Targeting APOC3: A Potential New Tool for Managing Hypertriglyceridemia
Elevated triglyceride levels remain a key contributor to residual cardiovascular risk, even among patients receiving optimal LDL-lowering therapy. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C3 (APOC3), is being investigated as a novel therapeutic approach to improve triglyceride metabolism and potentially reduce cardiovascular events. In this interview, Brian Bergmark, MD, discusses recent findings from a clinical trial evaluating olezarsen in patients with moderate hypertriglyceridemia and elevated cardiovascular risk, including its impact on lipid profiles, safety outcomes, and implications for future research and clinical practice.
Key Highlights
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Olezarsen, an antisense oligonucleotide targeting APOC3, led to approximately a 60% reduction in triglyceride levels in patients with moderate hypertriglyceridemia.
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The safety profile was favorable, with no meaningful concerns related to platelet counts, renal function, or liver abnormalities.
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Further research, including a cardiovascular outcomes trial, is needed to determine whether lowering APOC3 can translate into reduced cardiovascular events.
Additional Resource:
- Bergmark BA, Marston NA, Prohaska TA, et al. Targeting APOC3 with olezarsen in moderate hypertriglyceridemia. N Engl J Med. 2025;393(13):1279-1291. doi:10.1056/NEJMoa2507227
Consultant360: What was the main rationale behind investigating APOC3 inhibition with olezarsen in this patient population?
Brian A. Bergmark, MD: Apolipoprotein C3, or APOC3, is a key regulator of triglyceride metabolism. It is an inhibitor of a protein called lipoprotein lipase, which breaks down triglyceride-rich lipoproteins. By inhibiting the inhibitor, drugs that target APOC3 can increase the body's ability to clear triglycerides from triglyceride-rich lipoproteins.
There are two general reasons to do this. One is for people with very high triglyceride levels—not really what we focused on here—but those with severe hypertriglyceridemia are at risk for acute pancreatitis and other complications, so there’s motivation to clear triglycerides for that reason.
We are looking at a different perspective here. There are strong epidemiological and genetic data that high triglycerides and triglyceride-rich lipoproteins contribute to residual risk for cardiovascular disease, atherosclerosis, myocardial infarction, and stroke. This pathway is of interest as a potential means to reduce cardiovascular risk. We studied this largely among patients with moderate hypertriglyceridemia—levels of 150 to less than 500 mg/dL—plus elevated cardiovascular risk.
Consultant360: Could you summarize the most clinically meaningful findings from the study?
Dr Bergmark: We studied two doses—a 50 mg dose and an 80 mg dose—given subcutaneously every 4 weeks, with a 12-month treatment period. The primary endpoint was the effect on triglycerides at 6 months.
There were substantial reductions in triglycerides with both doses compared with placebo—approximately 60%, which is far more than what's currently available. In addition, there were favorable changes to the lipid profile, including reductions in non-HDL cholesterol and apolipoprotein B (apoB).
One limitation with other triglyceride-targeting therapies studied in this population is that apoB-containing particles, which are thought to be atherogenic, are not reduced overall. You may clear triglycerides but still have the same number of atherogenic particles circulating. Here, we saw a significant reduction in those particles, suggesting—though still theoretical—that this could reduce the risk of cardiovascular events.
Consultant360: How should primary care physicians and cardiologists interpret these results in the context of managing patients with moderate hypertriglyceridemia?
Dr Bergmark: At the moment, there’s no direct clinical implication. What we have now is an understanding of the drug’s effects, which are compelling enough to test the hypothesis.
What’s clear is that lowering apoB by lowering LDL cholesterol reduces cardiovascular events. What remains unknown is whether lowering apoB to the same degree by targeting triglyceride-rich lipoproteins—rather than cholesterol-rich LDL—will also reduce events. That’s what remains to be seen.
The immediate clinical takeaway is that the safety profile was very good. The most immediate pathway to approval is for patients with severe hypertriglyceridemia. Those trial results will be presented at the AHA in about a month, and this study contributes to the safety database for that potential indication.
Consultant360: What should clinicians know about the safety profile of olezarsen?
Dr Bergmark: Overall, it looked very safe. We paid close attention to a few things. Older versions of antisense oligonucleotides, given at higher doses, were associated with low platelet counts, renal dysfunction, and liver abnormalities.
This drug is a later-generation antisense oligonucleotide targeted to the liver—the site of APOC3 synthesis—allowing for a lower dose and theoretically less concern about systemic effects. In fact, that’s what we observed: no meaningful concerns about platelet counts, kidney function, or liver abnormalities.
Consultant360: Looking ahead, what are the next steps for this research, and how do you see olezarsen potentially fitting into clinical practice down the line?
Dr Bergmark: Setting aside the severe group—olezarsen is approved for patients with familial chylomicronemia syndrome—we’re now looking at the much larger population of patients with moderate hypertriglyceridemia and cardiovascular risk.
Olezarsen is part of a broader group of therapies converging on similar metabolic pathways. There’s an siRNA targeting APOC3, another siRNA targeting ANGPTL3, and an earlier antisense oligonucleotide with safety limitations.
All of these agents are getting closer to addressing the central question: can we reduce cardiovascular risk by targeting these pathways? The next step is an appropriately powered randomized cardiovascular outcomes trial in an at-risk population.