What happened
Olezarsen fails to reduce noncalcified coronary plaque volume despite substantial triglyceride and remnant cholesterol lowering.
Both trial investigators agree that despite robust triglyceride lowering, the neutral plaque result means a dedicated cardiovascular outcomes trial is needed before clinical benefit can be claimed.
Experts acknowledge olezarsen's dramatic triglyceride lowering but note the neutral plaque imaging result leaves cardiovascular benefit unproven, with a outcomes trial still needed.
Olezarsen produced large triglyceride and remnant cholesterol reductions but failed to shrink coronary plaque at 12 months, leaving experts cautious about its clinical payoff. Investigators frame the lipid data as informative while stressing that a cardiovascular outcomes trial is the necessary next step. The open question is whether long-term treatment or combination therapy could translate these lipid changes into hard clinical benefit.
Whether longer treatment duration or combination with another lipid-lowering therapy could produce plaque or outcomes benefit remains unanswered.
It is also unclear why such large triglyceride and remnant cholesterol reductions did not translate into measurable plaque regression at 12 months.
“Treatment with olezarsen on top of standard of care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia substantially lowers triglycerides and remnant cholesterol and modestly lowers ApoB, but did not affect non-calcified coronary plaque volume at 12 months.”
News Coverage ↗From published coverage, not an answer posted here.
Brian Bergmark
Results readoutInterventional cardiologist, Brigham and Women's HospitalTriglyceride lowering exceeded existing therapies, but broader efficacy is not yet established
Original post ↗Børge Nordestgaard
ContextProfessor, Copenhagen University HospitalCalled the trial results very, very important
Original post ↗“The positive results of this study are an important step in bringing forward a potential new treatment for people with severely elevated triglycerides. Following the FDA approval and encouraging launch of TRYNGOLZA (olezarsen) for people living with familial chylomicronemia syndrome (FCS), a rare, genetic form of severely elevated TGs, these data support olezarsen's potential to benefit the much broader population of people living with sHTG.”
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Why the trial, key points, tables, limitations, PICO, abstract, media & sources
Why the trial?
The trial was conducted to evaluate whether olezarsen treatment, in addition to standard lipid-lowering therapy, could reduce noncalcified coronary plaque volume in patients with moderate hypertriglyceridemia.
Does olezarsen reduce non-calcified plaque volume in adults with moderate hypertriglyceridemia and cardiovascular risk?
RCT (n=468)
Randomized
Does olezarsen reduce non-calcified plaque volume in adults with moderate hypertriglyceridemia and cardiovascular risk?
Despite significant reductions in triglycerides and remnant cholesterol, APOC3 inhibition with olezarsen did not reduce noncalcified coronary plaque volume at 12 months.
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Expert reaction
Circulation · ACC Annual Scientific Session 2025
3 experts quoted, 1 with a clear stance so far. We show the split once 3 have one.
Expert labels are toward ESSENCE-TIMI 73b's result, from named public quotes (n=1). As of Oct 8, 2026.
Experts acknowledge olezarsen's dramatic triglyceride lowering but note the neutral plaque imaging result leaves cardiovascular benefit unproven, with a outcomes trial still needed.
Olezarsen produced large triglyceride and remnant cholesterol reductions but failed to shrink coronary plaque at 12 months, leaving experts cautious about its clinical payoff. Investigators frame the lipid data as informative while stressing that a cardiovascular outcomes trial is the necessary next step. The open question is whether long-term treatment or combination therapy could translate these lipid changes into hard clinical benefit.
Both trial investigators agree that despite robust triglyceride lowering, the neutral plaque result means a dedicated cardiovascular outcomes trial is needed before clinical benefit can be claimed.
Whether longer treatment duration or combination with another lipid-lowering therapy could produce plaque or outcomes benefit remains unanswered. It is also unclear why such large triglyceride and remnant cholesterol reductions did not translate into measurable plaque regression at 12 months.
Marston reported that olezarsen on top of standard lipid-lowering therapy substantially lowers triglycerides and remnant cholesterol and modestly lowers ApoB, but did not affect non-calcified coronary plaque volume at 12 months. He concluded that a cardiovascular outcomes trial is needed to determine whether long-term ApoC3 inhibition, alone or in combination, delivers cardiovascular benefit.
Bergmark highlighted that monthly olezarsen produced triglyceride lowering greater than currently available therapies, with more than 80% of patients achieving normal levels. He noted that olezarsen's efficacy and safety in a broader population with hypertriglyceridemia and elevated cardiovascular risk are not yet established, and that the trial provides good information about what is happening to the lipids.
Nordestgaard described the findings as "very, very important" without elaborating on the specific implications.
Clinicians should not anticipate plaque benefit from olezarsen; challenges the triglyceride hypothesis for atherosclerosis progression.
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). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apolipoprotein B by 16.0% over placebo, with no difference in LDL-C. The percent change in NCPV with olezarsen from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference 2.98%; 95% CI -3.4 to 9.3; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. 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 noncalcified coronary plaque volume.
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Marston et al. (2026) conducted an RCT in Coronary atherosclerosis and moderate hypertriglyceridemia (n=468). Olezarsen vs. Placebo was evaluated on percent change from baseline to 12 months in non-calcified plaque volume (NCPV) (MD 2.98%, 95% CI -3.4 to 9.3, p=0.36). Olezarsen did not significantly change noncalcified coronary plaque volume at 12 months compared with placebo (mean difference 2.98%; 95% CI -3.4 to 9.3; p=0.36).
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