Effect of Olezarsen on Coronary Plaque in Moderate Hypertriglyceridemia

30 Mar 20264 min read0 viewsJournal Feed

GIST

Circulation, Ahead of Print. Background: 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.Methods: 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).Results: 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 mm³(IQR 63.2—213.3).

Clinical Editorial

Study design and scope

The investigation was embedded in Essence-TIMI 73b, a randomized, placebo-controlled trial comparing olezarsen versus placebo.
Eligible adults had triglycerides ≥150 mg/dL, elevated cardiovascular risk or disease presence, and baseline non-calcified coronary plaque on CCTA.
The primary imaging endpoint assessed the percent change from baseline to 12 months in non-calcified plaque volume (NCPV).
The analysis leveraged coronary computed tomography angiography (CCTA) data collected at predefined intervals.

Population and baseline characteristics

Enrolled participants totaled 468 (349 receiving olezarsen, 119 placebo).
Median age was 63 years (interquartile range 56–70); 31% were women.
Most participants (97%) were on standard-of-care lipid-lowering therapy.
Baseline triglycerides averaged around 249 mg/dL (IQR 197–331), and remnant cholesterol averaged 53 mg/dL (IQR 38–76).
Median baseline NCPV was 125.3 mm³ (IQR 63.2–213.3).

Biochemical and plaque response signals

At 6 months, olezarsen achieved substantial lipid changes atop standard therapy: triglycerides reduced by approximately 63.9%, remnant cholesterol by about 71.9%, and apolipoprotein B by ~16% compared with placebo.
LDL-C remained unchanged with olezarsen relative to placebo at 6 months.

Imaging outcomes and interpretation

The primary plaque outcome—percent change in NCPV from baseline to month 12—showed no differential effect of olezarsen versus placebo after adjustment (placebo-adjusted least-squares mean difference 2.98%; 95% CI −3.4 to 9.3; p = 0.36).
No significant differences were observed between olezarsen and placebo for changes in low-attenuation, calcified, or total plaque volumes at 12 months.

Context and limitations

Despite marked reductions in triglyceride-rich lipoproteins and remnant cholesterol, olezarsen did not alter non-calcified coronary plaque volume over 12 months when added to contemporary lipid-lowering therapy in a population largely characterized by moderate hypertriglyceridemia.
The report represents a single imaging cohort within a larger trial; results pertain to non-calcified plaque volume and related plaque subtypes as measured by CCTA.
Limitations of the study are not extensively detailed in the provided content; uncertainty remains regarding longer-term outcomes or effects in different triglyceride strata.