Remnant cholesterol reduction for reduction of residual ASCVD risk

Olezarsen is a novel N-acetylgalactosamine (GalNAc) conjugated antisense oligonucleotide targeting APOC3 mRNA production with the purpose of lowering plasma apolipoprotein C3 thereby increasing lipoprotein lipase activity in plasma and subsequently lowering of remnant cholesterol and plasma triglycerides.1 In the ESSENCE-TIMI 73b trial, a Phase 3 randomized, double-blind, placebo-controlled study, olezarsen was evaluated in individuals at elevated cardiovascular risk with mild-to-moderate hypertriglyceridemia (1.7–5.6 mmol/L; 150–499 mg/dL) for lowering remnant cholesterol and triglycerides. Participants received monthly subcutaneous injections of 50 mg or 80 mg of olezarsen or placebo for 6 months. Compared to placebo, olezarsen reduced remnant cholesterol by 66% in the 50 mg group and by 68% in the 80 mg group (Figure 1) and correspondingly triglycerides by 58 and 61%, respectively. Olezarsen also reduced non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B, while low-density lipoprotein (LDL) cholesterol remained unchanged. Safety was similar across groups, with no increase in serious adverse events. The study demonstrates that olezarsen robustly lower remnant cholesterol and triglycerides in this high-risk population, offering a promising therapeutic for residual cardiovascular risk. From novel remnant cholesterol reducing drugs to potential reduction in atherosclerotic cardiovascular disease (ASCVD). The top part illustrates the likely scenario from lipoprotein lipase activity increase to reduction of remnant cholesterol and subsequent reduction in atherosclerosis and ASCVD. The bottom part shows max effect size for novel remnant cholesterol-lowering agents. Details for the publications shown are listed in the references. A part of this figure is created using Biorender.com. ANGPTL, angiopoietin-like protein; ApoC3, apolipoprotein C3; ASCVD, atherosclerotic cardiovascular disease; ASO, antisense oligonucleotide; NatMed, Nature Medicine; NEJM, the New England Journal of Medicine; PAD, peripheral artery disease; siRNA, small interfering RNA. The APOC3 gene encodes apolipoprotein C3, a regulator of lipoprotein metabolism: after lipoproteins are synthesized by the liver or the small intestine, apolipoprotein C3 is associated to triglyceride- and cholesterol-rich lipoproteins like chylomicrons, chylomicron remnants, very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL),2 where the cholesterol content in these particles is remnant cholesterol. Here, apolipoprotein C3 inhibits lipoprotein lipase–mediated triglyceride hydrolysis and hepatic particle uptake, hereby increasing remnant cholesterol levels. Genetic loss-of-function variants in APOC3 result in enhanced lipoprotein lipase–mediated hydrolysis of the triglyceride component of remnants, faster receptor-mediated remnant particle clearance by the liver, and markedly reduced circulating remnant cholesterol and triglycerides, typically by 40–50%. Using these variants, human genetic studies have provided compelling causal evidence linking apolipoprotein C3 inhibition to reduced risk of atherosclerotic cardiovascular disease (ASCVD). Indeed, across multiple population-based cohorts and Mendelian randomization studies, individuals with APOC3 loss-of-function variants have substantially lower risk of ASCVD, often comparable in magnitude to genetically lower LDL cholesterol. Mechanistically, when remnant cholesterol carrying lipoproteins circulate in the bloodstream, some traverse the endothelial lining to the subintimal space of the arterial wall, along LDL.3 Here, they are engulfed by macrophages which turn into foam cells, leading to atherosclerotic plaque formation. The progressive formation of arterial plaques, along with their increasing instability, ultimately leads to myocardial infarction, stroke, and peripheral artery disease. This causal role of remnant cholesterol in ASCVD is supported by mechanistic, causal genetic, and observational data, with some studies indicating that remnant cholesterol carrying particles are up to four times more atherogenic per particle compared with LDL.4 As currently available lipid-lowering therapy only lower remnant cholesterol and triglycerides moderately, individuals with elevated remnant cholesterol and triglycerides face an unmet medical need for aggressive remnant cholesterol and triglyceride reduction to prevent future ASCVD. The reductions observed from olezarsen therapy are an exciting contribution to the field and hold the potential for large clinical implications.1 In the absence of cardiovascular outcomes trials, the ASCVD risk reduction through remnant cholesterol and triglyceride lowering has been estimated by modelling of observational cohort data from the general population.5 In individuals with very high cardiovascular risk scores, a lower remnant cholesterol of 2 mmol/L (77 mg/dL) was estimated to lower the 10-year absolute risk of ASCVD by 11–17%, while the corresponding estimated risk reduction was 7–11% for a 1 mmol/L (39 mg/dL) lower level and 2–6% for a 0.5 mmol/L (19 mg/dL) lower remnant cholesterol level.5 These estimates, calculated in a primary prevention setting, illustrate a substantial clinical potential held by this novel agent through remnant cholesterol and triglyceride lowering. Beside olezarsen mentioned above,1 five other recent randomized trials evaluated additional novel remnant cholesterol- and triglyceride-lowering therapies (Figure 1). Plozasiran is another nucleotide-based inhibitor of apolipoprotein C3, whereas four additional agents (zodasiran, solbinsiran, MAR00001, and