2025 SISA共识文件：血浆甘油三酯在心血管疾病中的作用

ARTICLE INFO

Handling Editor: Prof. F. Galletti

Keywords: Triglycerides VLDL IDL Apolipoprotein B Cardiovascular risk Lipid-lowering strategies Remnant cholesterol Acute pancreatitis

ABSTRACT

Aims: Hyperriglyceridaemia is a common clinical condition. Triglycerides (TGs) have long been recognised as a risk factor for atherosclerotic cardiovascular disease (ASCVD). Genetics, epidemiological studies and clinical trials have demonstrated a causal relationship between plasma triglycerides and ASCVD. In the bloodstream, TGs are mainly transported by lipoproteins such as VLDL and their remnants, the so-called TG-rich lipoproteins (TRL). A better understanding of the pathological consequences of elevated plasma TG levels is essential, especially in the context of addressing residual cardiovascular risk, when other major risk factors, in particular low-density lipoprotein cholesterol (LDL-C), are optimally controlled.

Data synthesis: This consensus paper highlights the available evidence on the physiology, metabolism and association with atherosclerosis of TRL and their remnants. We update the current knowledge in a multidisciplinary approach and highlight targeted therapeutic approaches including: i) diet and lifestyle, ii) established treatments such as fibrates and omega-3 fatty acid supplements, iii) novel pharmacological strategies to lower serum TG levels to reduce residual cardiovascular risk in patients on maximal LDL-C-lowering treatment, and iv) new therapeutic options in patients with severe hypertriglyceridaemia.

Conclusions: Managing TRL plasma concentration with a comprehensive approach that includes lifestyle changes and targeted pharmacological strategies is a key clinical approach for addressing cardiovascular (residual) risk and improving patient outcomes, especially in individuals with well-controlled primary target lipid levels such as

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

LDL-C. In case of severe TG elevation, an intensive TG-lowering approach is of paramount importance for reducing the risk of acute pancreatitis.

1. Triglycerides and TG-rich lipoproteins

Triglycerides (TGs) are neutral esters of glycerol and circulate in the blood carried by lipoproteins. All lipoproteins contain triglycerides in varying amounts, and under normal circumstances most TGs are transported by chylomicrons (in non-fasting conditions), very low-density lipoproteins (VLDL) and their remnants, collectively referred to as TG-rich lipoproteins (TRL) [1].

Chylomicrons are only present in plasma during postprandial absorption of dietary fats in the small intestine and their TGs are rapidly hydrolysed by lipoprotein lipase (LPL) on the surface of capillary beds. VLDL are mainly produced by the liver, which uses free fatty acids (FFAs) for TG synthesis derived from multiple sources such as de novo lipogenesis, intracellular storage or from the circulation (fatty acids released from adipose tissue or chylomicron remnants). VLDL are then secreted to provide tissues with a TG source in the fasting state. As a major structural protein, chylomicrons contain apolipoprotein B-48 (apoB-48), a truncated form of apolipoprotein B-100 (apoB-100) produced by the intestine, while VLDL contain apoB-100 produced by the liver, and each lipoprotein contains only one molecule of apoB [2–4].

LPL hydrolyses the TG in both chylomicrons and VLDL [3,4], generating partially lipolysed products called TRL remnants, which are TG-poor and cholesterol-enriched lipoproteins. Of note, LPL activity is regulated by multiple factors, with apolipoprotein C-II (apoC-II) and apolipoprotein A-V (apoA-V) and insulin acting as activators and apolipoprotein C-III (apoC-III) and angiopoietin-like 3, 4 and 8 acting as inhibitors [5]. The remnants are cleared by the liver or, in the case of VLDL remnants, can be converted into low-density lipoproteins (LDL). Therefore, remnant levels depend on several steps, including the extent and efficiency of lipolysis, the conversion of VLDL remnants to LDL, and the efficiency of hepatic clearance of VLDL and chylomicron remnants.

During the day, the lowest TG concentration is measured after an overnight fast. After a meal, the TG increase is directly related to the TG concentration in fasting plasma and the amount of dietary fats [6]. Metabolic changes leading to hypertriglyceridaemia (HTG) are combination of TRL overproduction, reduced lipolysis rates and delayed hepatic clearance of particles from the circulation [7–9]. In severe HTG, reduced TRL lipolysis predominates, which is usually associated with the accumulation of chylomicrons and TG-rich VLDL. In contrast, mild-to-moderate HTG is characterised by increased production of VLDL by the liver and accumulation of TRLs and their remnants, with at least partial preservation of the lipolytic process [1]. Like LDL, cholesterol-enriched remnants can enter the arterial wall and be retained thanks to their ability to bind to components of the extracellular matrix, such as proteoglycans. Once in the intima, the remnants can be taken up by the resident macrophages and promote the formation of lipid-filled foam cells. They can also promote local inflammation and endothelial dysfunction.

2. Definition of hyperriglyceridaemia

The diagnosis of hypertriglyceridaemia is based on the determination of fasting TG values. According to the latest consensus statement of the European Atherosclerosis Society (EAS), an optimal TG value is < 1.2 mmol/L (<<100 mg/dL); several cut-off values have been established to define borderline, moderately elevated, severe and extreme HTG (Table 1). Moderately elevated TG is a common condition, while TG values > 5.7 mmol/L (>500 mg/dL) are less common and exceed values of 10 mmol/L (880 mg/dL) of very rare cases, the latter frequently being associated with genetic (primary) forms of HTG [1]. Due to the large heterogeneity and variability of TG measurements, a joint consensus of

the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recommended that TG > 175 mg/dL in the non-fasting state should be considered elevated and abnormal, while for fasting samples the cut-off value for an elevated concentration was set at TG > 150 mg/dL [10]. These values can also be used as a reference for patients with coronary heart disease.

The current 2019 ESC/EAS guidelines on lipids recommend measuring fasting plasma TG to obtain a more accurate estimate of individual CV risk, but no specific goals for TG levels are suggested. TG levels ≥1.7 mmol/L (≥150 mg/dL) should indicate increased risk and the need to screen for other risk factors [11]. Moreover, it has been suggested that in patients with hypertriglyceridaemia it may be useful to determine non-HDL-C (calculated as total cholesterol minus HDL-C), which is a good estimate of all apoB-containing lipoproteins, e.g. VLDL and their remnants as well as LDL-C [11] and a powerful predictor of CV risk [12].

Increased production and/or impaired catabolism of TRL may be due to mutation of genes that modulate key steps of TRL metabolism (primary or genetic HTG), or it may be a key component of common clinical conditions such as diabetes/insulin resistance or secondary to pharmacological treatments or dietary habits (secondary HTG, the most common form) [13]. A classification of primary and secondary forms of HTG and their characteristics is proposed in Table 2 and Table 3.

3. Primary hypertriglyceridaemias

3.1. Familial chylomicronaemia syndrome (FCS) and multifactorial chylomicronaemia syndrome (MCS)

Familial chylomicronaemia syndrome (FCS) is a rare monogenic inherited disorder due to the absence of LPL activity as a result of a homozygous mutation in the gene coding for LPL or in genes coding for one of its cofactors (apoC-II, apoC-III, apoA-V, LMF1, GPIHBP1 and GPD1) [14]. These mutations are inherited in an autosomal recessive manner and severe HTG is observed in patients who are homozygous or compound heterozygous for mutations in the LPL gene. FCS occurs at paediatric age, although often diagnosed in adulthood, and is characterised by the accumulation of chylomicrons in plasma due to a severely impaired LPL mediated catabolic pathway. TG levels exceed 1000 mg/dL (approximately 11 mmol/L) and blood samples have a milky appearance. Patients with FCS have a high risk of developing recurrent acute pancreatitis, which can lead to chronic pancreatitis and secondary diabetes associated with exocrine pancreatic disease [14]. These patients may present with eruptive xanthomas on the trunk and extremities, hepato-splenomegy and neurological symptoms such as irritability, memory problems, depression and dementia [14].

Moderate/severe forms of HTG (TG range: 2.0–10.0 mmol/L) are often associated with multifactorial chylomicronaemia syndrome (MCS), a more common polygenic disorder resulting from the concurrence of multiple genetic variants, each with a small TG-increasing effect, but which cumulatively lead to the development of

Table 1

Plasma triglyceride cut-points for the identification of hypertriglyceridemia [1].

|Category|Triglyceride level| |---|---| |Optimal|<..100 mg/dL (<1.2 mmol/L)| |Borderline|100–150 mg/dL (1.2–1.7 mmol/L)| |Moderately elevated|150–500 mg/dL (1.7–5.7 mmol/L)| |Severe|500–880 mg/dL (5.7–10.0 mmol/L)| |Extreme|>880 mg/dL (>10 mmol/L)|

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

chylomicronaemia and hypertriglyceridaemia, when secondary factors known to increase TG levels (diabetes, hypothyroidism and pregnancy), environmental factors (overweight, alcohol abuse, unhealthy diet) and certain medications (glucocorticoids, ethinylestradiol, neuroleptics) are present [9]. In contrast to FCS, MCS manifests itself later in life. MCS patients have a higher risk of acute pancreatitis, but the relative risk is much lower than in patients with FCS [1,14]. The MCS phenotype has many similarities with FCS. However, plasma TG levels in MCS are more variable over time and respond better to diet and fibrate therapy due to the less compromised lipolytic function in MCS.

