Olezarsen lowers triglycerides and acute pancreatitis risk in severe hypertriglyceridemia with diabetes, phase 3 trial analyses show
Presenter: Yu Mi Kang, MD, PhD, MPH, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA
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. Presented June 6, 2026.
Olezarsen, an investigational antisense drug, sharply reduced triglycerides while also lowering the rate of acute pancreatitis in patients who had both severe hypertriglyceridemia and diabetes, according to data presented at the American Diabetes Association 2026 Scientific Sessions.
The triglyceride reductions were large and nearly identical whether or not patients had diabetes, ranging from 57% to 65% depending on dose, study authors reported in an analysis of two phase 3 trials.
The triglyceride-lowering effect of olezarsen was preserved in this higher-risk group, according to Yu Mi Kang, MD, PhD, MPH, and co-authors.
Patients with diabetes carried a substantially higher risk of acute pancreatitis than those without, both before and during the trials, they explained in their report.
Olezarsen lowers production of apolipoprotein C-III, a liver protein that regulates triglyceride metabolism. The authors set out to examine whether that triglyceride lowering held in patients with diabetes, a group in whom severe hypertriglyceridemia and a heightened risk of acute pancreatitis often coincide.
The analysis pooled patients from CORE-TIMI 72a (NCT05079919; N = 617) and CORE2-TIMI 72b (NCT05552326; N = 446), two phase 3, multicenter, randomized, double-blind, placebo-controlled trials conducted with the TIMI Study Group.
Adults with triglyceride levels of 500 mg/dL or higher, all on standard-of-care lipid therapy, were randomly assigned 1:1:1 to receive subcutaneous olezarsen 50 mg, olezarsen 80 mg, or placebo every 4 weeks for 12 months. The primary endpoint was the placebo-adjusted percent change in triglycerides at 6 months, with acute pancreatitis among the secondary endpoints.
Of 1,063 patients, 673 (63%) had diabetes, the authors reported. In that group, the median hemoglobin A1c level was 7.3%, and the median duration of diabetes was 9 years. A total of 37% were taking insulin, and 25% were on a glucagon-like peptide 1 receptor agonist.
Baseline triglyceride levels were similar in patients with and without diabetes (median 784 vs 807 mg/dL, P = .43), but those with diabetes were more likely to have had a prior episode of acute pancreatitis (21% vs 14%, P = .005), reported results show.
During the trials, patients with diabetes had a 3.6-fold higher rate of acute pancreatitis than those without (3.76 vs 1.04 events per 100 patient-years, incidence rate ratio 3.6 [95% confidence interval 1.1–12.0], P = .034), the investigators reported.
Compared with placebo, olezarsen lowered triglyceride levels by 57.4% at the 50-mg dose (95% confidence interval 48.6–66.2) and by 64.8% at the 80-mg dose (95% confidence interval 56.0–73.6) among patients with diabetes. The reductions were essentially the same in patients without diabetes, at 57.0% (95% confidence interval 45.7–68.3) and 65.1% (95% confidence interval 53.9–76.4), respectively.
Pooled across the two active doses, olezarsen lowered the rate of acute pancreatitis relative to placebo, with an absolute reduction of 6.91 events per 100 patient-years among patients with diabetes, and 2.86 events per 100 patient-years among those without, the authors also reported.
Olezarsen lowered triglycerides by 57% to 65% and reduced the risk of acute pancreatitis in patients with severe hypertriglyceridemia and diabetes, a population at higher baseline risk for pancreatitis, the authors concluded.
Olezarsen is approved in the United States and the European Union for the treatment of familial chylomicronemia syndrome. In February 2026, the US Food and Drug Administration (FDA) accepted a supplemental new drug application for olezarsen in severe hypertriglyceridemia for priority review, with a target action date of June 30, 2026.
The FDA filing rested on the overall CORE and CORE2 results, in which olezarsen produced placebo-adjusted triglyceride reductions of up to 72% and an 85% reduction in acute pancreatitis events across the full trial population, figures distinct from the diabetes-subgroup results reported here.
Disclosures
The CORE trials were funded by Ionis Pharmaceuticals through an institutional research grant to the TIMI Study Group at Brigham and Women's Hospital. Presenting author Yu Mi Kang, MD, PhD, MPH, reported no disclosures. Several co-authors are employees of or shareholders in Ionis Pharmaceuticals.
References
Kang YM, Bergmark B, Alexander VJ, et al. 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. Abstract 1217-OR. ADA 2026 Scientific Sessions. June 6, 2026.
Ionis Pharmaceuticals. Olezarsen sNDA accepted by the FDA for priority review for the treatment of severe hypertriglyceridemia (sHTG). Press release, February 26, 2026.
Feroz K, Parvez A, Ramzan NUH, et al. Efficacy and safety of olezarsen in patients with hypertriglyceridemia: a meta-analysis of randomized controlled trials. Cardiovascular Therapeutics 2026; 2026:9984822. doi:10.1155/cdr/9984822.