What is the clinical evidence from this study?

Study design: RCT. Population: Severe hypertriglyceridemia and diabetes mellitus (n=1063). Intervention: Olezarsen vs. Placebo. Primary outcome: Placebo-adjusted % change in TGs at 6 months (64.8% reduction, 95% CI 56.0-73.6).

What question did this study set out to answer?

Assess the efficacy of olezarsen in lowering triglycerides and pancreatitis risk in patients with severe hypertriglyceridemia and diabetes mellitus.

June 8, 2026

1217-OR: ApoC3 Inhibitor Olezarsen Markedly Reduces Triglycerides and Risk of Pancreatitis in Severe Hypertriglyceridemia Patients with Diabetes Mellitus: Insights from CORE-TIMI 72a and CORE2-TIMI 72b

Q: What does this research mean for the field?

Olezarsen significantly reduces triglycerides by 57-65% and lowers the risk of acute pancreatitis in patients with severe hypertriglyceridemia and diabetes mellitus. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

Olezarsen 80 mg reduced triglycerides by 64.8% (95% CI 56.0-73.6) compared with placebo in patients with severe hypertriglyceridemia and diabetes, and reduced the risk of acute pancreatitis.

Key Points

Assess the efficacy of olezarsen in lowering triglycerides and pancreatitis risk in patients with severe hypertriglyceridemia and diabetes mellitus.
Randomized controlled trials CORE-TIMI 72a (N=617) and CORE2-TIMI 72b (N=446)
Participants received subcutaneous olezarsen 50 mg or 80 mg versus placebo every four weeks for 12 months
Primary endpoint was % change in triglycerides at 6 months, with secondary endpoints including acute pancreatitis incidents.
Olezarsen reduced triglycerides by 57.4% (50 mg) and 64.8% (80 mg) in patients with diabetes, compared to placebo.
Absolute reduction of acute pancreatitis incidents was 6.91/100PY in diabetic patients receiving olezarsen.
Patients with diabetes were at a 3.6-fold increased risk for pancreatitis compared to non-diabetic patients.

Study Design

Type

RCT (n=1,063)

Randomization

1:1:1

Structured PICO

Does olezarsen reduce triglycerides and the risk of acute pancreatitis in patients with severe hypertriglyceridemia and diabetes mellitus?

Population

1,063 patients with severe hypertriglyceridemia (TG ≥500mg/dL), 63% of whom had diabetes mellitus, randomized to olezarsen or placebo for 12 months.

Intervention

Olezarsen 50 mg or 80 mg subcutaneous every 4 weeks for 12 months

Comparator

Placebo subcutaneous every 4 weeks for 12 months

Outcome

Placebo-adjusted % change in triglycerides at 6 monthssurrogate

Olezarsen significantly reduces triglycerides and the risk of acute pancreatitis in patients with severe hypertriglyceridemia, particularly those with comorbid diabetes mellitus.

Main Result

Effect estimate: 64.8% reduction (95% CI 56.0-73.6)

Abstract

Introduction and Objective: We assessed the efficacy of olezarsen, an antisense oligonucleotide targeting APOC3, in pts with severe hypertriglyceridemia (sHTG) and DM. Methods: The phase 3 RCTs CORE-TIMI 72a (N=617) and CORE2-TIMI 72b (N=446) randomized pts with sHTG (TG ≥500mg/dL) 1:1:1 to SC olezarsen 50mg, 80mg, or placebo Q4W for 12 mths. The primary endpoint was placebo-adjusted % change in TGs at 6 mths. Secondary endpoints included acute pancreatitis (AP). Results: Of 1,063 pts, 673 (63%) had DM (median HbA1c 7.3% IQR 6.6-8.2; DM duration 9 4-14 yrs; 25% on GLP-1RAs and 37% on insulin). Baseline TGs were similar in pts with DM (median 784 IQR 589-1,224 mg/dL) vs w/o DM (807 606-1,269 mg/dL; P=0.43), but those with DM were more likely to have had prior AP (21% vs. 14%; p=0.005). During the trial, pts with DM were at a 3.6-fold higher risk of AP compared with pts w/o DM (IR 3.76 vs 1.04/100PY; IRR 3.6 1.1-12.0, P=0.034). Compared with placebo, the 50 mg Current; Amgen, Ionis, Pfizer, Philips, Inari, AstraZeneca, Abbott Vascular. Consultant; Current; Shockwave, Teleflex, Abbott Vascular, Abiomed, Bain Life Science, Morgan Stanley, SpectraWAVE, Bolt, Boston Scientific. V.J. Alexander: Employee; Current; Ionis Pharmaceuticals. T.A. Prohaska: Employee; Current; Ionis Pharmaceuticals. Stock/Shareholder; Current; Ionis Pharmaceuticals. X. Ran: Other - Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital to conduct the CORE trials; Current; Ionis Pharmaceuticals. Other - I am a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi-Sankyo, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche,; Current; other company. S. Murphy: Other - Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital to conduct the CORE trials; Current; Ionis Pharmaceuticals. Other - I am a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi-Sankyo, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche,; Current; Many - see Other field. E.L. Goodrich: Other - Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital; Current; Ionis Pharmaceuticals. F. Moura: None. A. Zimerman: Advisory Panel; Ended; Novartis Pharmaceuticals Corporation. Speaker's Bureau; Ended; Novartis Pharmaceuticals Corporation. E. Waldman: Employee; Current; Ionis Pharmaceuticals. J. Weinland: Employee; Current; Ionis Pharmaceuticals. Stock/Shareholder; Current; Ionis Pharmaceuticals. S. Zhang: None. S. Xia: Employee; Current; Ionis Pharmaceuticals. D. Li: None. S. Tsimikas: Employee; Current; Ionis Pharmaceuticals. R.P. Giugliano: Research Support; Current; Amgen Inc., Daiichi Sankyo, Ionis Pharmaceuticals, Novartis AG. Other - Honoraria for Academic Lectures / CME programs; Current; Amgen Inc., Daiichi Sankyo. Other - Honoraria for Academic Lectures / CME programs; Ended; Dr. Reddy’s Laboratories Ltd. Other - Honoraria for Academic Lectures / CME programs; Current; Medical Education Resources. Other - Honoraria for Academic Lectures / CME programs; Ended; SUMMEET. Consultant; Current; Daiichi Sankyo, Inventiva Pharma. M.S. Sabatine: Other - Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital; Consulting; Current; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH. Research Support; Current; Inno Medicine, Ionis Pharmaceuticals, Marea. Other - Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital; Consulting; Current; Merck Current; Novartis AG, Pfizer Inc. Consultant; Current; General Medicines. N. Marston: Research Support; Current; Ionis Pharmaceuticals. Advisory Panel; Current; Ionis Pharmaceuticals. Research Support; Current; Amgen Inc. Advisory Panel; Current; Amgen Inc. Research Support; Current; Marea Therapeutics. Advisory Panel; Current; Arrowhead Pharmaceuticals, Inc. Advisory Panel; Ended; New Amsterdam. Advisory Panel; Current; Radence, Arboretum.

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