A European expert panel proposed a diagnostic algorithm based on clinical and laboratory elements, including multiple severe elevations in fasting plasma TG levels (>885 mg/dL, 10 mmol/L), absence of secondary factors, episodes of acute pancreatitis or unexplained recurrent abdominal pain, young age at onset and lack of response to standard TG-lowering therapies [14].

3.2. Severe hypertriglyceridaemia and the risk of acute pancreatitis: possible mechanisms

A severely elevated plasma TG level is a potentially life-threatening condition associated with an increased risk of acute pancreatitis (AP). The pathogenesis of hypertriglyceridaemic pancreatitis (HTG-P) is not yet fully understood. Several hypotheses have been proposed, including pancreatitis induced by FFAs or pancreatitis caused by chylomicron toxicity [15–17], hypotheses that are not mutually exclusive (Fig. 1).

Triglycerides are transported by TRL, which play a key role in the transport and release of FFAs into adipose tissue for storage and into the heart for energy production [1]. The clearance of TRL depends on both the lipolytic activity of LPL on TG and hepatic clearance. In the pancreas, TRLs are hydrolysed and this leads to a significant release of FFAs [18]. High levels of FFAs saturate the total binding capacity of plasma alumin and cause self-aggregation into micellar structures, leading to ischaemia, acidosis and vascular damage in the pancreas. These mechanisms could maintain and enhance the production and release of toxic FFAs. Furthermore, FFAs are capable of directly damaging pancreatic acinar cells by activating trypsinogen in the acinar cells and releasing intracellular calcium, leading to acute pancreatitis (AP) [18,19]. Finally, FFAs can be considered a direct trigger of the inflammatory process through the activation of TNFα, IL-6 and IL-10 [20,21]. Ischaemia can also be caused by increased plasma viscosity due to high chylomicron levels, particularly in complete LPL deficiency, where large "nascent" TRLs are produced without a concomitant increase in remnants [22,23]. However, few patients with HTG develop AP, whereas AP is more commonly observed in patients with HTG associated with alcohol, poorly controlled diabetes, pregnancy, drugs, and genetic abnormalities (i.e., mutation in the cystic fibrosis transmembrane conductance regulator, TNF promoter polymorphism, ε4 allele APOE) [16,24,25]. Therefore, it is likely that factors associated with HTG trigger pancreatitis independent of serum levels of TG.

Another possible mechanism of injury could be related to the altered secretion of vasoconstrictor and vasodilator agents (i.e. thromboxane a2 and prostaglandin), which reduce normal microcirculation with excessive contraction of capillaries, invariably leading to ischaemia of pancreatic vasa.

Table 3

Secondary (and iatrogenic) forms of hypertriglyceridemia [8,13].

|SECONDARY Clinical conditions|Diet with positive energy balance (high glycemic index or high fat content) Excessive alcohol consumption Obesity, especially central Metabolic Syndrome Diabetes Mellitus, particularly type 2 NAFLD - NASH Endocrine diseases such as Cushing and Hypothyroidism Renal diseases (nephrotic syndrome, ESRD, CKD -especially uremia and glomerulonephritis) HIV Paraproteinemia, SLE or other autoimmune disorders Pregnancy (mostly 3rd trimester)| |---|---| |IATROGENIC Drugs|Thiazides diuretics Steroids Beta-blockers Estrogen (> those taken orally) Tamoxifen Phenothiazines and some 2nd generation anti-psychotic drugs (clozapine, olanzapine, ...) Antiretroviral drugs (> those for HIV infections) Antiblastic drugs|

NAFLD: Non-Alcoholic Fatty Liver Disease; NASH: Non-Alcoholic Steato-Hepatitis; ESRD: End Stage Renal Disease; HIV: Human Immunodeficiency Virus; CKD: Chronic Kidney Disease; SLE: Systemic Lupus Erythematosus.

4. Secondary hypertriglyceridaemia

Various clinical conditions can be responsible for secondary hyper-triglyceridaemia; however, obesity and type 2 diabetes (especially with elevated HbA1c) are the most common causes [1]. Hyper-triglyceridaemia has been observed in over 80 % of overweight or obese people [26]. In a recently published cohort of 160 patients with TGs above 2000 mg/dL, uncontrolled diabetes was the determining factor in almost 75 % of patients [27]. Both obesity and type 2 diabetes are characterised by insulin resistance, which leads to increased production of VLDL as a result of increased hepatic de novo lipogenesis (due to insulin resistance and the resulting portal hyperinsulinaemia), excessive liver uptake of adipose tissue-derived fatty acids, as well as reduced degradation of apoB, possibly associated to a genetic predisposition for HTG [28,29]. The presence of insulin resistance in adipocytes leads to impaired suppression of hormone-sensitive lipase with excessive release of FFAs from these cells, which promotes the synthesis of TGs and secretion of VLDL by the liver. The role of TRL remnants is also of fundamental importance. In insulin resistance, the production of TRL remnants is increased, which favours the formation of small and dense LDL particles [29] and increases the atherogenic potential at any LDL-C level. Therefore, in the presence of insulin resistance, it is recommended to assess cardiovascular risk by calculating non-HDL cholesterol (non-HDL-C) [30]. Similar pathophysiological mechanisms occur in all clinical situations associated with secondary insulin resistance.

Table 2

Classification of genetic hypertriglyceridemia.

|Name|Prevalence|Genetic disorder (Mode of transmission)|Lipoproteins|Triglyceride level| |---|---|---|---|---| |MCS|Rare|Polygenic|↑ chylomicrons|++/+++| ||||↑/-/1 VLDL-C|↑/-/1 VLDL-C| |FCS or LPL deficiency|Very rare|Monogenic; AR|↑ ↑ chylomicrons and VLDL-C|+++++| |Familial dys-beta-lipoproteinaemia|Rare|Polygenic|↑ ↑ IDL and chylomicron remnants (b VLDL)|++/+++| ||||||

LDL-C: Low-Density Lipoprotein Cholesterol; VLDL-C: Very Low-Density Cholesterol; AR: autosomal recessive; MCS: Multifactorial Chylomicronaemia Syndrome; FCS: Familial Chylomicronaemia Syndrome; LPL: Lipoprotein Lipase; IDL: Intermediate Density Lipoprotein.

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

![graph TD\n A1[exceeding TBC albumin] --> A2[↑ serum FFAs and toxic FFAs]\n A2 --> A3[damage to vascular endothelium and PLT]\n A3 --> A4[direct damage to acinar cells]\n A3 --> A5[FFA self-aggregation into micellar structures]\n A4 --> A8[intra-acinar activation of trypsinogen release of intracellular calcium]\n A5 --> A6[Ischæmia and acidosis]\n A6 --> A7[Acute Pancreatitis]\n A8 --> A7\n A9[↑ serum triglycerides] --> A10[↑TRL]\n A9 --> A1\n A10 --> A11[reduced/absent LpI activity]\n A10 --> A12[↑ chylomicrons]\n A11 --> A12\n A12 --> A13[↑ plasma viscosity]\n A13 --> A14[Capillary plugging]\n A14 --> A6\n A15[TRL: triglycerides-rich lipoprotein; LpI: lipoprotein lipase; TBC: total binding capacity]\n](1/parseimages/figure29fe11809fe847a98e080eb19e9610fb_0_2.png) Fig. 1. Acute pancreatitis pathophysiology.

5. Triglycerides in atherosclerotic cardiovascular disease

5.1. Pathophysiological mechanisms

Over the past decade, genetic studies, clinical trials and epidemiological observations have provided clear evidence of a causal relationship between TRL levels (both fasting and postprandial) and atherogenesis, in addition to and independent of LDL-C. The mechanisms by which elevated TRL levels may cause atherosclerosis are complex. TRL (especially the relatively small ones such as remnants) can penetrate and become trapped in the arterial wall, similar to what has been observed with the smaller LDL particles. In contrast to LDL particles, TRL and their remnants can be directly taken up by macrophages (without the need for oxidation/modification), turning these cells into foam cells, the characteristic cells of atherosclerotic plaque. Once in the

intima, TRL and TRL remnants induce the accumulation of cholesterol and can cause severe local inflammation and necrosis through the release of free fatty acids and monoacylglycerols [31–34], (Fig. 2).

