👤 Julia Weinland

Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL cholesterol (LDL-C), and reduces apolipoprotein B (apoB) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. We conducted a coronary computed tomography angiography (CCTA) study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen vs. placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence or high risk for cardiovascular disease, and non-calcified plaque on baseline CCTA. The primary endpoint was percent change from baseline to 12 months in non-calcified plaque volume (NCPV). Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (IQR 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (IQR 197-331), and remnant cholesterol was 53 mg/dL (IQR 38-76). Median baseline NCPV was 125.3 mm Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. Show less

Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.). Show less