Key Points
- In this sub study of coronary computed tomography angiography (CCTA) within Essence-TIMI 73b trial, olezarsen produced profound reductions in triglycerides (~64%) and remnant cholesterol but minimal LDL-C change.
- Despite robust lipid effects, there was no significant reduction in non-calcified plaque volume at 12 months.
- No meaningful differences were observed in low-attenuation (high-risk) plaque or other plaque subtypes.
- Findings challenge the assumption that targeting triglyceride-rich lipoproteins (TRLs) alone modifies coronary atherosclerosis over short-term follow-up.
Triglyceride-rich lipoproteins (TRLs) and remnant cholesterol have been increasingly implicated in atherosclerotic cardiovascular disease risk, with some data suggesting they may confer risk independent of LDL cholesterol. Apolipoprotein C-III (APOC3) regulates TRL metabolism, and genetic loss-of-function variants are associated with lower triglycerides and reduce coronary artery disease risk. Olezarsen, an antisense oligonucleotide targeting APOC3, has demonstrated potent triglyceride-lowering effects. However, whether this translates into structural changes in coronary atherosclerosis remains uncertain.
The Essence-TIMI 73b trial (NCT05610280; N = 1478) randomized patients with moderate-to-severe hypertriglyceridemia and elevated cardiovascular risk to olezarsen (50 mg or 80 mg subcutaneously every 4 weeks) versus placebo. The study design was published in American Heart Journal and the results of the main trial in NEJM in 2025.
The coronary CTA sub study included 468 patients with quantifiable non-calcified plaque volume (NCPV) at baseline and follow-up imaging at 12 months. The primary endpoint was placebo-adjusted percent change in NCPV; key secondary endpoints included low-attenuation plaque volume (LAPV) and other plaque components. Approximately 400 paired scans were targeted for adequate power. This sub study was simultaneously published in Circulation.
Olezarsen significantly reduced triglycerides by ~64% (absolute reduction ~132 mg/dL), with parallel reductions in remnant cholesterol (~61%), VLDL-C (~72%), and modest reductions in apolipoprotein B (~16%), while LDL-C remained largely unchanged.
Despite these favorable biomarker changes, the primary imaging endpoint was neutral: placebo-adjusted change in NCPV was +3.0% (95% CI -3.36 to 9.33; p=0.36). Similarly, there was no significant effect on LAPV (-68.2% relative difference; p=0.50) or other plaque subtypes including fibrous, fibrofatty, and calcified components. Notably, plaque progression in the placebo group was minimal, likely reflecting high baseline use of standard lipid-lowering therapies.
This sub study highlights a potential disconnect between triglyceride lowering and short-term modification of coronary plaque burden. While APOC3 inhibition robustly improves atherogenic lipid profiles, these changes did not translate into measurable differences in coronary atherosclerosis over 12 months. The findings suggest that TRL and remnant cholesterol reduction alone may not exert rapid structural benefits comparable to LDL-C lowering, or that longer treatment duration may be required.
Limitations include relatively short follow-up, reliance on CCTA rather than intravascular imaging, and a well-treated population with limited plaque progression. Importantly, genetic data linking APOC3 to lifetime cardiovascular risk reduction leaves open the possibility that longer-term outcomes may differ. As presented by Nicholas Marston, MD, “These data do not support the hypothesis that reductions in remnant cholesterol and TRLs have an outsized cardiovascular benefit compared with reductions in LDL-C.”