Of note, remnant particles can contain up to four-fold more cholesterol per particle than LDL [1], so it is likely that the increased risk of cardiovascular disease is due to (or directly related to) the increased level of TRL remnants. Furthermore, hypertriglyceridaemia activates the cholesteryl ester transfer protein (GETP) in plasma, which is responsible for the intravascular remodelling of lipoproteins. CETP transfers TG from TRL, such as VLDL and chylomicrons, to HDL and LDL particles in exchange for cholesteryl esters [35,36]. TG-rich HDL is then rapidly metabolised, while TG-rich LDL is converted to the highly atherogenic small dense LDL [36,37]. HTG also leads to changes in LDL composition, particularly the formation of small, dense LDL particles [38], and to significant disturbances in high-density lipoprotein (HDL) metabolism,

 Fig. 2. Contribution of triglyceride-rich lipoprotein and remnants to the initiation and progression of the atherothrombotic lesion due to impaired triglyceride-rich lipoproteins metabolism. Adapted from Ginsberg et al. [1].

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

resulting in altered HDL-cholesterol (HDL-C) levels and consequently attenuation of vasoprotective functions (including reverse cholesterol transport, antioxidant and anti-inflammatory activities) [1,39,40].

People with fasting hypertriglyceridaemia have abnormal post-prandial lipid profiles, characterised by hyperlipidaemia that is more pronounced and longer lasting than in normolipidemic individuals.

5.2. Epidemiological observations

Epidemiological observations suggest that TRL are strong and independent predictors of ASCVD and all-cause mortality [1,34,41]. A direct association between TG levels and the incidence of major cardiovascular events was observed in several studies [42–50], but it is worth noting that this direct association was attenuated once adjusted for other lipid parameters such as HDL-C, non-HDL-C or apoB. Accordingly, analysis of data from ~300,000 individuals from 68 studies showed that elevated fasting and non-fasting TG were associated with an increased risk of ischaemic heart disease, but this association was lost once adjusted for non-HDL-C [44]. This observation is important because it suggests that it is not TG, but the cholesterol content in remnant particles that is responsible for the increased risk. Combining data from two large general populations confirmed the association between elevated TG and an increased risk of myocardial infarction, ischaemic heart disease, and all-cause mortality [1,2,51]. This association also exists in patients with established ASCVD [52], even when effectively treated with a statin at optimal LDL-C levels [53]. Based on these and other findings, it has been postulated that TRL can contribute significantly to the so-called “residual risk” and thus represent a potential therapeutic target in secondary prevention [12]. The guidelines therefore recommend the treatment of hypertriglyceridaemia as part of the strategy to control residual CV risk in these individuals [11]. Conversely, the role of hypertriglyceridaemia in influencing CV outcomes in low-to-moderate risk individuals who do not require statin therapy is less clearly established.

5.3. Evidence from genetic studies

Several genetic studies have investigated the causal relationship between variants in genes associated with elevated TG levels and the risk of CVD. These genes include those coding for LPL, apoC-III, apoA-IV, apoA-V, ANGPTL3, 4 and 8 [54-60]. Loss-of-function mutations in the APOC3 gene (which encodes an LPL inhibitor) were associated with 39 %–Herg TG levels and a 40 % lower risk of coronary heart disease [61]. In another study, heterozygotes for variants in the APOC3 gene were associated with 44 % lower TG levels and a 36 % lower risk of ischaemic heart disease [62]. Similar observations were made in a study investigating the effects of loss-of-function mutations in the ANGPTL3 gene, which encodes another LPL inhibitor. These variants were associated with 17 % lower TG levels and 12 % lower LDL-C levels [63]. Such an improved lipid profile was associated with a 34 % lower risk of coronary artery disease. Overall, the these data suggest that factors other than LDL-also contribute to the risk of myocardial infarction, namely TRL. This has paved the way for the search for molecules that can inhibit these proteins, which has led to the development of drugs that are now being used in certain patient groups.

5.4. Evidence from intervention clinical trials (failures and successes)

Although plasma TG levels are a potential target for CV risk reduction, clinical trials investigating the effects of TG-lowering drugs on cardiovascular outcomes have produced controversial results, despite achieving significant reductions in TG levels. Fibrates are drugs that can lower fasting TG levels as well as postprandial TG and TRL remnant levels. Fibrates activate the peroxisome proliferator-activated receptor α (PPARα), a transcription factor that regulates various steps of lipid and lipoprotein metabolism. Via this pathway, fibrates induce the synthesis of the major HDL apolipoproteins, apolipoprotein A-1 (apoA-1) and

apolipoprotein A-II (apoA-II), reduce hepatic apoC-III production, increase lipoprotein lipase activity, and stimulate cellular fatty acid uptake. All these effects lead to a decrease in VLDL production and increased TRL catabolism. All available fibrates reduce TG levels by 30–50 % and cause an increase in HDL-C levels by <20 % [11,64].

The clinical benefits of fibrates have been investigated in several randomised controlled trials (RCTs) with conflicting results. The Helsinki Heart Study (HHS) and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) reported a significant reduction in CVD outcomes with gemfibrozil [65,66], with an even greater benefit in patients with high TG and low HDL-C levels [67]. However, two trials of bezafibrate, the Bezafibrate Infarction Prevention (BIP) trial and the Lower Extremity Arterial Disease Event Reduction (LEADER) trial, failed to confirm this beneficial effect in the overall population, although a benefit was also observed in the subgroup of patients with high TG and low HDL-C [68,69]. Similarly, two trials of fenofibrate, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial [70,71], showed that treatment with fenofibrate did not测 her risk for the primary endpoint, except in patients with atherogenic dyslipidaemia, a finding that was also confirmed in the extended follow-up of the ACCORD Lipid study [72]. Of note, treatment with fenofibrate was associated with a lower risk of diabetic retinopathy progression in both the FIELD and ACCORD trials [70,71]. Most recently, the randomized and placebo-controlled Lowering Events in Non-proliferative Retinopathy in Scotland (LENS) study focusing on 1151 patients with type 1 or type 2 diabetes with early retinopathy, showed that over a median follow-up of 4 years, fenofibrate led to a 27 % reduction in risk of progression, or treatment for diabetic retinopathy or maculopathy compared with placebo. These effects occurred independently of lipid level reduction and confirm the previous results found in sub-analyses of previous fenofibrate trials [73].

The recently developed pemafibrate is a selective PPARα modulator. Its chemical structure provides increased PPARα activation potency and a high degree of PPARα subtype selectivity compared to other fibrates [74]. The PROMINENT trial of pemafibrate, a highly selective PPARα receptor modulator, was initiated to evaluate the potential CV benefit of adding a fibrate to a statin in patients with type 2 diabetes with high TG and low HDL-C levels [75]. Despite significant reductions in TG and remnant cholesterol levels, no clinical benefit was observed after a median follow-up of 3.4 years. LDL-C and apoB levels were slightly increased, which could partly explain the failure of the trial. The results of the PROMINENT trial reinforce the concept that lowering TG per se is not associated with CV benefits. Rather, it is the reduction in the total number of atherogenic apoB particles, reflected by a reduction in apoB levels, that confers the CV benefits associated with any lipid-lowering approach. Since fibrates are not usually associated with a significant reduction in plasma apoB levels in patients with diabetes, the overall concentration of atherogenic lipoproteins that can become trapped the only arterial wall is not reduced, and consequently no CV benefit is accomplished [76].

Omega-3 polyunsaturated fatty acids have a TG-lowering effect, but clinical trials investigating the role of these agents in reducing the risk of ASCVD have produced conflicting results. The REDUCE-IT trial showed that treatment with high doses (4 g/day) of purified EPA (icosapentethyl, IPE) resulted in a 25 % risk reduction of a clinically relevant composite cardiovascular endpoint (cardiovascular death, stroke, myocardial infarction, coronary revascularisation and unstable angina) in a statin-treated population consisting mainly of diabetic patients (58 %) with established CVD (71 %) [77]. This trial used a triglyceride risk-based approach by including patients with ASCVD or those with diabetes mellitus plus additional ASCVD risk factors and elevated TGs [77]. Interestingly, the reduction in CV events observed in this trial was independent of the TG level achieved and much greater than expected based on the modest difference in apoB between the two treatment arms. This suggests that the clinical benefit of purified EPA is largely

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

determined by non-lipid-lowering effects and is likely due to concomitant effects on inflammation and platelet aggregation [78]. Other trials investigating other omega-3 fatty acid supplements, including STRENGTH, OEMI and VITAL, failed to reduce the risk of ASCVD. The initial concerns about the placebo formulation have been debated and analysed in details highlighting the limited, if any, impact of the mineral oil in accounting for the significant benefit of IPE on both primary and secondary clinical endpoints [79]. The lack of benefit of a DHA/EPA combination in the STRENGTH trial [80] suggests that DHA and EPA may differ in their effect on ASCVD. The results of the REDUCE-IT trial have been incorporated into the latest guidelines and scientific statements [11]. Based on current scientific evidence, a further reduction of triglycerides may be obtained by adding high dose (3-4 g/day) omega-3 fatty acids if TG are persistently elevated, thus lowering the risk of acute pancreatitis. However, only high dose EPA has been shown effective in reducing CV risk.