LY3475766) target variants of the angiopoietin-like protein (ANGPTL) pathway.6–10 In the plozasiran trial, quarterly or half-yearly dosing reduced remnant cholesterol by up to 49% and triglycerides by 62% after 24 weeks.6 Further, zodasiran, an siRNA targeting ANGPTL3 also produced robust dose-dependent remnant cholesterol reduction by 73% in the 50 mg group, 76% in the 100 mg group, and 82% in the 200 mg group and corresponding triglyceride reductions of 51%, 57%, and 63% respectively.7 Also, solbinsiran, another siRNA against ANGPTL3, similarly lowered remnant cholesterol by 42–50% and triglycerides by 36–53%.8 Additionally, early phase testing of an ANGPTL4 monoclonal antibody and a monoclonal antibody against the ANGPTL3/8 complex led to reductions in remnant cholesterol as well.9,10 Especially, a monoclonal antibody against the ANGPTL3/8 complex, LY3475766 showed dose-dependent lipid effects with remnant cholesterol reduction by up to 86% and triglycerides by up to 70%.10 All these agents demonstrated acceptable safety profiles. Overall, these agents show potent and sustained remnant cholesterol and triglyceride lowering with promising safety highlighting their potential to address residual atherogenic risk. In conclusion, potent remnant cholesterol- and triglyceride-lowering agents with large potential clinical benefits are now developing; however, there remains a critical need for large Phase 3 randomized trials to determine whether lowering remnant cholesterol and triglycerides through apolipoprotein C3 or ANGPTL3/4/8 inhibition truly lower the risk of ASCVD (Figure 1). Definitive outcome data are essential to confirm causal benefit and guide clinical adoption. This work was supported by the Capital Region of Denmark [research fund to TD (grant number A7165 and A7272)]; the Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark; and the Japan Society for the Promotion of Science [JSPS: Postdoctoral Fellowship for Research Abroad to TD (grant number 202360405)]. The funders had no direct role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. No new data were generated or analysed in support of this paper. Takahito Doi MD, PhD is a fully trained cardiologist and a postdoctoral researcher within cardiovascular sciences at the Copenhagen University Hospital-Herlev and Gentofte, Denmark. He finished his clinical training in general internal medicine, general cardiology, and interventional cardiology at the National Cerebral and Cardiovascular Center, and subsequently obtained his Ph.D. with honour from Tohoku University, both in Japan. He has continued his interest in the pathogenesis, diagnosis, and treatment of atherosclerotic cardiovascular disease in the current institution mainly supported by the Capital Region of Denmark and the Japan Society for the Promotion of Science. He is pursuing his research focused on cholesterol especially remnant cholesterol and plasma triglycerides on cardiovascular disease from a population-based perspective with large cohort studies of the Copenhagen City Heart Study, the Copenhagen General Population Study, the UK Biobank, and Nationwide in Denmark. Original articles include publications in European Heart Journal and JACC. He reviews for more than 10 scientific journals including top cardiology journals. He is also a member of development committee for Japanese guidelines for prevention of atherosclerotic cardiovascular disease and for familial hypercholesterolaemia. Karen Hvid MD is a medical doctor from the University of Copenhagen and is currently pursuing a Ph.D. at the Department of Clinical Biochemistry at the Copenhagen University Hospital—Herlev and Gentofte. Her research is supported by the Danish Diabetes and Endocrine Academy and the Danish Cardiovascular Academy, and focuses on the role of remnant cholesterol, LDL cholesterol, and related lipid measures in cardiometabolic disease, with particular emphasis on high-risk individuals, individuals with diabetes, and the metabolic syndrome. She works with large-scale epidemiological datasets, such as the Copenhagen General Population Study, the UK Biobank, and nationwide Danish register data, to investigate how atherogenic lipoproteins contribute to cardiovascular risk across metabolic phenotypes, aiming to improve prevention and risk stratification in high-risk patient groups. Børge G. Nordestgaard MD, DMSc is Professor and Chief Physician at Copenhagen University Hospital—Herlev and Gentofte, University of Copenhagen, Denmark. He is also President of the European Atherosclerosis Society. Prof. Nordestgaard studied and worked in Copenhagen, New York, and London. He has for more than 40 years continued his interest in the pathogenesis, diagnosis and treatment of familial hypercholesterolaemia, hyperlipidaemia, lipoprotein(a), remnant cholesterol, triglycerides, atherosclerosis, diabetes, and liver, renal, and cardiovascular disease, and has written extensively on these conditions. He is chairing the Copenhagen General Population Study and is a steering committee member of the Copenhagen City Heart Study and five Phase 3 cardiovascular intervention trials. Prof. Børge G. Nordestgaard has supervised 75 Ph.D. students and 35 postdoctoral fellows, and has published 1006 original articles and 165 reviews, book chapters, consensus statements, and editorials. His H-index is 176 in Web of Science and he is listed among the top 0.1% researchers worldwide with the most highly cited papers. Original articles include publications in NEJM, Lancet, JAMA, Nature, Science, baby Nature Journals, BMJ, baby Lancet Journals, Circulation, European Heart Journal, JACC, and baby JAMA Journals.