Objective

To investigate the effect of olezarsen, an antisense oligonucleotide to apolipoprotein CIII (APOC3), on coronary plaque in adults with largely moderate hypertriglyceridemia.

Study design

A computed tomography coronary angiography (CCTA) imaging substudy of the Essence-TIMI 73b trial, a multicentre, randomized, double-blind, placebo-controlled trial of olezarsen versus placebo in adults with largely moderate hypertriglyceridemia.

Study population

Essence-TIMI 73b enrolled adults with moderate hypertriglyceridemia (triglycerides ≥150 mg/dL or ≥2.26 mmol/L) and increased cardiovascular risk or severe hypertriglyceridemia (triglycerides ≥500 mg/dL or ≥5.6 mmol/L) on stable, standard-of-care background lipid-lowering therapy. The key inclusion for the imaging substudy was the presence of non-calcified plaque on the baseline CCTA, defined as tissue ≥1 mm³ within or adjacent to the coronary lumen that can be separated from the surrounding epicardial fat and other tissues.

Main study variables

The primary endpoint was the placebo-adjusted percent change from baseline to 12 months in coronary non-calcified plaque volume (NCPV). The key secondary endpoint was the placebo-adjusted percent change in low-attenuation plaque volume.

Methods

Eligible patients§ with quantifiable non-calcified plaque were enrolled in the imaging study and underwent repeat CCTA at 12 months. NCPV was defined as coronary plaque with attenuation <350 Hounsfield units (HU) and was quantified in mm³. Patient-level NCPV was calculated by summing plaque volumes across all coronary segments evaluable at both baseline and 12 months; segments not evaluable at both timepoints were excluded from baseline and follow-up totals. Plaque subcomponents were defined as low-attenuation plaque (<30 HU), fibro-fatty plaque (30–59 HU), fibrous plaque (60–349 HU), and calcified plaque (≥350 HU); total plaque was the sum of these components.

The prespecified primary analysis compared pooled olezarsen (both 50 mg and 80 mg doses) versus pooled placebo. The percent change in NCPV was evaluated using analysis of covariance with treatment group as a factor and baseline NCPV and triglyceride stratum (<500 vs ≥500 mg/dL) as covariates.

Results

In total, 468 patients were enrolled in the CCTA analysis cohort, 349 assigned to olezarsen (254 to 80 mg, 95 to 50 mg) and 119 assigned to placebo. Baseline characteristics of the two groups were generally similar, with median age 63 years and 31.2% female. At baseline, median triglycerides were 249 mg/dL (interquartile range [IQR], 197–331), remnant cholesterol 53 mg/dL (IQR, 38–76), LDL-C 81 mg/dL (IQR, 60–109), and apolipoprotein (apo)B 93 mg/dL (IQR, 76-111). Almost all (97.4%) patients received at least one background lipid-lowering medication, predominantly a statin (78.6%). 

At 6 months, treatment with olezarsen reduced triglycerides by a least-squares mean of 63.9% (95% confidence interval [CI], 49.0 to 78.8) compared with placebo (p<0.001), with the effect largely sustained at 12 months. Treatment with olezarsen also significantly reduced remnant cholesterol by 71.9%, non-high-density lipoprotein cholesterol by 22.9%, and apoB by 16.0% compared with placebo (all p<0.001). There was no difference between the groups in the change in LDL-C at 12 months.

The percent change in NCPV from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference 2.98%, 95% CI -3.36 to 9.33; p=0.36). The median percent change in NCPV was -3.91% (IQR, -22.12 to 8.83) with placebo and -5.35% (IQR,           -17.51 to 11.91) with olezarsen. Additionally, the key secondary endpoint did not differ between olezarsen and placebo at 12 months.

Author conclusions

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 non-calcified coronary plaque volume.