Triglyceride-Lowering Drug Olezarsen Fails to Reduce Arterial Plaque Despite 60% Triglyceride Reduction
核心洞察
Olezarsen achieved a 60% reduction in triglycerides and 15% lowering of apolipoprotein B (搜索) in patients with hypertriglyceridemia (搜索) but showed no significant impact on non-calcified coronary plaque volume at 12 months.
The Essence-TIMI 73b sub-study included 468 participants with triglycerides over 150 mg/dL and high atherosclerosis (搜索) risk who underwent coronary computed tomography angiography at baseline and 12 months.
Results challenge the assumption that triglyceride reduction translates to immediate plaque reduction, highlighting the need for longer-term cardiovascular outcomes trials to determine clinical benefits.
Despite achieving substantial triglyceride reductions, the investigational drug olezarsen failed to reduce arterial plaque buildup in high-risk patients over one year, according to results from a sub-study of the Essence-TIMI 73b trial presented at the American College of Cardiology's Annual Scientific Session (ACC.26).
The study included 468 participants with triglycerides over 150 mg/dL and high atherosclerosis (搜索) risk who underwent coronary computed tomography angiography (CCTA) at baseline and 12 months after randomization. While olezarsen treatment resulted in a 60% reduction in triglycerides and 15% lowering of apolipoprotein B (搜索), patients showed no significant change in non-calcified coronary plaque volume compared to placebo.
Study Design and Patient Population
Participants had a median age of 63 years, with 31% being female and over 50% having diabetes (搜索). At baseline, the median triglyceride level was 249 mg/dL, LDL-cholesterol was 81 mg/dL, and apolipoprotein B (搜索) was 93 mg/dL. All participants had measurable plaque on baseline CCTA and either high risk or known presence of atherosclerosis (搜索).
Patients were randomly assigned to receive olezarsen at either 50 mg or 80 mg daily or placebo, administered on top of standard lipid-lowering therapy. The differences between the two olezarsen dose groups were minimal, leading researchers to pool them together for the CCTA analysis.
Mechanism and Rationale
Olezarsen is designed to reduce apolipoprotein C3 (搜索), which plays a role in regulating triglyceride metabolism. Unlike traditional lipid-lowering therapies, it does not affect LDL-cholesterol, making it a useful test case for understanding the specific role of triglycerides in cardiovascular disease risk.
"Treatment with olezarsen on top of standard of care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia (搜索) substantially lowers triglycerides and remnant cholesterol and modestly lowers ApoB, but did not affect non-calcified coronary plaque volume at 12 months," said Nicholas Marston, MD, MPH, a cardiologist and assistant professor of medicine at Brigham and Women's Hospital and Harvard Medical School in Boston and the study's lead author.
Clinical Implications
The primary endpoint focused on percent change in non-calcified plaque volume, which represents softer plaque more prone to rupture and cause blockages. While researchers hypothesized that triglyceride lowering might slow progression of this type of plaque, the results showed no significant differences compared to placebo across primary and secondary endpoints.
These findings contrast sharply with established therapies that reduce LDL-cholesterol, which have clearly demonstrated the ability to slow or reverse plaque buildup and prevent heart attacks and strokes. The disconnect raises questions about the immediate cardiovascular benefits of triglyceride reduction, despite elevated triglyceride levels being linked with increased cardiovascular risk.
Study Limitations and Future Directions
The 12-month follow-up period, while considered adequate to observe plaque volume changes, may have been insufficient to capture the full effects of triglyceride lowering. Additionally, olezarsen's effect on apolipoprotein B (搜索) was relatively modest, suggesting that agents with more substantial impacts on both triglycerides and apolipoprotein B might yield different results.
Marston noted that previous research has suggested triglyceride-rich particles carry at least as much cardiovascular risk as LDL particles, but emphasized that longer-duration studies are needed to fully understand this 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 (搜索), the maker of olezarsen, and was simultaneously published online in Circulation at the time of presentation.