Genetic Testing Reveals Distinct Treatment Paths for Severe High Triglycerides

Severe hypertriglyceridemia (SHTG), defined as fasting triglycerides ≥500 mg/dL, is a clinically heterogeneous condition carrying risks of acute pancreatitis, fatty liver disease, and cardiovascular events. Despite decades of treatment with fibrates, statins, and omega-3 fatty acids, many patients remain inadequately controlled. This systematic review, conducted in accordance with PRISMA 2020 guidelines, sought to comprehensively map the genetic architecture of SHTG, correlate genotypes with clinical phenotypes, and evaluate outcomes from emerging targeted therapies.

The review queried PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from January 2005 through August 2025, identifying 550 records and ultimately including 10 studies encompassing 2,521 patients. Study designs spanned observational cohorts, registries, and randomized controlled trials. Quality was assessed using ROBINS-I for observational studies and RoB-2 for interventional trials. Due to substantial between-study heterogeneity, results were synthesized descriptively rather than via formal meta-analysis.

A clear genotype–phenotype gradient emerged. Biallelic pathogenic variants in LPL, APOC2, GPIHBP1, or LMF1, the molecular basis of familial chylomicronemia syndrome (FCS), accounted for fewer than 5% of all SHTG cases but produced the most severe phenotypes: mean triglycerides exceeding 2,800 mg/dL and a pancreatitis prevalence above 70%. These patients exhibit classical features including eruptive xanthomas and lipemia retinalis and are largely refractory to conventional lipid-lowering therapy. Carriers of APOA5, APOC3, and APOB variants occupied an intermediate zone, with triglycerides in the 500–1,500 mg/dL range and high rates of metabolic dysfunction-associated steatotic liver disease (MASLD). APOB loss-of-function variants paradoxically impair VLDL export, promoting hepatic fat accumulation despite lower plasma cholesterol.

Polygenic hypertriglyceridemia represented approximately 70–80% of all cases, with median triglycerides around 2,200 mg/dL and a pancreatitis prevalence of 15–20%, strongly modulated by secondary metabolic triggers including obesity, insulin resistance, alcohol use, and uncontrolled diabetes. MASLD was present in over 70% of polygenic cases, supporting a proposed 'two-hit' model in which hepatic overproduction of triglyceride-rich lipoproteins amplifies circulating triglyceride excess. This bidirectional relationship between hepatic steatosis and impaired lipoprotein clearance represents a critical therapeutic target.

Emerging therapies demonstrated compelling efficacy. APOC3 antisense oligonucleotides (volanesorsen, olezarsen) achieved triglyceride reductions of 70–80%, while ANGPTL3 inhibition reduced triglycerides by 50–55%. GLP-1 receptor agonists reduced hepatic fat by 30–35% and resolved NASH in up to 59% of treated patients, making them particularly relevant for polygenic/MCS cases with concurrent fatty liver disease. The authors propose a precision-medicine framework: APOC3/ANGPTL3 inhibitors for FCS patients unresponsive to conventional therapy, and combined triglyceride-lowering plus metabolic agents for the polygenic majority.

These findings carry important implications for both clinical practice and health systems. Integrating polygenic risk scores with targeted gene panel testing could stratify patients more accurately, guiding therapy selection and reducing the burden of recurrent pancreatitis and progressive liver disease. The recognition that over 70% of SHTG patients carry polygenic risk interacting with modifiable metabolic factors also supports preventive lifestyle and metabolic interventions as first-line adjuncts. Notable caveats include the small number of included studies, descriptive rather than meta-analytic synthesis, and the short duration of most interventional trials.