Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk - CORE-TIMI 72a and CORE2-TIMI 72b

Nov 24, 2025

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Author/Summarized by Author:
Carlos A Vergara Sanchez, MD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC; R. Scott Wright, MD, FACC
Original Posted Date:
11/24/2025
On this page:
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Contribution To Literature:

CORE-TIMI 72a and CORE2-TIMI 72b trials found that olezarsen significantly reduced triglyceride levels at 6 months, as well as decreased the incidence of acute pancreatitis.

Study Design:

  • Total number of enrollees: 1,061 patients
    • CORE-TIMI 72a: 617 patients
    • CORE2-TIMI 72b: 444 patients
  • Randomization 1:1:1 ratio
    • Monthly administration of olezarsen 50 mg, olezarsen 80 mg, or placebo.
  • Duration of follow-up: 12 months
  • Median patient age: 55 years
  • Demographics (i.e., gender and race, etc.):
  CORE-TIMI 72a CORE2-TIMI 72b
Characteristics Placebo (n=208) Olezarsen, 50 mg (n=205) Olezarsen, 80 mg (n=204) Placebo (n=148) Olezarsen, 50 mg (n=149) Olezarsen, 80 mg (n=147)
Female- no. (%) 42 (20.2) 52 (25.4) 53 (26) 27 (18.2) 39 (26.2) 37 (25.2)
White 195 (93.8) 191 (93.2) 189 (92.6) 124 (83.8) 125 (83.9) 114 (77.6)
Black 7 (3.4) 2 (1.0) 4 (2) 1 (0.7) 3 (2) 5 (3.4)
Asian 5 (2.4) 3 (1.5) 4 (2.0) 17 (11.5) 15 (10.1) 13 (8.8)
Hispanic or Latino 10/202 (5) 7/195 (3.6) 12/200 (6) 31/148 (20.9) 33/149 (22.1) 35/147 (23.8)

Principal Findings:

Primary outcome:

  • Percentage change in triglyceride levels at 6 months
Variable CORE-TIMI 72a

CORE2-TIMI 72b
Triglycerides Placebo Olezarsen, 50 mg Olezarsen, 80 mg Placebo Olezarsen, 50 mg Olezarsen, 80 mg
At baseline - mg/dL 1,208 +/- 1,295.4 1,168.9 +/- 825.8 1,168 +/- 973.7 1018.6 +/- 1053.7 967.8 +/- 599.9 1088.4 +/- 964.5
At 6 months - mg/dL 1083.7 +/- 1,105.1 389.9 +/- 581.6 267.1 +/- 300.5 809.6 +/- 935.4 315.3 +/- 383.8 289.6 +/- 349
Placebo-adjusted least-squares mean (LSM)- %   -62.9 (-72.2 to -53.6) p<0.001 -72.2 (-81.4 to -63.1) p<0.001   -49.2 (-59.7 to -38.8) p<0.001 -54.5 (-65.1 to -44) p<0.001

Secondary outcomes:

Percentage change from baseline in:

  • Triglyceride level at 12 months
  • Apolipoprotein C-III
  • Remnant cholesterol
  • Non-high-density lipoprotein (non-HDL)

Acute pancreatitis events:

  • Mean rate ratio: 0.15 (95% CI, 0.05 to 0.40); p<0.001.
  • Number needed to treat (NNT):
    • Overall: 20
    • High-risk group (prior pancreatitis): 4

Safety:

  • No significant differences in:
    • Adverse events
    • Serious adverse events
    • Discontinuation due to adverse events across Olezarsen and placebo groups during the 12-month treatment period.
Variable CORE-TIMI 72a CORE2-TIMI 72b
Apolipoprotein C-III Placebo Olezarsen, 50 mg Olezarsen, 80 mg Placebo Olezarsen, 50 mg Olezarsen, 80 mg
At baseline - mg/dL 37.4 +/- 15.9 39.4 +/- 16 36.9 +/- 15 36.5 +/- 13.6 38 +/- 15.6 36.9 +/- 14.8
At 6 months - mg/dL 35.3 +/- 18.1 10.8 +/- 10.9 6.9 +/- 7.4 31.5 +/- 17 11.7 +/- 13.2 8.3 +/- 9.4
Placebo-adjusted least-squares mean (LSM)- %   -68.3 (-73.9 to -62.8) p<0.001 -77.4 (-83 to -71.9) p<0.001   -56.5 (-63.9 to -49.2) p<0.001 -63.5 (-70.9 to -56) p<0.001
Remnant Cholesterol            
Placebo-adjusted least-squares mean (LSM)- %   -57.2 (-65.3 to -49.2); p<0.001 -70.1 (-77.9 to -62.2) p<0.001   -50.6 (-62.4 to -38.7) p<0.001 -52.2 (-64.2 to -40.1) p<0.001
Non- HDL Cholesterol            
Placebo-adjusted least-squares mean (LSM)- %   -24.8 (-30.3 to -19.3) p<0.001 -32.6 (-38 to -27.3) p<0.001   -19.3 (-25.3 to -13.3) p<0.001 -22.3 (-28.4 to -16.1) p<0.001

Interpretation:

In patients with persistent severe hypertriglyceridemia despite optimal standard lipid-lowering therapies, olezarsen administered monthly at 50 mg or 80 mg demonstrated a dose-dependent reduction in triglycerides, with nearly half of patients achieving normalization at the highest dose. Additionally, significant reductions in apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were observed. The treatment was associated with a marked reduction in acute pancreatitis risk, particularly in high-risk individuals, with no significant safety concerns identified.


References

Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for Managing Severe Hypertriglyceridemia and Pancreatitis Risk. N Engl J Med. Published online Nov. 8, 2025. doi:https://doi.org/10.1056/nejmoa2512761

Presented by Nicholas A. Marston, MD, at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 8, 2025.

Resources

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia

Keywords: AHA25, AHA Annual Scientific Sessions, Dyslipidemias, Metabolic Syndrome