes: consulting or advisory and funding grants. Watts reports a relationship with Esperion that includes: consulting or advisory and funding grants. Watts reports a relationship with Sanofi that includes: consulting or advisory and funding grants. Watts reports a relationship with CSL Sequirus that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Amgen that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Arrowhead Pharmaceuticals Inc that includes: consulting or advisory and funding grants. Gaudet reports a relationship with 89Bio that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Eli Lilly that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Ionis Pharmaceuticals Inc that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Merck that includes: consulting or advisory and funding grants. Gaudet reports a relationship with New Amsterdam that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Novartis that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Regeneron that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Sanofi that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Ultragenyx that includes: consulting or advisory and funding grants. Gaudet reports a relationship with Verve Therapeutics, Inc. that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Abbott Diagnostic that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Akcea that includes: funding grants. Ballantyne reports a relationship with Amgen that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Arrowhead Pharmaceuticals Inc that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Ionis that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Merck that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with New Amsterdam that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Novartis that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Novo Nordisk that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with Roche Diagnostic that includes: consulting or advisory and funding grants. Ballantyne reports a relationship with 89Bio that includes: consulting or advisory. Ballantyne reports a relationship with Amarin that includes: consulting or advisory. Ballantyne reports a relationship with AstraZeneca that includes: consulting or advisory. Ballantyne reports a relationship with Denka Seiken that includes: consulting or advisory. Ballantyne reports a relationship with Eli Lilly that includes: consulting or advisory. Ballantyne reports a relationship with Esperion that includes: consulting or advisory. Ballantyne reports a relationship with Genentech that includes: consulting or advisory. Ballantyne reports a relationship with Illumina that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

1 Shelness G.S. Sellers J.A. Very-low-density lipoprotein assembly and secretion Curr Opin Lipidol 12 2 2001 151 157 10.1097/00041433-200104000-00008 11264986

2 Dron J.S. Hegele R.A. Genetics of hypertriglyceridemia Front Endocrinol 11 2020 455 10.3389/fendo.2020.00455 PMC7393009 32793115

3 Hegele R.A. Ginsberg H.N. Chapman M.J. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management Lancet Diabetes Endocrinol 2 8 2013 655 10.1016/S2213-8587(13)70191-8 24731657 PMC4201123

4 Virani S.S. Morris P.B. Agarwala A. 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 78 9 2021 960 993 10.1016/j.jacc.2021.06.011 34332805

5 Frayn K.N. Shadid S. Hamlani R. Regulation of fatty acid movement in human adipose tissue in the postabsorptive-to-postprandial transition Am J Physiol 266 3 Pt 1 1994 10.1152/ajpendo.1994.266.3.E308 E308-317 8166251

6 Julve J. Martín-Campos J.M. Escolà-Gil J.C. Blanco-Vaca F. Chylomicrons: advances in biology, pathology, laboratory testing, and therapeutics Clin Chim Acta 455 2016 134 148 10.1016/j.cca.2016.02.004 26868089

7 Retterstøl K. Narverud I. Selmer R. Severe hypertriglyceridemia in Norway: prevalence, clinical and genetic characteristics Lipids Health Dis 16 1 2017 115 10.1186/s12944-017-0511-9 28606150 PMC5469061

8 Ortega E. Vlacho B. Treserres R.P. Severe hypertriglyceridemia prevalence at a primary care setting in Catalonia, Spain J Clin Lipidol 17 6 2023 777 787 10.1016/j.jacl.2023.09.002 37741728

9 Gaudet D. Stevenson M. Komari N. The burden of familial chylomicronemia syndrome in Canadian patients Lipids Health Dis 19 2020 120 10.1186/s12944-020-01302-x 32487261 PMC7268343

10 Bashir B. Downie P. Forrester N. Ethnic diversity and distinctive features of familial versus multifactorial chylomicronemia syndrome: insights from the UK FCS National Registry Arterioscler Thromb Vasc Biol 44 11 2024 2334 2346 10.1161/ATVBAHA.124.320955 39234690 PMC11495541

