Remnant Cholesterol‍ Emerges as Key factor in Heart Disease

Updated June 02, 2025

The understanding of atherosclerotic cardiovascular disease (ASCVD) is evolving, with increasing attention on the role of⁤ remnant cholesterol and triglyceride-rich lipoproteins (TRLs). Børge G. ‍Nordestgaard, MD, DMSc, addressed the 2025 National Lipid Association (NLA) Scientific Sessions,⁤ highlighting the significance of ‍cholesterol content within TRLs as a primary driver of ASCVD risk. Nordestgaard’s presentation emphasized ‍that cholesterol, not triglycerides, is the key culprit in ASCVD, paving the way for new therapeutic strategies targeting remnant cholesterol management.

Remnant cholesterol, found within TRLs like very low-density lipoprotein (VLDL) and chylomicron remnants, directly ‍contributes to atherosclerosis. Unlike triglycerides, which the body metabolizes, cells do not degrade cholesterol within remnants, leading to its accumulation in atherosclerotic plaques. ⁢Nordestgaard supported this with pathology slides showing that cholesterol from LDL and remnants, rather than triglycerides, predominates in lipid-laden plaques extracted from coronary arteries.

Epidemiological studies, including the Copenhagen General Population Study and the Copenhagen City Heart Study, reinforce the link between elevated remnant cholesterol⁢ and ASCVD events. Analyses of over 100,000 individuals revealed ‍that those with ⁢higher nonfasting triglyceride levels, a marker for remnant cholesterol, faced a substantially elevated risk of myocardial infarction over several decades.

While LDL cholesterol (LDL-C) remains a primary focus in treatment guidelines, remnant cholesterol presents an additional, independent risk.‍ TRLs transport both cholesterol and triglycerides. Upon lipolysis,they release free fatty⁣ acids,potentially worsening local inflammation,while the cholesterol component⁣ persists,fueling plaque formation. This dual action ‍makes remnant cholesterol ⁢especially atherogenic, contributing to both early atherogenesis ‍and acute events like myocardial infarction upon plaque rupture.

Nordestgaard also discussed remnant⁤ hyperlipidemia,or dysbetalipoproteinemia,a genetic condition characterized by elevated remnant cholesterol,tuberoeruptive xanthomas,and accelerated ASCVD. Patients⁤ with this condition often exhibit normal LDL-C levels but face ⁣high⁣ ASCVD risk due to remnant cholesterol accumulation.

Several therapies targeting remnant ⁤cholesterol and TRLs are under examination or have recently become available, including antisense oligonucleotides (ASOs) and small ⁢interfering RNA (siRNA) therapies.Clinical ‍trials of these agents have demonstrated promising ⁢reductions in both triglycerides ⁣and remnant cholesterol, according to⁤ Nordestgaard.

One such agent,olezarsen (Tryngolza; Ionis Pharmaceuticals),an ASO,received FDA ‍approval ‍on December 19,2024,as a dietary adjunct for adults with familial chylomicronemia syndrome (FCS).the phase 3 BALANCE trial (NCT04568434) showed that⁣ olezarsen reduced triglyceride levels by 50% to 60% ⁤and lowered the incidence‍ of acute pancreatitis in FCS ‍patients. the pooled hazard ratio for acute pancreatitis was 0.12 (95% CI: 0.02-0.66), representing an 88% risk reduction.

Another therapy, plozasiran (ARO-APOC3; Arrowhead Pharmaceuticals), an siRNA targeting apolipoprotein C-III, demonstrated approximately 50%⁤ reductions in triglycerides and up to 80% reductions in remnant cholesterol in‍ patients with severe hypertriglyceridemia in the phase 3 SHASTA-2 trial (NCT04720534). The trial data indicated an 83% relative risk reduction in acute pancreatitis compared to placebo, with a hazard ratio of 0.17.

Volanesorsen (Waylivra; Akcea Therapeutics), an ASO approved by the European Medicines ‍Agency (EMA), demonstrated triglyceride reductions of 50% to 70% in phase 3 COMPASS (NCT02300233) and APPROACH (NCT02211209) trials. ⁢However, the FDA declined its application in 2018 due to concerns about thrombocytopenia.

These therapies⁤ mark a important advancement in lipid-lowering treatments,potentially addressing residual cardiovascular⁢ risk beyond⁤ LDL-C. While LDL-C remains the primary target, Nordestgaard emphasized that non–high-density lipoprotein (HDL) cholesterol, encompassing both LDL and remnant cholesterol, should also inform clinical decisions.

Nordestgaard reviewed international lipid guidelines, noting that while⁤ U.S. guidelines (2018 American College of Cardiology/American Heart Association) primarily focus on LDL-C, European (2019 European Society of Cardiology/European Atherosclerosis Society) and Canadian (2021 Canadian Cardiovascular Society) guidelines explicitly include non-HDL cholesterol and apolipoprotein B as secondary targets. This highlights the need for professional judgment in interpreting lipid profiles,especially in patients with persistently elevated triglycerides despite statin therapy.

High-intensity statins remain the foundation of therapy,but adjunctive treatments like fibrates,omega-3 fatty acids,or emerging agents⁤ such as olezarsen and plozasiran may be considered for patients ⁤with persistent elevations ⁢in ⁣triglycerides and remnant ⁤cholesterol. Nordestgaard stressed the importance of tailoring therapy to individual risk profiles and noted that his Copenhagen laboratory routinely reports remnant cholesterol alongside LDL-C and triglycerides to guide treatment⁤ decisions.

What’s next

The evolving understanding of remnant cholesterol and TRLs ⁤signifies a shift in lipid management, recognizing them as key ⁢drivers of atherosclerotic risk.As new therapies⁣ emerge, clinicians must assess ⁣residual cardiovascular risk beyond LDL-C. Incorporating remnant cholesterol into routine risk assessment‍ may represent the next step in precision lipid management,⁤ offering new opportunities to reduce cardiovascular events in at-risk patients‍ despite optimal LDL-C control.