Severe hypertriglyceridemia (sHTG) has been arbitrarily defined by different national guidelines as either triglyceride (TG) concentrations ≥500 mg/dL (≥ 5.7 mmol/L) by the American Heart Association (AHA)/American College of Cardiology (ACC) Multispecialty Cholesterol and Canadian Cardiovascular Society Guidelines (Grundy et al., 2019; Pearson et al., 2021) or TG levels ≥880 mg/dL (≥ 10 mmol/L) according to the European Society of Cardiology guidelines (Mach et al., 2019). The severity of the HTG is largely dependent on lipoprotein lipase (LPL) activity. Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive genetic disorder resulting from two biallelic defects in LPL or LPL regulating genes, whereas multifactorial chylomicronemia syndrome (MCS) and sHTG are due to either one rare heterozygous large-effect variant or a high burden of common small-effect variants which predispose individuals to sHTG. These more common small-effect variants (polygenic) and secondary disorders, such as diabetes mellitus, alcohol use, chronic kidney disease, and others, either increase very low-density lipoprotein (VLDL) production or impair the clearance of chylomicrons and VLDL. The treatment of sHTG is of utmost importance as it increases the risk of acute pancreatitis (AP) (Sanchez, Ge, Wei, Ponda, & Rosenson, 2021). According to both the ACC/AHA Multispecialty and European Society of Cardiology (ESC) guidelines (Mach et al., 2019; Virani et al., 2021) TGs should be reduced to <500 mg/dL to minimize the risk of AP in patients with sHTG.

Plasma total triglyceride (TG) concentration encompass the TG content of multiple lipoprotein particles (Fig. 1). Multiple genes influence TG metabolism including APOC2, APOA5, LPL, ANGPTL3, ANGPTL4, APOC3, APOE, and others, leading to variations in TG concentrations (Johansen & Hegele, 2012). Genetic studies have led to the identification of TG metabolic pathways, which have led to novel pathway-specific pharmacotherapeutic options. In this state-of-the art review, we describe these pathways and provide a novel framework for the management of sHTG and chylomicronemia phenotypes based on underlying genetic defects. For the purpose of this review, we select a threshold of TGs ≥ 500 mg/dL according to the ACC/AHA guidelines given that novel pharmacotherapeutics are targeting patients with TGs above this threshold.