11 Saadatagah S, Naderian M, Larouche M, Gaudet D, Kullo IJ, Ballantyne CM Epidemiology and longitudinal course of chylomicronemia: insights from NHANES and a large health care system. J Clin Lipidol . 2025 In press. doi:10.1016/j.jacl.2025.02.008 . 10.1016/j.jacl.2025.02.008 40155283

12 Larouche M. Watts G.F. Ballantyne C. Gaudet D. An overview of persistent chylomicronemia: much more than meets the eye Curr Opin Endocrinol Diabetes Obes 32 2 2025 75 88 10.1097/MED.0000000000000903 39927417 PMC11872273

13 Javed F, Garg A, Patni, Nivedita, Gaudet D, Hegele RA, Ahmad Z. Familial chylomicronemia syndrome: expert opinion. J Clin Lipidol . In press, 2025. 10.1016/j.jacl.2025.03.013 40234111

14 Paquette M. Bernard S. Hegele R.A. Baass A. Chylomicronemia: differences between familial chylomicronemia syndrome and multifactorial chylomicronemia Atherosclerosis 283 2019 137 142 10.1016/j.atherosclerosis.2018.12.019 30655019

15 Chait A. Eckel R.H. The chylomicronemia syndrome is most often multifactorial: a narrative review of causes and treatment Ann Intern Med 170 9 2019 626 634 10.7326/M19-0203 31035285

16 Brahm A.J. Hegele R.A. Chylomicronaemia–current diagnosis and future therapies Nat Rev Endocrinol 11 6 2015 352 362 10.1038/nrendo.2015.26 25732519

17 Gallo A. Béliard S. D'Erasmo L. Bruckert E. Familial chylomicronemia syndrome (FCS): recent data on diagnosis and treatment Curr Atheroscler Rep 22 11 2020 63 10.1007/s11883-020-00885-1 32852651

18 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 . In press, 2025. doi:10.1016/j.jacl.2024.09.008 . 10.1016/j.jacl.2024.09.008 39537503

19 Moulin P. Dufour R. Averna M. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): expert panel recommendations and proposal of an “FCS score Atherosclerosis 275 2018 265 272 10.1016/j.atherosclerosis.2018.06.814 29980054

20 Chait A. Hypertriglyceridemia Endocrinol Metab Clin North Am 51 3 2022 539 555 10.1016/j.ecl.2022.02.010 35963627

21 Shah N.P. Cho L. Ahmed H.M. Familial chylomicronemia syndrome J Am Coll Cardiol 72 10 2018 1177 1179 10.1016/j.jacc.2018.06.042 30165992

22 Benlian P. De Gennes J.L. Foubert L. Zhang H. Gagné S.E. Hayden M. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene N Engl J Med 335 12 1996 848 854 10.1056/NEJM199609193351203 8778602

23 Gill P.K. Dron J.S. Hegele R.A. Genetics of hypertriglyceridemia and atherosclerosis Curr Opin Cardiol 36 3 2021 264 271 10.1097/HCO.0000000000000839 33818545

24 Paquette M. Bernard S. The evolving story of multifactorial chylomicronemia syndrome Front Cardiovasc Med 9 2022 886266 10.3389/fcvm.2022.886266 PMC9046927 35498015

25 Tremblay K. Méthot J. Brisson D. Gaudet D. Etiology and risk of lactescent plasma and severe hypertriglyceridemia J Clin Lipidol 5 1 2011 37 44 10.1016/j.jacl.2010.11.004 21262505

26 Deshotels M.R. Hadley T.D. Roth M. Genetic testing for hypertriglyceridemia in academic lipid clinics: implications for precision medicine—Brief report Arterioscler Thromb Vasc Biol 42 12 2022 1461 1467 10.1161/ATVBAHA.122.318445 36325899

