Severe Hypertriglyceridemia: New Therapies and Evolving Understanding

• Severe hypertriglyceridemia (sHTG, TG >500 mg/dL) affects approximately 1 in 88 adults in pooled global estimates and is linked to elevated risks of acute pancreatitis and atherosclerotic cardiovascular disease.

• Current pharmacologic options often fail to achieve sustained triglyceride control. The siRNA therapy plozasiran, which targets apoC-III, has shown robust TG reductions and reduced pancreatitis risk in the Phase III PALISADE trial.

• Pediatric sHTG management, particularly for hospitalized children, lacks dedicated guidelines; genetic causes are common in this population.

• Prevalence estimates vary widely by region and definition, underscoring the need for standardized thresholds and longitudinal incidence studies.

Background

Hypertriglyceridemia (HTG) is an established independent risk factor for cardiovascular disease. Severe HTG (sHTG), defined by most current guidelines as fasting triglycerides (TG) >500 mg/dL, and extreme HTG (>1,000 mg/dL) are associated with a markedly increased risk of recurrent acute pancreatitis and represent a substantial unmet medical need. Despite the availability of lifestyle interventions, fibrates, omega‑3 fatty acids, and statins, many patients fail to achieve adequate TG lowering, particularly those with monogenic disorders such as familial chylomicronemia syndrome (FCS) or polygenic forms compounded by secondary factors such as obesity, insulin resistance, and poorly controlled diabetes. In 2025–2026, a wave of novel therapies has begun to reshape the treatment landscape. This article synthesizes recent evidence on emerging pharmacologic strategies, epidemiology, and pediatric management of sHTG, drawing from a contemporary review, a Phase III trial on apoC‑III inhibition, a pediatric management chapter, and a comprehensive prevalence study.