Despite experiencing significant reductions in triglycerides, patients with triglycerides over 150 mg/dL and a high risk of atherosclerosis did not experience any significant change in the amount of non-calcified plaque in their coronary arteries after taking the triglyceride-lowering drug olezarsen, in a one-year sub-study presented at the American College of Cardiology's Annual Scientific Session (ACC.26).
Triglycerides are particles of fat in the blood. Having elevated triglyceride levels (known as hypertriglyceridemia) is linked with increased cardiovascular risk, but to date, therapies designed to lower triglycerides have not delivered clear benefits in reducing the risk of serious cardiac events. In contrast, therapies that reduce low-density lipoprotein cholesterol (LDL-C), another common marker of cardiovascular risk, have been clearly shown to slow or reverse plaque buildup in the arteries and thereby help to prevent heart attacks and strokes.
Findings from the Essence-TIMI 73b study published in 2025 found that olezarsen significantly lowered triglycerides in patients with hypertriglyceridemia. This sub-study of the trial included 468 participants who underwent coronary computed tomography angiography (CCTA)—a non-invasive imaging test to measure plaque in the coronary arteries—at baseline and 12 months after randomization. The results suggest that the changes in blood components seen in the Essence-TIMI 73b trial—a 60% reduction in triglycerides and 15% lowering of apolipoprotein B—may not translate into an immediate reduction in the buildup of the coronary plaques that are responsible for atherosclerosis and lead to events such as heart attacks and strokes.
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."
Nicholas Marston, MD, MPH, cardiologist and assistant professor of medicine at Brigham and Women's Hospital and Harvard Medical School in Boston and study's lead author
Olezarsen is designed to reduce apolipoprotein C3, which plays a role in regulating triglyceride metabolism. It does not affect LDL-C, making it a useful test case to help researchers pinpoint the role of triglycerides in heart disease risk.
Before the trial, all participants in the sub-study had triglyceride levels of 150 mg/dL or higher, measurable plaque on baseline CCTA, and either a high risk or known presence of atherosclerosis. Their median age was 63 years, 31% were female and over 50% had diabetes. At baseline, participants had a median triglycerides level of 249 mg/dL (meaning most participants had moderately but not severely elevated triglycerides), LDL-C of 81 mg/dL and ApoB of 93 mg/dL.
Participants were randomly assigned to receive olezarsen at either 50 mg or 80 mg per day or a placebo. The differences between groups assigned to receive olezarsen were minimal, and patients receiving either dose of olezarsen were pooled together for the CCTA sub-study.
The primary endpoint for the CCTA sub-study was percent change in the volume of non-calcified plaque—a type that is softer and more prone to break apart and cause blockages—between the baseline and 12-month CCTA scans. While plaques that have already calcified, or hardened, were not expected to be affected by triglyceride-lowering medication, researchers hypothesized that lowering triglycerides might slow the progression of non-calcified plaque. However, the results revealed no significant change in non-calcified plaque volumes compared to placebo and no difference in related secondary endpoints.
The study's 12-month follow-up is relatively short, although researchers said that this length of time should have been long enough to observe differences in plaque volume. Olezarsen's effect on ApoB was also relatively modest. Marston said it's possible that an agent with a more substantial impact on both triglycerides and ApoB might potentially result in a measurable effect on plaque volumes.
Previous research has suggested that triglyceride-rich particles carry at least as much cardiovascular risk as LDL particles; however, researchers said that more studies are needed with longer duration to fully understand the relationship.
"Ultimately, a cardiovascular outcomes trial would need to be performed to determine the cardiovascular benefit of long-term ApoC3 inhibition, tested either as a monotherapy or in combination with another lipid-lowering therapy," Marston said.
The study was funded by Ionis Pharmaceuticals, maker of olezarsen.
This study was simultaneously published online in Circulation at the time of presentation.
Marston will present the study, "Effect of Intensive Triglyceride Lowering with Olezarsen on Progression of Coronary Atherosclerosis: A Coronary CTA Substudy of the Essence-TIMI 73b Randomized Trial," on Monday, March 30, at 8:30 a.m. CT / 13:30 UTC in the Main Tent, Great Hall.
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