27 Ginsberg H.N. Packard C.J. Chapman M.J. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies—A consensus statement from the European Atherosclerosis Society Eur Heart J 42 47 2021 4791 4806 34472586 10.1093/eurheartj/ehab551 PMC8670783

28 Campos C. Ahmad Z. Ashraf A. Development of a clinical diagnostic score for familial chylomicronemia syndrome (FCS) [abstract] J Clin Lipidol 18 2024 e536 (4 Supplement)

29 Brisson D. Larouche M. Chebli J. Khoury E. Gaudet D. Correlation between chylomicronemia diagnosis scores and post-heparin lipoprotein lipase activity Clin Biochem 114 2023 67 72 10.1016/j.clinbiochem.2023.02.002 36780934

30 Chait A. Multifactorial chylomicronemia syndrome Curr Opin Endocrinol Diabetes Obes 31 2 2024 78 83 10.1097/MED.0000000000000846 37994661

31 Spagnuolo CM, Wang J, McIntyre AD, Kennedy BA, Hegele RA Comparison of patients with familial chylomicronemia syndrome and multifactorial chylomicronemia syndrome. J Clin Endocrinol Metab . In press, 2025. doi:10.1210/clinem/dgae613 . 10.1210/clinem/dgae613 PMC11913094 39238074

32 Okazaki H. Gotoda T. Ogura M. Current diagnosis and management of primary chylomicronemia J Atheroscler Thromb 28 9 2021 883 904 10.5551/jat.RV17054 33980761 PMC8532063

33 Guay S.P. Paquette M. Taschereau A. DNA methylation levels may contribute to severe hypertriglyceridemia in multifactorial chylomicronemia syndrome Clin Biochem 135 2025 110873 10.1016/j.clinbiochem.2025.110873 39756670

34 Berberich A.J. Hegele R.A. A modern approach to dyslipidemia Endocr Rev 43 4 2022 611 653 10.1210/endrev/bnab037 34676866 PMC9277652

35 Maltais M. Brisson D. Gaudet D. Non-alcoholic fatty liver in patients with chylomicronemia J Clin Med 10 4 2021 Feb 9 669 10.3390/jcm10040669 33572376 PMC7916177

36 Szatmary P. Grammatikopoulos T. Cai W. Acute pancreatitis: diagnosis and treatment Drugs 82 12 2022 1251 1276 10.1007/s40265-022-01766-4 36074322 PMC9454414

37 Hansen S.E.J. Varbo A. Nordestgaard B.G. Langsted A. Hypertriglyceridemia-associated pancreatitis: new concepts and potential mechanisms Clin Chem 69 10 2023 1132 1144 10.1093/clinchem/hvad094 37530032

38 Kimura W. Mössner J. Role of hypertriglyceridemia in the pathogenesis of experimental acute pancreatitis in rats Int J Gastrointest Cancer 20 3 1996 177 184 10.1007/BF02803766 9013278

39 Kiss L. Fűr G. Pisipati S. Mechanisms linking hypertriglyceridemia to acute pancreatitis Acta Physiol 237 3 2023 e13916 10.1111/apha.13916 36599412

40 Havel R. Pathogenesis, differentiation and management of hyperglyceridemia Adv Intern Med 15 1969 117 154 4908616

41 Saharia P. Margolis S. Zuidema G.D. Cameron J.L. Acute pancreatitis with hyperlipemia: studies with an isolated perfused canine pancreas Surgery 82 1 1977 60 67 877857

42 Gaudet D. Signorovitch J. Swallow E. Medical resource use and costs associated with chylomicronemia J Med Econ 16 5 2013 657 666 10.3111/13696998.2013.779277 23428107

43 Nawaz H. Koutroumpakis E. Easler J. Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis Am J Gastroenterol 110 10 2015 1497 1503 10.1038/ajg.2015.261 26323188

44 Toth P.P. Grabner M. Ramey N. Higuchi K. Clinical and economic outcomes in a real-world population of patients with elevated triglyceride levels Atherosclerosis 237 2 2014 790 797 10.1016/j.atherosclerosis.2014.09.029 25463122