6. Triglycerides, Apolipoprotein B and non-HDL-C

Elevated plasma TG levels are associated with an increased risk of cardiovascular disease. However, this correlation must take into account that TGs are transported by TG-rich lipoproteins and can therefore co-vary with the apoB and cholesterol content of these lipoproteins. Tri-glycerides are constitutive components of apoB-containing lipoproteins, particularly VLDL and their remnants (which are also recapitulated by non-HDL-C, i.e. the cholesterol content in all apoB-containing lipoproteins; therefore, HTG could be a marker for increased levels of VLDL and remnants [11]. Lowering TG with fibrates has been shown to reduce the risk of CV events, which is dependent on the reduction of non-HDL-C and apoB-containing lipoproteins [81]. This observation supports the concept that the effects of TG on ASCVD are mediated by variations in the concentration of circulating TG-rich lipoproteins. But which component of TG-rich lipoproteins better inform about the relationship to risk and true causality?

All atherogenic apoB-containing lipoproteins (including VLDL, TG-rich remnant particles, and LDL) contain a single apoB molecule per particle, so quantification of apoB directly estimates the number of atherogenic particles in plasma [82]. Given the central causal role of apoB-containing lipoproteins in the initiation and progression of atherosclerosis, direct measurement of their circulating concentration would be ideal for both estimating risk and making treatment decisions [83]. There are standardised, automated, accurate and cost-effective methods for determining apoB in plasma that are superior to measuring or calculating LDL-C and non-HDL-C for CV risk assessment [84].

In addition, the results of clinical trials evaluating the cardiovascular benefits of TG lowering have taught us that lowering plasma TG and/or non-HDL-C is not sufficient to provide clinical benefit if it is not accompanied by a significant reduction in apoB levels. For instance, the PROMINENT study showed that the addition of pemafibrate to a statin had no clinical benefit despite a significant reduction in TG and remnant cholesterol levels. LDL-C and apoB levels increased slightly, which may partly explain the observed lack of efficacy of the drug [75]. This trial supports the concept that TG lowering per se is not associated with CV benefits, but that the reduction in the number of atherogenic apoB particles, reflected by a decrease in poB levels, is the reason for the CV benefit associated with any lipid-lowering approach.

A Mendelian randomisation study has suggested that lowering plasma TG levels via the LPL pathway and lowering LDL-C levels via the LDL receptor pathway are associated with a very similar proportional reduction in the risk of cardiovascular events for the same reduction in apoB-containing lipoproteins. These results reinforce the concept that, despite different changes in plasma lipids, the effect of apoB-containing particles on the risk of ASCVD appears to be largely determined by the concentration of circulating apoB particles, which in turn determines the number of particles retained in the arterial wall, regardless of whether

these particles contain mainly cholesterol or triglycerides [85].

Overall, several clinical trials of TG-lowering drugs, including fibrates or omega-3 fatty acids, suggest that the specific reduction in TG levels may not be accompanied by a corresponding significant reduction in apoB levels and therefore cannot reliably estimate the expected clinical benefit of lipid-lowering therapies in individuals with elevated triglycerides with or without diabetes.

7. Non-pharmacological therapy: lifestyle

Non-pharmacological control of elevated plasma TG levels requires integrated lifestyle interventions that include both diet and physical activity.

In most cases, HTG is caused by a combination of genetic predisposition and secondary factors; in these patients, lifestyle interventions are usually highly effective. In patients with FCS, in whom TG metabolism is disrupted due to specific deficiencies in the lipolytic pathway, such measures are usually not effective. In people with transient/occasional hypertriglyceridaemia, which is largely prevalent in the population, the dietary measures to be adopted are essentially based on:

$\bullet$ Reducing calorie intake in the presence of overweight and/or increased abdominal circumference, which indicates intra-abdominal fat deposition;

* Reducing or avoiding alcohol consumption;

* Limiting carbohydrate intake, especially refined carbohydrates (with a high glycaemic index) and simple sugars. Restricting fat intake is often useless and can be counterproductive;

* Increasing the consumption of foods (especially fatty fish) with a high content of long-chain omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]).

A global and balanced restriction of calorie intake, preferably in combination with an increase in energy expenditure, is the first measure that should be taken when hypertriglyceridaemia is associated with overweight [86]. Most studies suggest that any dietary intervention that leads to calorie restriction is effective if it leads to significant weight loss. It is unclear whether intermittent fasting or calorie restriction in specific time windows has a greater effect on triglyceridaemia than non-timed calorie restriction. The reduction in TG levels that can be achieved by calorie restriction is highly variable and usually proportional to baseline levels. If the baseline values are only slightly elevated, the reduction is often in the range of 10-15 % of the baseline value [87].

Restriction of fats, especially saturated fatty acids (SFA), which is often recommended in clinical practice, generally has no specific effect on triglyceridaemia, unless it is accompanied by a large and uncompensated reduction in calorie intake. Selective intervention on dietary fats (especially SFA) may even have a paradoxical effect if it leads to a compensatory increase in the intake of simple, refined or high-glycaemic index carbohydrates [88]. Replacing SFA with monounsaturated or polyunsaturated omega-6 fatty acids appears to be ineffective, whereas partial replacement of saturated fatty acids with polyunsaturated fatty acids with a significant omega-3 content may instead contribute to a reduction in TG levels. Long-chain omega-3 fatty acids (EPA and DHA) indeed exert a dose-dependent TG-lowering effect, which can also be observed when consuming fatty fish [89]. Alpha-linolenic acid (ALA) appears to influence triglyceridaemia essentially when it is converted into long-chain compounds, although its direct effect is less clear.

Limiting the intake of carbohydrates in the diet, especially refined carbohydrates with a high glycaemic index or simple sugars, is probably the most effective dietary measure to reduce triglyceridaemia. Fructose, which is present in considerable amounts in fruit (especially in autumn or tropical fruit), is often thought to have a particular ability to increase triglyceridaemia. This effect has only been observed in studies investigating fructose supplementation, and not in substitution studies, and therefore does not appear to be specific [90]. Since consumption of any

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

alcoholic beverage is associated with an increase in triglyceridaemia, limiting or avoiding alcohol consumption must be considered if plasma triglyceride levels are high [91].

Increasing the protein content of the diet is effective in lowering plasma TG levels in some studies, probably because this leads to an overall lower calorie intake (perhaps due to the satiating effect of proteins).

In terms of dietary patterns, the Mediterranean model is associated with better control of triglyceridaemia [92]. The Palaeolithic diet (based on the consumption of fruit, vegetables, lean meat, fish, eggs, nuts and seeds) may help to reduce plasma TG levels, probably due to the low content of simple or refined carbohydrates [93].

8. Pharmacological therapy to REDUCE TG levels

In the current guidelines, the use of TG-lowering drugs is only considered in high-risk patients with a TG level of >2.3 mmol/L (>200 mg/dL) that cannot be controlled by lifestyle measures. Drugs recommended to reduce TG levels include a high-intensity statin to reduce cardiovascular risk and fibrates and icosapent-ethyl in combination with a statin for persistently high TG levels.

The most important adverse events observed during treatment with fibrates are myopathy (with gemfibrozil), liver enzymes elevations and choleithiasis. The risk of myopathy is higher with gemfibrozil both in monotherapy and in combination with statins. This is because gemfibrozil competes with statins for the hepatic microsomal enzymes uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and inhibits the human hepatic uptake transporter organic anion transporter 2 (OATP2), leading to increased statin plasma concentrations. The risk of myopathy is lower with fenofibrate as it follows a different pharmacokinetic pathway.

In patients with severe hypertriglyceridaemia, two or more drugs,

such as fibrates and omega-3 fatty acids, may be required to reduce TGs to <500 mg/dL. Omega-3 supplements are among the best-known di- etary supplements, and there have been many recent advances in their use for HTG [94]. The main active ingredients are the omega-3 fatty acids EPA and DHA. They can be used in pharmacological doses to lower TG and VLDL, but their effects on other lipoproteins appear to be trivial. The recommended doses of omega-3 for lowering TGs are between 3 and 4 g/day. Lower doses appear to be less effective in lowering TGs and, more importantly, do not reduce the CV risk associated with HTG [95]. Recently, there has been much debate about which omega-3 fatty acid at appropriately high doses is responsible for the observed reduction in cardiovascular risk [96], as two large trials [77,80] have produced conflicting results.

