Lipid-efficacy RCT · N Engl J Med 2026
CORE/CORE2 trial
Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk.
The bottom line
In patients with severe hypertriglyceridemia, olezarsen substantially lowered triglycerides and reduced acute pancreatitis risk compared with placebo, though higher-dose treatment carried more liver enzyme and platelet-related side effects.
Primary lipid endpoint metUS status: US-approved
At a glance
- Medicine
- Olezarsen 50 mg or 80 mg monthly for 12 months
- Compared with
- Placebo
- People
- 1,061
- Who took part
- Patients with severe hypertriglyceridemia
- Design
- Two double-blind, randomized, placebo-controlled trials
- Follow-up
- 12 months
- Main question
- Percent change in triglyceride level at 6 months (placebo-adjusted)
Main result
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).
Effect on LDL cholesterol
Not specifically reported; decreases in triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons)
Other results
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).
Safety
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.
In the trial's own words
“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).”
Quoted from the abstract of N Engl J Med 2026, checked word for word against PubMed. PubMed 41211918 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Olezarsen (Tryngolza) and volanesorsen
Common questions
What did the CORE/CORE2 trial find?
In patients with severe hypertriglyceridemia, olezarsen substantially lowered triglycerides and reduced acute pancreatitis risk compared with placebo, though higher-dose treatment carried more liver enzyme and platelet-related side effects.
Who was in CORE/CORE2?
1,061 people. Patients with severe hypertriglyceridemia.
What was CORE/CORE2's main result?
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).
How much did LDL cholesterol change in CORE/CORE2?
Not specifically reported; decreases in triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons)
Related trials
- CTX310 phase 1 (2025)A single dose of the CRISPR-Cas9 gene-editing therapy CTX310 was generally well tolerated and produced dose-dependent reductions in ANGPTL3 levels, supporting further clinical development for dyslipidemia.
- ESSENCE-TIMI 73b (2025)In patients with moderate hypertriglyceridemia and elevated cardiovascular risk, olezarsen significantly lowered triglyceride levels at 6 months compared with placebo, with similar rates of serious adverse events.
- PALISADE (2025)In patients with persistent chylomicronemia, plozasiran (siRNA against APOC3) sharply lowered triglycerides and reduced acute pancreatitis episodes compared with placebo, with a similar overall adverse event rate but a signal for hyperglycemia in those with prediabetes/diabetes.
- PROLONG-ANG3 (2025)In adults with mixed dyslipidaemia on background statin therapy, solbinsiran 400 mg significantly reduced apoB levels compared with placebo and was generally well tolerated, though its effect on cardiovascular outcomes is still unknown.
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