45 Pedersen S.B. Langsted A. Nordestgaard B.G. Nonfasting mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis JAMA Intern Med 176 12 2016 1834 1842 10.1001/jamainternmed.2016.6875 27820614

46 Guan L. Ding L. Wan J. Serum triglyceride levels are associated with recurrence in patients with acute hypertriglyceridemic pancreatitis Front Med (Lausanne) 10 2023 1079637 10.3389/fmed.2023.1079637 PMC10050706 37007797

47 Saadatagah S. Jose M. Dikilitas O. Genetic basis of hypercholesterolemia in adults NPJ Genomic Med 6 1 2021 28 10.1038/s41525-021-00190-z PMC8046820 33854068

48 Fahed A.C. Wang M. Homburger J.R. Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions Nat Commun 11 1 2020 3635 10.1038/s41467-020-17374-3 32820175 PMC7441381

49 Perera S.D. Wang J. McIntyre A.D. Hegele R.A. Variability of longitudinal triglyceride phenotype in patients heterozygous for pathogenic APOA5 variants J Clin Lipidol 17 5 2023 659 665 10.1016/j.jacl.2023.08.003 37586912

50 Beaumont J.L. Berard M. Antonucci M. Delplanque B. Vranckx R. Inhibition of lipoprotein lipase activity by a monoclonal immunoglobulin in autoimmune hyperlipidemia Atherosclerosis 26 1 1977 67 77 10.1016/0021-9150(77)90141-1 836349

51 Pruneta-Deloche V. Marçais C. Perrot L. Combination of circulating antilipoprotein lipase (anti-LPL) antibody and heterozygous S172 fsX179 mutation of LPL gene leading to chronic hyperchylomicronemia J Clin Endocrinol Metab 90 7 2005 3995 3998 10.1210/jc.2005-0205 15840743

52 Miyashita K. Lutz J. Hudgins L.C. Chylomicronemia from GPIHBP1 autoantibodies J Lipid Res 61 11 2020 1365 1376 10.1194/jlr.R120001116 32948662 PMC7604722

53 Mazaheri-Tehrani S. Khoshhali M. Heidari-Beni M. Poursafa P. Kelishadi R. A systematic review and meta-analysis of observational studies on the effects of epigenetic factors on serum triglycerides Arch Endocrinol Metab 66 2022 407 419 10.20945/2359-3997000000472 35551677 PMC9832862

54 Masson W. Barbagelata L. Fleitas M. Screening program for familial hyperchylomicronemia syndrome detection: experience of a university health system Arch Endocrinol Metab 67 3 2023 408 415 10.20945/2359-3997000000601 36748937 PMC10247249

55 Swami N. Yamoah K. Mahal B.A. Dee E.C. The right to be screened: identifying and addressing inequities in genetic screening Lancet Reg Health Am 11 2022 100251 10.1016/j.lana.2022.100251 PMC9903822 36778922

56 Suther S. Kiros G.E. Barriers to the use of genetic testing: a study of racial and ethnic disparities Genet Med 11 9 2009 655 662 10.1097/GIM.0b013e3181ab22aa 19752639

57 Lee C. Rivera-Valerio M. Bangash H. Prokop L. Kullo I.J. New case detection by cascade testing in familial hypercholesterolemia Circ Genomic Precis Med 12 11 2019 e002723 10.1161/CIRCGEN.119.002723 PMC9875692 31638829

58 Miller A.A. Bangash H. Smith C.Y. Wood-Wentz C.M. Bailey K.R. Kullo I.J. A pragmatic clinical trial of cascade testing for familial hypercholesterolemia Genet Med 24 12 2022 2535 2543 10.1016/j.gim.2022.08.026 36173399 PMC9944844

59 Rengarajan R. McCullough P.A. Chowdhury A. Tecson K.M. Identifying suspected familial chylomicronemia syndrome Proc Bayl Univ Med Cent 31 3 2018 284 288 10.1080/08998280.2018.1463784 29904289 PMC5997083