9. Novel therapeutic approaches

New approaches to reduce plasma triglycerides and TRL involve either limiting lipoprotein production in the liver or increasing lipoprotein catabolism in the periphery (Fig. 3).

The use of lomitapide (which is currently approved for the treatment of patients with homozygous familial hypercholesterolaemia, HoFH) in patients with severe hypertriglyceridaemia is currently being investigated in various clinical trials. The rationale is based on the mechanism of action of lomitapide, which inhibits the loading of lipids (tricycerides, cholesterol esters and others) onto apoB by blocking the enzyme microsomal triglyceride transfer protein (MTP), thus reducing hepatic lipoprotein synthesis and secretion, resulting in a significant TG reduction of >50 %. While the beneficial effects of this approach were initially tested and demonstrated in HoFH patients, they appear to be transferable to patients with severe HTG [97]. It is worth noting that lomitapide was granted orphan drug status for hyperlipoproteinaemia type I (familial chylomicronaemia) in Europe in December 2010 and in

 A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

the USA in March 2011.

Only a few cases are known in the literature in which loimitapide was used to treat patients with severe HTG. One patient with FCS (TG > 2000 mg/dL) and recurrent severe pancreatitis was treated with lomitapide at high doses of 20–40 mg/day for 13 years and achieved plasma TG levels below 1000 mg/dL [98]. Notably, the last biopsy showed marked macrovesicular steatosis and a transition to fibrosis, which led to the discontinuation of the drug. The hepatic steatosis could be an obvious side effect related to the mechanism of action: the excessive accumulation of lipids, which cannot be transferred to apoB within hepatocytes, leads to an increase in ectopic fat deposition and liver fat mass. A 46-year-old man with genetically confirmed FCS had his first episode of pancreatitis at the age of 9 years [99]. Treatment with loimitapide reduced TG levels by 67% from baseline and achieved a TG level <1000 mg/dL. After two years of treatment, a liver biopsy showed a marked increase in hepatic steatosis and mild fibrosis. These side effects were investigated during the clinical development of the drug in HoFH patients, and the available data suggest that treatment with lomitapide in combination with a low-fat diet limits fat accumulation in the liver, at least in HoFH patients. Whether this also applies to patients with severe hypertriglyceridaemia is currently under investigation and requires longer follow-up to assess the risk of liver fibrosis progression.

More recently, the open-label, single-arm 'LOCHNES' study of lomitapide enrolled adults with genetically confirmed FCS, elevated fasting TG levels (≥750 mg/dL) and a history of pancreatitis [100]. Patients received lomitapide at the maximum tolerated dose for 26 weeks. From a baseline of 1803.5 mg/dL, the median fasting TG was reduced to 305 mg/dL at week 26 with a median lomitapide dose of 35 mg/day; 13 patients achieved a TG ≤ 750 mg/dL. Liver imaging at baseline and week 26 showed an increase in liver fat from a median of 12.0 %-32.5%, while median liver stiffness remained normal.

A second approach to lower plasma TG and TRL levels is to increase their catabolism. Lipases such as LPL, hydrolyse TGs in lipoproteins and deliver free fatty acids to tissues such as muscle and the heart. The activity of LPL and other lipases is inhibited by various proteins such as apoC-III and ANGPTL3. The observation that loss-of-function mutations in these two proteins are associated with low plasma TG levels set the stage for investigating strategies targeting either apoC-III or ANGPTL3 to promote catabolic processes that favour TRL clearance and that are independent of LPL and could therefore be used in FCS patients. APOC3 gene silencing (volanesersen and olezarsen) or ANGPTL3 inhibition by monoclonal antibodies (evinacumab) or gene silencing have been developed as therapeutic approaches for severe hypertriglyceridaemia.

Volanesorsen, a second-generation antisense oligonucleotide (ASO), targets APOC2 mRNA and inhibits the production of apoC-III protein after subcutaneous administration. This results in a significant reduction in plasma TG levels, even in the absence of LPL activity. Phase III studies (APPROACH and COMPASS) in patients with FCS showed a 70%–80% reduction in TG levels and an 84% reduction in apoC-III levels after 3 months of weekly administration of 300 mg volanesorsen [101,102]. Other positive effects were a reduction in acute pancreatitis and an improvement in insulin resistance. However, the drug increased the risk of thrombocytopenia and increased LDL-C [103].

Olezarsen is an N-acetygalactosamine-conjugated ASO that selectively targets hepatic synthesis of apoC-III; the presence of the GalNAc moiety ensures lower doses and less frequent administration [104]. It significantly lowers TG concentration in healthy subjects with elevated TG levels as well as in patients with elevated TG levels and established or at-risk for CVD [104,105]. Treatment with olezarsen improved the lipid profile, apoB was slightly reduced and LDL-C did not increase; there were no signs of thrombocytopenia [106]. Several phase 3 trials are currently investigating the effect of olezarsen in various clinical settings.

Plozasiran (ARO-APOC3), is a small interfering RNA that specifically targets APOC3 mRNA in the liver thanks to its GalNAc moiety. In a phase 1 study, subcutaneous administration of ARO-APOC3 significantly and dose-dependently reduced TG levels in healthy participants (up to -69

%), in patients with HTG (up to -81 %) and in patients with chylomi-cronaemia (-85.5%) [107]. In patients with FCS and MCS, ARO-APOC3 reduced TG levels by ~90 % [108]; non-HDL-C levels were also significantly reduced. Recently, plozasiran was found to markedly reduce plasma TG levels and significantly decrease the incidence of acute pancreatitis in patients with persistent chylomicronemia, including those with genetically defined FCS [109].

Evinacumab reduces TG levels in healthy individuals, in HoFH patients and in individuals with TG > 150 but ≤450 mg/dL or severe hypertriglyceridaemia, with >70 % reduction in plasma TG levels compared to baseline [110,111]. Other approaches targeting ANGPTL3 are currently under intensive clinical investigation. Among them, ARO-ANG3 (also called zodasiran) is the most advanced GalNAc-conjugated siRNA specifically targeting ANGPTL3 mRNA in the liver. A phase 1 trial showed that repeated administration of ARO-ANG3 reduced ANGPTL3 levels by approximately 80–90 %, a reduction that was greater than that observed with a single administration of ARO-ANG3 [112]. The ARCHES-2 study recently showed that ARO-ANG3 significantly reduced TG, non-HDL-C and remnant cholesterol levels in adults with mixed dyslipidaemia; furthermore, apoB and LDL-C levels were significantly reduced [113,114]. ARO-ANG3 is currently being investigated in clinical trials in HoFH patients. Another GalNAc-conjugated siRNA targeting hepatic ANGPTL3 expression, solbinsiran, has recently been developed. In the phase II PROLONG-ANG3 trial, solbinsiran elicited sustained reductions in atherogenic poB-containing lipoproteins and TG levels in patients with mixed dyslipidaemia [115]. Nevertheless, data from CV outcome trials are still lacking for both these drugs, and being injectable and potentially costly may limit the feasibility of large-scale implementation for CV risk prevention in patients with elevated TG.

10. Conclusions

This consensus document highlights the available evidence on the physiology, metabolism and association with ASCVD of TRL and their remnants. It recapitulates available and new therapeutic approaches including: i) diet and lifestyle, ii) established treatments such as fibrates and omega-3 fatty acids to lower serum TG levels to reduce residual cardiovascular risk in patients on maximal LDL-C-lowering treatment, and iii) new therapeutic options in patients with severe hyper-triglyceridemia (Box 1).

The key messages can be summarised as follow:

1) Genetics, epidemiological studies and clinical trials have demonstrated a causal relationship between plasma triglycerides and ASCVD. TGs are mainly transported by lipoproteins such as VLDL and their remnants defined as TG-rich lipoproteins or TRL TG-lowering per se is not associated with macrovascular or microvascular benefits, but reduction in plasma TRL concentration when associated to a reduction in the number of atherogenic apoB-containing particles, reflected by a decrease in apoB levels, is the reason for the CV benefit associated with TRL lowering strategies and overall any lipid-lowering approach, even in patients with optimally controlled LDL-C.

2) In patients at high and very-high-risk CV risk and with mild to moderately elevated TG levels, on optimized LDL-C lowering therapy, treatment with either a fibrate in those without established ASCVD, or high-dose omega-3 fatty acids (icosapent-ethyl) in patients with ASCVD, may be considered. Combination with fenofibrate may be considered for both macro- and micro-vascular benefits in patients with type 2 diabetes mellitus without previous cardiovascular events.

3) Severe HTG is associated with an increased risk of acute pancreatitis which generally is recurrent and clinically severe. Reduction of the number of episodes of pancreatitis and of their clinical severity is therefore a possible clinical target of drug therapy. Recent evidence

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

Box 1

Practical approach to hypertriglyceridemia

In all patients with triglycerides >150 mg/dL:

$\bullet$ Adjust lifestyle: healthy diet (low-fat diet/ low glycemic index diet), physical activity and weight loss

$\bullet$ Address secondary causes of hypertriglyceridemia (including obesity, diabetes, hypothyroidism, renal and liver disease).

