The FDA approved olezarsen (brand name Tryngolza) in June 2026, making it the first drug ever cleared specifically to reduce the risk of acute pancreatitis in adults with severe hypertriglyceridemia — a disease that has caused preventable, agonizing crises for decades with no adequate pharmacologic solution.[1]
Severe hypertriglyceridemia (sHTG) is defined as fasting triglycerides consistently above 500 mg/dL, and often above 1,000 mg/dL. At those levels, the risk of acute pancreatitis — a potentially life-threatening and extremely painful emergency — rises substantially. Until olezarsen, the standard approach was maximal fibrate therapy, omega-3 fatty acids, and stringent dietary fat restriction. These measures help but rarely achieve the triglyceride reductions needed to meaningfully reduce pancreatitis risk.
Olezarsen is an antisense oligonucleotide (ASO) that silences APOC3, a protein that prevents lipoprotein lipase from clearing triglyceride-rich particles from the blood. With APOC3 suppressed, lipoprotein lipase clears triglycerides far more efficiently. The drug is given as a once-monthly subcutaneous injection.
The pivotal CORE and CORE2 trials enrolled adults with sHTG and demonstrated placebo-adjusted fasting triglyceride reductions of 49–72% at 6 months, depending on dose (50 mg or 80 mg) and trial.[2] In the pooled pancreatitis analysis, acute pancreatitis events at 12 months occurred at a pooled rate ratio of 0.15 (95% CI, 0.05–0.40; p<0.001) compared with placebo — an 85% relative reduction. Among patients receiving 80 mg, 86% achieved triglycerides below 500 mg/dL.[2]
Clinical Context
Acute pancreatitis due to hypertriglyceridemia is typically more severe than gallstone or alcohol-induced pancreatitis, with higher rates of pancreatic necrosis, ICU admission, and mortality. Patients with familial chylomicronemia syndrome (FCS) — caused by loss-of-function mutations in LPL, APOC2, APOA5, LMF1, or GPD1 — are particularly vulnerable, sometimes suffering pancreatitis attacks multiple times per year. Olezarsen was previously approved for FCS; this supplemental approval extends it to the broader sHTG population.
Fibrates reduce triglycerides by 30–50% in most patients but have modest effects in those with genetic forms of sHTG. Omega-3 fatty acids (icosapent ethyl, omega-3-acid ethyl esters) provide additional reductions but rarely enough to eliminate pancreatitis risk in the highest-risk patients.
If you have a patient with fasting triglycerides consistently above 500 mg/dL — especially above 1,000 mg/dL — despite maximal conventional therapy, olezarsen is now an option. The once-monthly injection makes adherence more achievable than daily oral fibrates. The main barriers will be cost and prior authorization. For patients with recurrent hypertriglyceridemia-induced pancreatitis, the clinical case for access is compelling.
Limitations
The pancreatitis reduction data, while striking, come from a relatively small number of events across short follow-up. The trial was not powered as a pancreatitis outcomes trial; the reduction was demonstrated in a secondary analysis. Long-term cardiovascular outcome data for olezarsen are not yet available. Cost will be a significant barrier for most patients.
References
[1] FDA Press Release. FDA Approves Olezarsen (Tryngolza) for Adults with Severe Hypertriglyceridemia. June 2026. [Drug Topics]
[2] Bergmark BA, et al. Olezarsen for Severe Hypertriglyceridemia (CORE and CORE2 Trials). N Engl J Med. 2024. DOI: 10.1056/NEJMoa2402426. [PubMed]