60 Stroes E.S.G. Alexander V.J. Karwatowska-Prokopczuk E. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome N Engl J Med 390 19 2024 1781 1792 10.1056/NEJMoa2400201 38587247

61 Watts G.F. Rosenson R.S. Hegele R.A. Plozasiran for managing persistent chylomicronemia and pancreatitis risk N Engl J Med 392 2 2025 127 137 10.1056/NEJMoa2409368 39225259

62 United States. Congress. H.R.4013—107th Congress (2001-2002): Rare Diseases Act of 2002. Available at: https://www.congress.gov/bill/107th-congress/house-bill/4013 . Accessed 20 February 2025.

63 Kirkpatrick C.F. Sikand G. Petersen K.S. Nutrition interventions for adults with dyslipidemia: a clinical perspective from the National Lipid Association J Clin Lipidol 17 4 2023 428 451 10.1016/j.jacl.2023.05.099 37271600

64 Richter W.O. Jacob B.G. Ritter M.M. Schwandt P. Treatment of primary chylomicronemia due to familial hypertriglyceridemia by ω-3 fatty acids Metabolism 41 10 1992 1100 1105 10.1016/0026-0495(92)90293-J 1406295

65 Goldberg A.P. Applebaum-Bowden D.M. Bierman E.L. Increase in lipoprotein lipase during clofibrate treatment of hypertriglyceridemia in patients on hemodialysis N Engl J Med 301 20 1979 1073 1076 10.1056/NEJM197911153012001 226883

66 Park Y. Harris W.S. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance J Lipid Res 44 3 2003 455 463 10.1194/jlr.M200282-JLR200 12562865

67 Bays H.E. Tighe A.P. Sadovsky R. Davidson M.H. Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications Expert Rev Cardiovasc Ther 6 3 2008 391 409 10.1586/14779072.6.3.391 18327998

68 Williams L. Rhodes K.S. Karmally W. Familial chylomicronemia syndrome: bringing to life dietary recommendations throughout the life span J Clin Lipidol 12 4 2018 908 919 10.1016/j.jacl.2018.04.010 29804909

69 Santamarina-Fojo S. Brewer H.B. The familial hyperchylomicronemia syndrome. New insights into underlying genetic defects JAMA 265 7 1991 904 908 1992190

70 Brisson D. Méthot J. Tremblay K. Tremblay M. Perron P. Gaudet D. Comparison of the efficacy of fibrates on hypertriglyceridemic phenotypes with different genetic and clinical characteristics Pharmacogenet Genomics 20 12 2010 742 10.1097/FPC.0b013e328340095e 21217359

71 Jarrett Z.S. Kou C.T.J. Wan W. Colburn J.A. The use of orlistat in an adult with lipoprotein lipase deficiency: a case report AACE Clin Case Rep 8 2 2022 93 95 10.1016/j.aace.2021.11.004 35415234 PMC8984509

72 Patni N. Quittner C. Garg A. Orlistat therapy for children with type 1 hyperlipoproteinemia: a randomized clinical trial J Clin Endocrinol Metab 103 6 2018 2403 2407 10.1210/jc.2018-00369 29659879 PMC6456945

73 Kamanna V.S. Kashyap M.L. Mechanism of action of niacin Am J Cardiol 101 8A 2008 20B 26B 10.1016/j.amjcard.2008.02.029 18375237

74 Novodvorský P. Haluzík M. The effect of GLP-1 receptor agonists on postprandial lipaemia Curr Atheroscler Rep 24 1 2022 13 21 10.1007/s11883-022-00982-3 35080714

75 Wilson J.M. Nikooienejad A. Robins D.A. The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes Diabetes Obes Metab 22 12 2020 2451 2459 10.1111/dom.14174 33462955 PMC7756479

