CLINICAL QUESTION
Does olezarsen (Tryngolza) reduce the risk of acute pancreatitis in people with severe hypertriglyceridemia, defined as at least 500 mg/dL (5.65 mmol/L)?
BOTTOM LINE
Olezarsen significantly lowers triglyceride levels and reduces episodes of acute pancreatitis (number needed to treat = 20 over 1 year). However, it is expensive—approximately $600,000 per year for patients with familial chylomicronemia syndrome. (Level of Evidence = 1b)
SYNOPSIS
Olezarsen targets messenger RNA to decrease production of apolipoprotein C-III, reducing hypertriglyceridemia. Olezarsen was originally approved for familial chylomicronemia syndrome as an orphan drug; the study attempts to expand the indication to patients with a triglyceride level of at least 500 mg/dL. The study is a combined report of two identical trials that randomized patients with a fasting triglyceride level of at least 500 mg/dL to receive olezarsen, 80 mg or 50 mg, or placebo given as a subcutaneous injection every 4 weeks for 48 weeks. Groups were balanced with a mean age of 54 years and a median triglyceride level of 793 mg/dL (8.96 mmol/L).
Approximately 25% of patients in one trial and 14% in the other had a previous episode of acute pancreatitis. Patients were followed up for 12 months; about 10% in each group dropped out, and analysis was by modified intention to treat including patients who received at least one dose. The drug was highly effective at reducing triglyceride levels: by 63% with the 50-mg dose and by 70% with the 80-mg dose compared with 0% to 14% in the placebo group. The patient-oriented outcome of acute pancreatitis events was significantly less likely in the pooled olezarsen group than in the placebo group (1.0 vs 6.2 events per 100 person-years; incidence rate ratio = 0.15; 95% CI, 0.05–0.40). This corresponds to a number needed to treat of 20. Adverse events leading to discontinuation were similar among groups (2.0% with placebo, 3.4% with 50 mg, and 4.3% with 80 mg). There was no difference among groups in cardiovascular events. Hepatic steatosis was nonsignificantly more common in the olezarsen groups (2.4% vs 1.1%; P = .17).
Study Design: Randomized controlled trial (double-blinded)
Funding Source: Industry
Allocation: Uncertain
Setting: Outpatient (any)
Reference: Marston NA, Bergmark BA, Alexander VJ, et al.; CORE-TIMI 72a and CORE2-TIMI 72b Investigators. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2026;394(5):429-441.
Editor’s Note: Dr. Ebell is cofounder and editor-in-chief of Essential Evidence Plus.
