Commentary
Article
NLA 2025: Emerging Therapies Target Remnant Cholesterol to Address Residual Cardiovascular Risk
Author(s):
Børge G. Nordestgaard, MD, DMSc, discussed the role of remnant cholesterol as an independent risk factor for atherosclerotic cardiovascular disease and the emerging therapies that may help manage residual cardiovascular risk beyond low-density lipoprotein cholesterol reduction.
The role of remnant cholesterol and triglyceride-rich lipoproteins (TRLs) in atherosclerotic cardiovascular disease (ASCVD) has garnered increasing attention in recent years, reshaping how clinicians and researchers approach lipid management.
At the 2025 National Lipid Association (NLA) Scientific Sessions, Børge G. Nordestgaard, MD, DMSc, discussed the evolving understanding of remnant cholesterol, TRLs, and their roles in ASCVD. In his presentation, Nordestgaard, a chief physician in clinical biochemistry at Copenhagen University Hospital, professor of genetic epidemiology at the University of Copenhagen, and president of the European Atherosclerosis Society, underscored the importance of cholesterol content, and not triglycerides themselves, as the primary driver of ASCVD risk, highlighting emerging therapeutic targets that address remnant cholesterol management.
Remnant Cholesterol
Remnant cholesterol—the cholesterol content within TRLs, such as very low-density lipoprotein (LDL) and chylomicron remnants—is a causal factor in atherosclerosis. Unlike triglycerides, which serve as an energy substrate and can be metabolized by various tissues, cholesterol within remnants is not degraded by cells and thus accumulates in atherosclerotic plaques. Nordestgaard showed pathology slides that highlighted this distinction with lipid-laden plaques extracted from coronary arteries, which predominantly contained cholesterol from LDL and remnants rather than triglycerides themselves.
Epidemiological data from the Copenhagen General Population Study and the Copenhagen City Heart Study further illustrate the link between elevated remnant cholesterol and ASCVD events, Nordestgaard explained. In analyses involving over 100,000 individuals, those with higher nonfasting triglyceride levels, which are used as a surrogate for remnant cholesterol, had significantly higher risks of myocardial infarction over decades of follow-up.
Pathophysiology and Clinical Implications
Fat and cholesterol in human blood. Image Credit: © charnsitr - stock.adobe.com
Although LDL cholesterol (LDL-C) remains a primary therapeutic target in guidelines, remnant cholesterol contributes an additional, independent risk. According to Nordestgaard, TRLs carry both cholesterol and triglycerides; upon lipolysis, they release free fatty acids, potentially exacerbating local inflammation, whereas the cholesterol component is retained and drives plaque formation. This dual mechanism highlights why remnant cholesterol is particularly atherogenic, contributing both to early atherogenesis and, upon plaque rupture, to thrombosis and acute events, such as myocardial infarction.
Nordestgaard also discussed remnant hyperlipidemia, historically known as type III hyperlipidemia or dysbetalipoproteinemia, as a genetic disorder marked by elevated remnant cholesterol, tuberoeruptive xanthomas, and accelerated ASCVD. Nordestgaard noted these patients also have a distinct phenotypic presentation with normal LDL-C levels and high ASCVD risk due to remnant cholesterol accumulation.
Clinical Trials and Emerging Therapies
Several agents targeting remnant cholesterol and TRLs, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) therapies, are either under investigation or have recently emerged on the market. According to Nordestgaard, clinical trials investigating these agents have shown promising results in reducing both triglycerides and remnant cholesterol.
One such agent is olezarsen (Tryngolza; Ionis Pharmaceuticals), an ASO that was approved by the FDA on December 19, 2024, as an adjunct to diet for adults living with familial chylomicronemia syndrome (FCS).1,2 In the phase 3 BALANCE trial (NCT04568434), olezarsen reduced triglyceride levels by 50% to 60% and lowered the incidence of acute pancreatitis in patients with FCS.1,3 The pooled HR for acute pancreatitis was 0.12 (95% CI: 0.02-0.66), corresponding to an 88% risk reduction.1
Another therapy, plozasiran (ARO-APOC3; Arrowhead Pharmaceuticals), is an siRNA that targets apolipoprotein C-III. In the phase 3 SHASTA-2 trial (NCT04720534), plozasiran demonstrated approximately 50% reductions in triglycerides and up to 80% reductions in remnant cholesterol in patients with severe hypertriglyceridemia. The trial data showed that plozasiran achieved an 83% relative risk reduction in acute pancreatitis compared with placebo, with an HR of 0.17.1,4
Volanesorsen (Waylivra; Akcea Therapeutics), an ASO, has been approved by the European Medicines Agency (EMA), although the FDA declined its application in 2018 due to concerns about thrombocytopenia.1,5 In phase 3 COMPASS (NCT02300233) and APPROACH (NCT02211209) trials, volanesorsen demonstrated triglyceride reductions of 50% to 70%.6,7
These therapies represent a significant shift in the lipid-lowering landscape, with the potential to address residual cardiovascular risk beyond LDL-C. Although LDL-C remains the primary therapeutic target in current guidelines, Nordestgaard emphasized that non–high-density lipoprotein (HDL) cholesterol, which includes both LDL and remnant cholesterol, should also guide clinical decision-making.
Guideline Perspectives
Nordestgaard reviewed international lipid guidelines, noting that although the US guidelines (2018 American College of Cardiology/American Heart Association) focus predominantly on LDL-C, the ones from Europe (2019 European Society of Cardiology/European Atherosclerosis Society) and Canada (2021 Canadian Cardiovascular Society) explicitly include non-HDL cholesterol and apolipoprotein B as secondary targets. For cardiology professionals practicing in the US, this underscores a need for professional judgment when interpreting lipid profiles—particularly in patients with persistently elevated triglycerides despite statin therapy.
High-intensity statins remain the cornerstone of therapy, but for patients with persistent elevations in triglycerides and remnant cholesterol, adjunctive therapies such as fibrates, omega-3 fatty acids, or emerging agents, such as olezarsen and plozasiran, may be considered as they become available. Nordestgaard emphasized the importance of tailoring therapy to individual risk profiles and noted that in his Copenhagen laboratory, remnant cholesterol is routinely reported alongside LDL-C and triglycerides to guide treatment.
The Evolving Landscape of Lipid Management Beyond LDL-C
Nordestgaard’s insights reinforce a growing shift in lipid management, where remnant cholesterol and triglyceride-rich lipoproteins are no longer viewed as secondary considerations but as key drivers of atherosclerotic risk. As the therapeutic landscape evolves with agents such as olezarsen and plozasiran, clinicians are increasingly called upon to assess residual cardiovascular risk beyond LDL-C alone. Incorporating remnant cholesterol into routine risk assessment and decision-making may represent the next frontier in precision lipid management, offering new opportunities to reduce cardiovascular events in patients who remain at risk despite optimal LDL-C control.