76 Zeng Q. Xu J. Mu X. Shi Y. Fan H. Li S. Safety issues of tirzepatide (pancreatitis and gallbladder or biliary disease) in type 2 diabetes and obesity: a systematic review and meta-analysis Front Endocrinol (Lausanne) 14 2023 1214334 10.3389/fendo.2023.1214334 PMC10613702 37908750

77 Gaudet D. Brisson D. Tremblay K. Targeting APOC3 in the familial chylomicronemia syndrome N Engl J Med 371 23 2014 2200 2206 10.1056/NEJMoa1400284 25470695

78 Borén J. Packard C.J. Taskinen M.R. The roles of apoC-III on the metabolism of triglyceride-rich lipoproteins in humans Front Endocrinol (Lausanne) 11 2020 474 10.3389/fendo.2020.00474 32849270 PMC7399058

79 Gouni-Berthold I. Alexander V.J. Yang Q. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial Lancet Diabetes Endocrinol 9 5 2021 264 275 10.1016/S2213-8587(21)00046-2 33798466

80 Gaudet D. Pall D. Watts G.F. Plozasiran (ARO-APOC3) for severe hypertriglyceridemia: the SHASTA-2 randomized clinical trial JAMA Cardiol 9 7 2024 620 630 10.1001/jamacardio.2024.0959 38583092 PMC11000138

81 Ballantyne C.M. Vasas S. Azizad M. Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia N Engl J Med 391 10 2024 899 912 10.1056/NEJMoa2404143 38804517

82 Polsani V.R. Nambi V. Virani S.S. Efficacy and tolerability of multidrug therapy for hypertriglyceridemia J Clin Lipidol 3 5 2009 341 344 10.1016/j.jacl.2009.09.003 21291832

83 Rosenson R.S. Gaudet D. Hegele R.A. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for mixed hyperlipidemia N Engl J Med 391 10 2024 913 925 10.1056/NEJMoa2404147 38809174

84 Raal F.J. Rosenson R.S. Reeskamp L.F. Evinacumab for homozygous familial hypercholesterolemia N Engl J Med 383 8 2020 711 720 10.1056/NEJMoa2004215 32813947

85 Rosenson R.S. Gaudet D. Ballantyne C.M. Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial Nat Med 29 3 2023 729 737 10.1038/s41591-023-02222-w 36879129 PMC10033404

86 Rosenson R.S. Burgess L.J. Ebenbichler C.F. Evinacumab in patients with refractory hypercholesterolemia N Engl J Med 383 24 2020 2307 2319 10.1056/NEJMoa2031049 33196153

87 Ahmad Z. Pordy R. Rader D.J. Inhibition of angiopoietin-like protein 3 with evinacumab in subjects with high and severe hypertriglyceridemia J Am Coll Cardiol 78 2 2021 193 195 10.1016/j.jacc.2021.04.091 34238441

88 Ahmad Z. Banerjee P. Hamon S. Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia Circulation 140 6 2019 470 486 10.1161/CIRCULATIONAHA.118.039107 31242752 PMC6686956

89 Gaudet D. Karwatowska-Prokopczuk E. Baum S.J. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia Eur Heart J 41 40 2020 3936 3945 10.1093/eurheartj/ehaa689 32860031 PMC7750927

90 Bhatt D.L. Bays H.E. Miller M. The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial Nat Med 29 7 2023 1782 1792 10.1038/s41591-023-02427-z 37355760 PMC10353930

91 Loomba R. Sanyal A.J. Kowdley K.V. Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH N Engl J Med 389 11 2023 998 1008 10.1056/NEJMoa2304286 37356033 PMC10718287

92 Loomba R. Lawitz E.J. Frias J.P. Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study Lancet Gastroenterol Hepatol 8 2 2023 120 132 10.1016/S2468-1253(22)00347-8 36521501

93 Institute of Medicine (US) Committee on Quality of Health Care in America Crossing the quality chasm: a new health system for the 21st century 2001 National Academies Press (US) Available at http://www.ncbi.nlm.nih.gov/books/NBK222274 Accessed 17 February 2025 25057539