BACKGROUND: Patients with severe hypertriglyceridemia have an increased risk of acute pancreatitis. The efficacy and safety of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III messenger RNA, have not been established in this population.
METHODS: We conducted two double-blind, randomized, placebo-controlled trials (CORE-TIMI 72a and CORE2-TIMI 72b). Patients with severe hypertriglyceridemia were assigned in a 1:1:1 ratio to receive olezarsen at a dose of 50 mg, olezarsen at a dose of 80 mg, or placebo monthly for 12 months. The primary outcome was the percent change from baseline in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group (placebo-adjusted change). Secondary lipid outcomes included the percent change from baseline in the triglyceride level at 12 months and in the levels of apolipoprotein C-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at 6 months and 12 months. Acute pancreatitis events were assessed across both trials.
RESULTS: A total of 1061 patients were included in the primary analysis (617 in the CORE-TIMI 72a trial and 444 in the CORE2-TIMI 72b trial). At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was -49.2 percentage points in the olezarsen 50-mg group and -54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (P<0.001 for all comparisons of olezarsen with placebo). Decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons). The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001). The incidence of any adverse events appeared to be similar across trial groups. Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000 per microliter) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted.
CONCLUSIONS: Among patients with severe hypertriglyceridemia, treatment with olezarsen led to a significantly greater reduction in the triglyceride level at 6 months and in the incidence of acute pancreatitis than placebo. (Funded by Ionis Pharmaceuticals; CORE-TIMI 72a and CORE2-TIMI 72b ClinicalTrials.gov numbers, NCT05079919 and NCT05552326.).
| Discipline Area | Score |
|---|---|
| Internal Medicine |  |
| Cardiology |  |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
This is an informative and well-designed study with clear clinical relevance for patients with severe hypertriglyceridemia who are frequently referred to specialist care. The large reductions in triglycerides and cholesterol, as well as the reduction in acute pancreatitis events, are clinically meaningful. Although olezarsen is unlikely to become a first-line therapy in primary care, the results help inform risk assessment and timely referral of patients with very high triglycerides. Given the potential impact on liver enzyme elevations, thrombocytopenia, and increased hepatic fat fraction, there is a need for careful monitoring should this therapy move into broader clinical use.
Hypertriglyceridemia is associated with frequent episodes of pancreatitis. Measuring triglyceride levels only makes sense in cases of unexplained pancreatitis (and unexplained elevated transaminases). Only patients with extremely elevated triglycerides (750-845 mg/dL) were included (11.4-25% had already had pancreatitis). Only triglyceride and other lipids were endpoints. The absolute risk reduction of 5.22% pancreatitis cases appears relevant, but generalizing this statement would require a study specifically designed for this purpose. 86% of pancreatitis cases occurred with triglyceride 880 mg/dl or higher – or with history of pancreatitis. In this high-risk group, the risk reduction was 32.5%/year. If significantly elevated triglycerides are found in individuals with pancreatitis or if triglycerides are repeatedly above 800 mg/dL in incidental findings, even after dietary measures or antihyperglycemic therapy, then olezarzen could be an option for (recurring) pancreatitis.