Patients with fasting triglycerides >150 mg/dL and < 880 mg/dL

$\rightarrow$ intervention to reduce cardiovascular risk:

$\bullet$ Start statin (+azetimibe) if the cardiovascular risk is intermediate/high

$\bullet$ Consider PCSK9 inhibitors if the LDL-C goal is not attained

$\bullet$ Consider icosapent-ethyl or fenofibrate to reduce TG levels

* Novel therapies: ANGPTL3 inhibitors and ApoC-III inhibitors

Patients with fasting triglycerides >880 mg/dL

$\rightarrow$ intervention to reduce acute pancreatitis risk:

* Address secondary causes of hypertriglyceridemia specifically in MCS patients

Alcohol abstinence, very low-fat diet, control of diabetes and obesity (if necessary)

Start fenofibrate, unless contraindicated (e.g. CKD with eGFR <30 ml/min/1,73 m$^{2}$; gallbladder disease; liver failure;...)

$\bullet$ Consider omega n-3 fatty acids, MCT, ApoC-III Inhibitors, volanesorsen, MTP Inhibitors, lomitapide

$\bullet$ Novel therapies: olezarsen, plozasiran, evinacumab, zodasiran, solbinsiran

* Reduced progression of diabetic retinopathy, independent from baseline lipid concentration.

with strategies targeting TRL production (lomitapide) and catabolism (apoC-III inhibitors: volanesorsen, olezarsen and plozasiran) suggests a significant clinical benefit and reduction of recurrent pancreatitis in patients with FCS.

In conclusion, evidence from clinical trials and real-world studies highlights the need for a personalised approach to lipid management, incorporating TRL lowering approaches, where appropriate, to optimize lipid profiles and mitigate the risk of ASCVD. As the landscape of dyslipidaemia management evolves, ongoing research and new clinical insights will continue to refine and enhance the role of modifying apob-containing lipoprotein management strategies to maximize ASCVD clinical benefits.

Contribution statement

Marcello Arca, Maurizio Averna, Anna Belfiore, Marco Bucci, Alberico L. Catapano, Luca Frulloni, Federica Galimberti, Luigi Gentile, Andrea Giaccari, Enzo Manzato, Giuseppe D. Norata, Andrea Poli, Giorgio Sesti, Pier Luigi Temporelli and Alberto Zambon equally contributed to the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

Luigi Gentile, Federica Galimberti, Enzo Manzato, Giorgio Sesti, Anna Belfiore, Andrea Poli, and Maurizio Averna report no disclosures Alberto Zambon received honoraria for lectures, speakers bureaus, or travel support, and/or honoraria for data safety monitoring board or advisory boards from Abbott, Amgen, Marin, Chiesi, Daichi-Sankyo,

MSD, Novartis, Sanofi, Servier, Ultragenyx, Viatris, Zentiva. Andrea Giaccari received honoraria for lectures, presentations or speakers bua- reaus from AstraZeneca, Lilly, Novo, Sanofi. Giuseppe D. Norata received consulting fees or grants from Amarin, Meda Pharma, MSD, Novartis. Pier Luigi Temporelli received honoraria for lectures, pre- sentations, speakers bureaus, manuscript writing or educational events and honoraria for data safety monitoring board or advisory boards from Alfasigma and Amarin Italia. Luca Frulloni received honoraria for lec- tures from Sobi and Viatris. Marco Bucci received honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amarin, Daichi-Sankyo, Dompè, Lusofarmaco, Menarini, Neopharmed, Novartis, Novo-Nordisk, Sandoz, Servier. Marcello Arca received grants, travel supports and/or honoraria for data safety monitoring board or advisory boards, consultancy or speaker bureaus from Akcea, Amarin, Amgen, Amryt, Chiesi, Daichii-Sankyo, Ionis, Lilly, Novartis, Pfizer, Regeneron, Sanofi, Ultragenyx. Alberico L Catapano received research funding and/or honoraria for advisory boards, con- sultancy or speaker bureaus from Amarin, Amgen, Amryt Pharma, AstraZeneca, Daichi-Sankyo, Esperion, Ionis Pharmaceutical Medscape, Menarini, Merck, Novartis, Novo Nordisk, PeerVoice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, The Corpus, Ultragenyx, Viatris.

Acknowledgments

The work of Alberico L Catapano and Federica Galimberti has been supported by Italian Ministry of Health - Ricerca Corrente - IRCCS MultiMedica.

References

[1] Ginsberg HN, Packard CJ, Chapman MJ, Boren J, Aguilar-Salinas CA, Averna M, et al. 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 2021;42:4791-806.

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

[2] Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2020;41:99–109c., 3 Manzato E, Zambon S, Marin R, Baggio G, Crepaldi G. Modifications of plasma lipoproteins after lipase activation in patients with chylomicronemia. J Lipid Res 1986;2:1472-1248–58. [4] Wu Sa, Kersten S, Qi L Lipoproteins IPase in its regulations: un unfolding story. Trends Endocrinol Metab 2021;32:48–61. [5] Norata GD, Tsimikas S, Pirillo A, Catapano AL. Apoliprotein C-III: from pathophysiology to pharmacology. Trends Pharmacol Sci 2015;36:675–87. [6] Ko Wu, QJ, Black, TDo S. Pregulation of intestinal metabolism: current concepts and relevance to disease. Nat Rev Gastroenterol Hepatol 2020;17:169–83. [7] Boren J-389, Markin MR, Bjornson E, Packard C.J. Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia. Nat Rev Cardiol 2022;19:577–92. [8] Jegede RA, Ginberg HN, Chapman MJ, Nordestgaard BG, Kiivenburg JA, Kenedard BG, Kiivenhoven JA, Averna M. et al. The polygenic nature of hypertriglyceridae: implications: for definition, diagnosis, and management. Lancet Diabetes Endocrinol 2014;2:655–66. [9] Dron JS, Hegele RA. Genetics of hypertriglyceridaemia. Front Endocrinol 2020;11:455. [10] Nordestgaard BG, Langlois MR, Langsted A, Chapman MJ, Alkreke KM, Baum H, et al. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Atherosclerosis 2020;29:44:6–61. [11] Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Madin, R. et al. (ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J 2019;41:11:11–88. 2020, 12:69–63. [12] Ganda OP, Bhatt DL, Mason RP, Miller M, Boden WE. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol 2018;7:22:330–43. [13] Simha V. Management of hypertriglyceridemia. BMI J 2020;37:1:m3109. [14] Moulin P, Dufour R, Averna M, Arca M, Cefalu AB, Noto D, et al. Identification and diagnosis of patients with familial chylomicronemia syndrome (FCS) expert parameteringsand recommendations of an "FCS score". Atherosclerosis 2018; 27:25:62–72. [15] Valdvielois P, Ramirez-Bueno, A Ewald. N. Current knowledge of hypertriglyceridemic pancreatitis. Eur. J Intern Med 2014;25:68–94. [16] Steher J. Singh VP, Pitchumoni CS, Yadani D. Issues in hypertriglyceridemic pancreatitis: an update. J Clin Gastroenterol 2014;48:195–203. [17] Vadud, P. Dichant-Sius. Charles in hypertriglyceridemic pancreatitis. J Clin Gastroenterol 2003;36:54–62. [18] de Pretis N, Amodio A, Frulloni L. Hypertriglyceridemic pancreatitis: Epidemiology, pathophysiology and clinical management. United European Gastroenterol J 2018;6:649–55. [19] Navina S, Acharya C, Delany JP, Orlichenko LS, Baty CJ, Sihra SS, et al. Lipoticity causes multiystem organ failure and esacerbiates acute pancreatitis in obesity. Sci Trans Med 2011;3:107ra10. [20] Wang SH, Chou YC, Shangkuan WC, Wei KY, Pan YH, Lin HC. Relationship between plasma triglyceride level and severity of hypertriglyceridemic pancreatitis. PLoS One 2016;11:e0163984. [21] Khatua B, El-Kurdi B, Singh VP, Obesity and pancreatitis. Curr Opin Gastroenterol J 2017;33:374–62. [22] Chapman MJ, Orsoni A, Tan R, Mellett NA, Nguyen A, Robillard P, et al. LDL subclass lipidomics in atherogenic dyslipidemia: effect of statin therapy on bioactive lipids and dense LDL. J Lipid Res 2020;61:91–312. [23] Chait , A Ginsberg H, Vaisar T, Heinecke JW, Goldberg J, Bornfeld. KE Remnants of the triglyceride-rich lipoproteins, diabetes, and cardiovascular disease. Diabetes 2020;69:50–108. [24] Chang YT, Chang MC, Su, TC Liang, PC Su, YN Kuo, CH, et al. Association of cystic fibrosis transmembrane conductance regulator (CFR) mutation/variant/hapotype and tumor necrosis factor (TNF) promoter polymorphism in hyperlipidiable panicureatis. Clin Chem 2008;41:301–311. [25] Ivanova R, Puerta S, Garrido A, Cueto I, Ferro A, Ariza MJ, et al. Triglyceride levels and apoiroprotein E polymorphisms in patient. Epopabatic Panecat Disent 2021;11:96–101. [26] Ford ES, IL Z, Zhao G, Pearson MS, Wokdad AH. Hypertriglyceridemia and its pharmacologic treatment among US adults. Arch Intern Med 2009;16:5972–8. [27] Esparza MI, Li X, Adams-Huet B, Vaandani C, Vora A, Das SR, et al. Very severe hypertriglyceridemia in a large US health care system: associated conditions and management. J Endor Soc 2019;3:1595–607. [28] Kissebah AH, Alberti S., Evans DJ, Adams PW. Integrated regulation of very low dipes lipopitide ruggioteride and apoloprotein-B kinetics in non-insulin-dependent diabetes mellitus. Diabetes 1982;31:217–25. [29] Taskin her, Boren J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015;239:483–95. [30] Mark L, Vallejo-Vaz AJ, Reiber I, Paragh G, Kondapally Seshasai SR, Ray KK. Non-HDL cholesterol goal attainment and its relationship with triglyceride concentrations among diabetic subjects with cardiovascular disease: a nationwide survey of 2674 individuals in Hungary. Atherosclerosis 2015;241:62–8. [31] Norata GD, Grigore L, Raselli S, Seccomandi PM, Hamren A, Maggi FM, et al. Triglyceride or-rich lipoproteins from hypertriglyceridemic subjects induce a non-inflammatory response in the endothelium: molecular mechanisms and gene expression studies. J Mol Cardi Cardi 2006;40:484–94. [32] Norata GD, Raselli G, Grigore L, Garlassichii K, Vianello D, Bertocco S, et al. Small dense LDL and VLDL predict common carotid artery IMT and eli.

