**Background:** Triglycerides (TGs) are the main constituents of dietary fat and energy storage. Severe hypertriglyceridaemia (SHTG), conventionally defined as TG >10 mmol/L (or >1000 mg/dL, 11.3 mmol/L), results from impaired clearance of triglyceride-rich lipoproteins due to reduced lipoprotein lipase (LPL) activity, hepatic overproduction, or reduced hepatic clearance. SHTG can be monogenic (familial chylomicronaemia syndrome, FCS) or polygenic compounded by secondary factors (multifactorial chylomicronaemia syndrome, MCS). This review examines the aetiology, genetic basis, clinical complications, and management of SHTG and chylomicronaemia.
**Methods:** This is a narrative review synthesizing existing literature on the epidemiology, genetics, clinical presentation, complications, and therapeutic options for SHTG and chylomicronaemia syndrome. The authors reference multiple guidelines (AHA/ACC, NCEP ATP III, Endocrine Society, ESC/EAS), population-based studies, clinical trials (APPROACH, COMPASS), meta-analyses, and observational cohorts.
**Key Results:** The prevalence of SHTG is <1% in the general population, with 0.21% reported in England and 0.1% in Norway and France. FCS has an estimated prevalence of 1:100,000–1,000,000, while MCS has a prevalence of 1:600. The most common cause of FCS is biallelic loss-of-function variants in the LPL gene (82% of genetically proven FCS cases in the APPROACH trial), with other causative genes including GPIHBP1, ApoA5, ApoC2, LMF1, GPD1, and CREB3L3. Pooled analysis across multiple studies showed that the prevalence of acute pancreatitis (AP) in FCS was 70% (321/459) versus 16% (412/2593) in MCS. Recurrent pancreatitis occurred in 49% of FCS versus 11% of MCS. Cardiovascular disease was present in 6% of FCS versus 18% of MCS. In a large US claims database, healthcare costs for chylomicronaemia patients with pancreatitis approached $33,000 per patient per year versus $8,000 for the whole chylomicronaemia cohort. The CALIBER study from England showed that after adjustment for covariates, the risk of myocardial infarction was not statistically significant for TG 10–20 mmol/L (HR 1.03, 95% CI 0.88–1.19) or TG >20 mmol/L (HR 1.02, 95% CI 0.75–1.40). The APPROACH trial demonstrated that volanesorsen reduced serum TG by 76.5% compared to placebo in FCS patients, with fewer AP episodes in the treatment group (zero vs. four). The COMPASS trial showed >70% reduction in mean TG, chylomicrons, and VLDL in predominantly MCS patients, with fewer AP episodes (zero vs. five). Thrombocytopenia is the predominant side effect of volanesorsen. Novel agents in development include olezarcen (GalNAc3-conjugated ApoC3 antisense oligonucleotide), evinacumab (ANGPTL3 monoclonal antibody), and ARO-ApoC3 (siRNA against ApoC3), all showing 40–70% TG reduction in early-phase trials.
**Clinical Implications:** SHTG and CS represent a major clinical burden with acute pancreatitis as the most feared complication, associated with higher mortality and morbidity than other causes of AP. FCS carries a substantially higher risk of pancreatic complications but lower cardiovascular risk compared to MCS. Low-fat diets (<15% of total caloric intake, 10–20 g fat/day) and elimination of secondary factors remain cornerstone management. The authors propose an algorithm for diagnosing and managing SHTG and for managing hypertriglyceridaemia-induced acute pancreatitis (HTGP). They advise against routine use of insulin infusion in the absence of hyperglycaemia and against continuous heparin infusion due to risk of rebound hypertriglyceridaemia and bleeding. Blood purification techniques (plasma exchange) show no convincing evidence of improved clinical outcomes despite greater TG reduction at 24 hours. Volanesorsen is the only EMA/NICE-approved pharmacotherapy for FCS. The authors highlight the need for standardized management guidelines for HTGP, prospective studies on ASCVD risk in SHTG, and establishment of national registries and international collaborations to address unmet needs in this rare condition.