inflammatory response in peripheral blood mononuclear and endothelial cells. Asterroscetus 2009;206:556-62. [33] Norata GD, Grigore L, Raselli S, Redaelli L, Hamsten A, Maggi F, et al. Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gese expression studies. Atherosclerosis 2007;193:321-7. [44] Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from Epidemiology, genetics, and biology. Circ Res 2016;118:547-633. [35] Guerin L M, Geoff W, Læssel TS, Van Tol A, Steiner G, Chapman MJ. Atherogenic role of CE transfer from HDL to VLDL(1) and dense LDL in type 2 diabetes: impact of the degree of triglyceridemia. Arterioscler Thromb Vasc Biol 2001;21:282-8. [36] Tenenbaum A, Kiempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor. Cardiovasc Diabetol 2014;13:159. [37] Ip. Lichtenstein AII, Chung M, Lau J, Balk EM. Systematic review: association of low-density lipoproteins with cardiovascular outcomes: Ann Intern Med 2009;150:474-84. [38] Packard C1, Boren J, Taskten MR. Causes and consequences of hypertriglyceridemia. Front Endocrinol 2020;11:252. [39] Manzato E, Marin R, Gasparotto A, Baggio G, Martini S, Gabelli C, et al. Liprotein modifications during dietary treatment in patients with primary type V hyperlipoproteinaemia. Eur J Clin Invest 1986;16:149-56. [40] Manzato E, Zambon S, Zambon A, Cortella A, Sartore G, Crepaldi G. Levels and physicochemical properties of lipoprotein subclasses in moderate hypertriglyceridemia. Clin Chim Acta 1993;219:57-65. [41] Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Norestegaard BG. Remmaat cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardol 2013;61:427-36. [42] Andersson C, Lyass A, Vasan RS, Massaro JM, D'Agostino RB, Robins SJ. Long-term risk of cardiovascular events across a spectrum of adverse major plasma combinations in the Framingham Heart Study. Am Heart J 2014;168:878-883 e1. [43] Bansal S, Bursing JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglyceridic and risk of cardiovascular events in women. JAMA 2007;298:309-16. [44] Emerging Risk Factors C, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, et al. Major lipide, apolipoproteins, and risk of vascular disease. JAMA 2009;309:102:393-141. [45] Faergeman O, Holme I, Fayyad R, Bhatia S, Grundy SM, Kastelein JJ, et al. Plasma triglycerides and cardiovascular events in the treating to new targets and incremental decrease in end-points through aggressive lipid lowering trials of statins in patients with coronary artery disease. Am J Cardiol 2009;104:459-63. [46] Freiberg JJ, Tytygjerg-Hansen A, Jensen J, Jensen JS, Nordestgaard BG. Nonfasting triglyceride levels and risk of ischemic stroke in the general population. JAMA 2008;300:2142-52. [47] Miller M, Gannon CP, Murphy SA, Qin J, Ray KK, Braunwald E, et al. Impact of triglyceride levels low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724-30. [48] Nordestgaard BG, Benn m, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007;298:299-308. [49] Sharart AR, Ballantine CM, Coady SA, Heiss G, Sorlie PD, Catellier D, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoproteins(a), apolipoproteins-A I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108-13. [50] Asannan G, Schulle H. The importance of triglycerides: results from the prospective cardiovascular muñster (PROCAM) study. Eur J Epidemiol 1992;8 (Suppl 1):99-103. [51] Nordestgaard BG, Barb M. Atriglycerides and cardiovascular disease. Lancet (Suppl 1):99-103. [52] Nordestgaard BG, Barb M. Atriglycerides and cardiovascular disease. Lancet (Corporated) 2014;39:86-252. [53] Forfeng to For M, Davidman SG, Farkouh ME, Lee DS, et al. Real-world risk of cardiovascular outcomes associated with hypertriglyceridaemia among individuks with atherosclerotic cardiovascular disease and potential eligibility (2009;1020;1917;2020;41:86-94. [54] Schwartz GG, Abt M, Bao W, DeMicco D, Kallend D, Miller M, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome tested with statins. J Am Coll Cardiol 2015;65:2267-75. [55] Dewey FE, Gusarova V, O'Dushlaine C, Gottesman O, Trejos J, Hunt C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med 2016;374:1123-18. [56] Do R, Stitziel NO, Won HH, Jorgensen AB, Duga S, Angelica Merlin P, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015;518:102-6. [57] Helkkula P, Kiiskinen T, Havulinna AS, Karjalainen J, Koskinen S, Salomaa V, et al. ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease. PLoS Genet 2021;17:1009501. [58] Kthere AV, Won HH, Peoso GM, O'Dushlaine C, Liu D, Stitziel NO, et al. Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease. J MAMA 2017;317:937-46. [59] Kim M, Kim M, Yoo HJ, Lee E, Chae JS, Lee SH, et al. A promoter variant of the APOAS gene increases atherogenic LDL levels and arterial stiffness in hypertriglyceridemic patients. PLoS One 2017;12:e0186693. [59] Lotta LA, Stewart ID, Sharp SJ, Day FR, Burgess S, Luan J, et al. Association of genetically enhanced lipoprotein lipase-mediated lipoposis and low-density

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

lipoprotein cholesterol-lowering alles with risk of coronary disease and type 2 diabetes. JAMA Cardiol 2018:957-66.60. [60] Myocardial Infarction G, Investigators CAEC, Stizitiel NO, Stirrupks KE, Masca NG, Erdmann J, et al. Coding variation in ANGPTIL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 2016:37:41:134-44. [61] Tg, Hd� Working Group of the Exome Sequencing Project NHL, Blood I, Croby J, Peloso GM, Auer PL. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. et al. N Engl J Med 2014:371:22-31. [62] Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014:371:32-41. [63] Sitizel NO, Khera AV, Wang X, Bierhals AJ, Vounrak AC, Sperry AE, et al. and ANGPTL deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017;69:2054-63. [64] Stacks B, Dallengeville J, A. Juwers, J. Schoonjans K, Leistendorf E, Fruchart JC. ANGPTL deficiency: an of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088-93. [65] Frick MHL Elo O, Haapa K, Heimonen OP, Heimsalmi P, Helo P, et al. Helsinki Heart Study: primary-prevention trial with femibrozii in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 2017;39:457-65. [66] Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol, Veterans Affairs Highs-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-8. [67] Mannisen V, Tenkanen L, Koskinen P, Huttunen J, Kmantii M, Heimonen OP, and apoliproteins: a serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Complications for treatment. Circulation 1992;85:37-45. [68] Beazfibrate Infarction Prevention s. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000:1421-7-7-8. [69] Meade T, Zuhrie R, Coc Co, Cooper J. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial. BMJ 2002;325:1139. [68] Keech AC, Mitchell P, Summanne PA O' Day J, Davis TM, Missof Thitt, as al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687-97. [69] For group, ASG� AES, Chew EY, Ambrosius WT, Davis MD, Davis RP, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;362:333-44. [67] Group AS, Ginsberg HN, Elam MB, Lovato LC, Crouse 3rd JR, Leiter LA, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74. [68] Preiss D, Logue J, Sammons E, Zayed M, Emberson J, Wade R, et al. Effect of fenofibrate on progression of diabetic retinopathy. NEJM E25d:2024:371-65. [69] Fruchart JC Pemafibrate (K-877), a novel selective peroxisome proliferator activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetot 2017;16:124. [75] Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med 2022;387:1923-34. [76] Farnier M, Vrablik M, Catapano AL. Is there still a place for fenofibrate-statin combination therapy? Fenofibrate-statin combination therapy. Euro Atherosclerosis J 2023;2:44-9. [87] Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with losopent 3007; for hypertricyceridemia. N Engl J Med 2019;380:11-22. [88] Mason RP, Eckel RH. Mechanistic insights from REDUCE-IT STRENGTHen the case against triglyceride lowering as a strategy for cardiovascular disease risk reduction. Am J Med 2021;334:1085-90. [89] Olshansky B, Chung MK, Budoff MJ, Philip S, Jiao L, Doyle Jr RT, et al. Mineral case against vise and as placebo in REDUCE-IT and other clinical studies. Eur Heart J Supp-2020;223:34-48. [80] Nicholls S, Ljlop, Garcia M, Bash B, Dallantyne CM, Carter PJ, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020;324:2268-80. [81] Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016;316:1289-97. [82] Calombiert F, Cautia M, Olmastron E, Apolipoprotein B compared with low-density lipoprotein cholesterol in the atherosclerotic cardiovascular diseases risk assessment. Pharmacol Res 2023;195:106873. [83] Langlois MR, Chapman MJ, Cobberta C, Mora S, Remaley AT, Ros E, et al. Quantifying atherogenic lipoproteins: current and future challenges in the era of personalized medicine and very low concentrations of LDL cholesterol. A consensus statement from EAS and EFLM, Clin Chem 2018;64:10006-33. [84] Sathaykumar V, Park J,ologo Azar, Lazo M, Quispe R, Gullar E, et al. Fasting versus nonfasting and low-density lipoprotein cholesterol accuracy. Circulation 2018;137:10-9. [85] Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Man J, Chapman, CM J, Packel, C, 321:12-12-13-14. [86] For group, ASGga, Gullar E, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.

[86] Yamanaka M, Sakuma M, Matsushita A, Tanaka S, Yamamoto Y, Asai T, et al. The effects of long-term dietary therapy on patients with hypertriglyceridemia. J Atherosclerosis Thromb 2019;26:39–49. [87] Stelmach-Mardas M, Walkowiak J. Dietary interventions and changes in cardio-metabolic parameters in metabolically healthy obese subjects: a systematic review with meta-analysis. Nutrients 2016;8. [88] Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the rate of serum total to HDL cholesterol and on serum lipids and apoliproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003;77:1146–55. [89] Weinberg RL, Brook RD, Rubenfire M, Eagle KA. Cardiovascular impact of nutritional suppressionation with omega-3 fatty acids: JACC focus seminar. J Am Coll Cardiol 2021;797:593–608. [90] Chiavaroli L, de Souza R, J Ha V, Cozma AI, Mirrahimi A, Wang DD, et al. Effect fructose on established lipid targets: a systematic review and meta-analysis of controlled feeding trials. J Am Heart Assoc 2015;4:e001700. [91] Gaubatz JW, Gillard BK, Rosales C, Pownall HJ. Dietary alcohol and fat differentially affect plasma cholesteryl est transfer activity and triglycerides in 42–225-40. and hypertriglycerides subjects. Lipids 2020;55:299–307. [92] Esposito K, Marfella R, Ciotola M, Di Palo C, Giugliano F, Giugliano G, et al. Effect of a mediterranean-style diet on endothelial dysfunction and markers of vascular inflammation in the metabolic syndrome: a randomized trial. JAMA 2004;292:1440–6. [93] Soohui MHL Fatihi S, Lari A, Lotfi M, Seifishahpar M, Gaman MA, et al. The effect of paleolithic diet di glucose metabolism and lipid profile among patients with metabolic disorders: a systematic review and meta-analysis of randomized controlled trials. Critc Rev Food Sci Nutr 2022;62:4551–62. [94] Authors/Tasker Force: SccfP Guidelines, Societies ESCNC. ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Alterosclerosis 2019;290:140–205. 2019. [95] Aung T, Halse J, Kromout D, Gerstein HC, Marchioli R, Tavazzi L, et al. Associations of omega-3 fatty acid supplement use with cardiovascular disease risk: meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol 2018;82:225-225. 34:48. [96] Goff ZD, Nissen SE. N-3 polyunsaturated fatty acids for cardiovascular risk. Curr 2010;622–357–63. [97] Emban AJ, Hege ReLA. I somitopide for the treatment of hypertriglyceridemia. Expet Opin� Heap DrA 2016;25:1457–63. [98] Sacks FM, Stanesa M, Hegele RA. Severe hypertriglyceridemia with pancreatitis: thirteen years’ treatment with to imitapide. JAMA Intern Med 2014;17:44:443–7. 99. [90] Cefalu AB, Gimannaco A, Noto D, Spina R, Cabibi D, Barbagallo CM, et al. Effect effectiveness and safety of loitapide in a patient with familial chylomicronemia syndrome. Endocrine 2021;71:344–50. [100] Cefalu AB, D'Erasmo L, Hannuzzo G, Noto D, Giammanco A, Montali A, et al. Efficacy and safety of limitapide in familial chylomicronemia syndrome. Atherosclerosis 2022;359:13–9. [101] Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, Williams KR, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019;381:521–42. [102] Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, et al. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2021; 9:264–75. [103] Zwol VW, Kimbert A, Kuivenhoven JA. The future of lipid-lowering therapy. J Clin Med 2019;8:12. [104] Alexander VJ, Xia S, Hurh E, Hughes SG, O’Dea L, Geary RS, et al. N-acetyl galactosamine conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoproteins. Eur Heart J 2019;40:2785–96. [105] Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Mortary PA, Atal. E, al. Apoproprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J 2022;43:148. [106] Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, Hegele RA, Arca M, Ballantine CM, et al. Olenzarsen, acute pancreatitis, and familial chylomicronemia syndrome. N Engl J Med 2024;390:1781–92. [107] Gaudet D, Clifton P, Sullivan D, Bivan D, Baker J, Schwabe C, Thackwray S, et al. RNA interference therapy targeting apolipoprotein C-iii in hypertriglyceridemia. NEJM genetically2:23:EVID2023:352. [108] Clifton P, Sullivan D, Baker J, Schwabe C, Thackwray S, Scott R, et al. ARO-APOCC, an investigational RNAi therapeutic, shows similar efficacy and safety in genetically confirm the PCCS and non-FCS participants with severe hypertriglyceridemia. Circulation 2021;144:A10357–. [109] Watts GF, Roenson RS, Hegele RA, Goldberg J, Gallo A, Mertens A, et al. Plojasarins for managing persistent chylomicronemia and pancreatitis risk. N Engl J Med 2025;392:127–37. [110] Ahmad Z, Banerjee P, Hamon S, Chan KC, Bouzelmat A, Sasiwa WJ, et al. Inhibition of angoliotoin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia. Circulation 2019;14:407–80. 86. [111] Ahmad Z, Perdy R, Rader DJ, Gaudet D, Ali S, Gonzaga-Jauregui C, et al. Inhibition of angoliotoin-like protein 3 with evinacumab in subjects with high and severe hypertriglyceridemia. J Am Coll Cardiol 2021;78:193–5. [112] Waats GF, Schwabe C, Scott R, Gladning PA, Sullivan D, Baker J, et al. RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts. Nat Med 2023;29:2216–23.

A. Zambon et al.

Nutrition, Metabolism and Cardiovascular Diseases 35 (2025) 104214

[113] Watts GF, Gaudet D, Altamirano D, Hegele R, Ballantyne CM, Nicholls S, et al. ARO-ANG3, an investigational RNAi therapeutic, silences the expression of ANGPTL3 and decreases atherogenic lipoproteins in patients with mixed dyslipidemia: ARCHES-2 study results. Circulation 2023;148. A17120-A.

[114] Rosenson RS, Gaudet D, Hegele RA, Ballantyne CM, Nicholls SJ, Lucas KJ, et al. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for mixed hyperlipidemia. N Engl J Med 2024;391:913-25.

[115] Ray KK, Oru E, Rosenson RS, Jones J, Ma X, Walgren J, et al. Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2025;405:1594-607.