{"doi":"10.1093/eurjpc/zwae095","title":"Therapeutic inhibition of angiopoietin-like protein 3 for hypertriglyceridaemia and residual risk of ASCVD: beginning of the end or end of the beginning?","abstract":null,"journal":"European Journal of Preventive Cardiology","year":2024,"id":651154,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1698110,"name":"Dick C Chan","orcid":null,"position":1,"is_corresponding":false},{"id":1549903,"name":"Gerald F Watts","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Therapeutic inhibition of angiopoietin-like protein 3 for hypertriglyceridaemia and residual risk of ASCVD: beginning of the end or end of the beginning?","abstract":"This editorial refers to ‘Reductions in Remnant Cholesterol and VLDL Cholesterol through Inhibition of ANGPTL3 Protein Synthesis: An Analysis from the TRANSLATE-TIMI 70 Trial’, by A. Zimerman et al., https://doi.org/10.1093/eurjpc/zwae090. Residual cardiovascular risk in patients on statin therapy can be attributed to hypertriglyceridaemia (HTG), a biomarker of the accumulation in plasma of atherogenic triglyceride-rich lipoproteins (TRLs), including very low-density lipoprotein (VLDL) and their remnants.1,2 Increasing evidence from population and Mendelian randomization analysis also suggest that TRL remnants could be more atherogenic than LDL per lipoprotein particle.3 TRLs can penetrate the arterial wall into the sub-intimal space, where they initiate cholesterol deposition, inflammation, foam cell formation, and progression of atherosclerotic plaques.1 Currently available triglyceride (TG)-lowering drugs, such as fibrates, omega-3-fatty acids and niacin only modestly lower plasma TG levels and, with the exception of high-dose pure eicosapentaenoic acid (EPA), their use for the prevention of atherosclerotic cardiovascular disease (ASCVD) is unsupported by outcome trials. Therefore, there remains an unmet need for effective treatments for lowering elevated TRLs, which in clinical practice typically occurs as part of mixed hyperlipidaemia or as an isolated abnormality after lowering of LDL cholesterol with a statin, ezetimibe or a proprotein convertase subtilisin/kexin Type 9 (PCSK9) inhibitor. Angiopoietin-like protein 3 (ANGPTL3) is a hepatokine exclusively secreted by the liver and a key regulator of lipoprotein metabolism through the antagonism of lipoprotein lipase (LPL) and endothelial lipase.4 Population and experimental genetic studies support the value of ANGPTL3 inhibition in the correction of dyslipidaemia and prevention of ASCVD.4,5 ANGPTL3 is accordingly a genetically validated therapeutic target. Inhibition of ANGPTL3 with RNA therapeutics recapitulates in principle genetic deficiency in ANGPTL3, offering a new approach for correcting dyslipidaemias, including HTG. Vupanorsen is a second-generation N-acetyl galactosamine-conjugated antisense oligonucleotide (ASO) that inhibits hepatic ANGPTL3 messenger RNA.6 Results from Phase I and II clinical trials of vupanorsen have demonstrated significant reduction in plasma TG, with a modest reduction in LDL cholesterol and apoB in subjects with elevated TG. In this issue of the Journal, Zimerman et al. report an analysis of the effect of vupanorsen on plasma remnant and VLDL cholesterol concentrations from the previously published TRANSLATE-TIMI 70 trial.7,8 The overall investigation comprised 286 subjects (>40 years of age) who had non-HDL cholesterol level ≥ 100 mg/dL (i.e. 3.8 mmol/L) and TG 150–500 mg/dL (i.e. 1.7–5.6 mmol/L) on stable statin treatment. They were randomized to either placebo or one of 7 vupanorsen regimens (80, 120, or 160 mg every 4 weeks, or 60, 80, 120, or 160 mg every 2 weeks) for 24 weeks. Remnant cholesterol concentration was calculated as total cholesterol minus directly measured LDL cholesterol and HDL cholesterol concentrations. Very low-density lipoproteins was isolated using ultra-centrifugation, with cholesterol content measured enzymatically. Inhibition of ANGPTL3 dose-dependently lowered remnant cholesterol by 42–59% and VLDL cholesterol by 52–67%, independent of age, sex, body mass index, baseline TG, and intensity of statin therapy. Vupanorsen also significantly reduced TG by 41–57%, non-HDL cholesterol by 22–28%, LDL cholesterol by 8–16%, and apoB by 6–15% compared with placebo.8 However, vupanorsen was associated with a dose-dependent increase in hepatic fat fraction (HFF) up to 76%, as measured by magnetic resonance imaging.9 This corresponded to a three-fold increase in aspartate aminotransferase or alanine aminotransferase in 30–45% of patients at the higher monthly doses. The apparent effects of vupanorsen on remnant cholesterol, VLDL cholesterol, hepatic fat, and enzymes were dose-dependently associated with the degree of ANGPTL3 inhibition.8,9 On the basis of the modest reductions in non-HDL cholesterol and apoB levels, and the increase in hepatic fat, the clinical development programme for vupanorsen has been terminated.10 Accordingly, a key question to consider is whether this signals the beginning of or end of other research programmes on ANGPTL3 inhibitors, and whether a better choice of therapy for testing in clinical trials of TG-lowering in the prevention of ASCVD prevention is gene silencing of APOC3. There are other methods for inhibiting ANGPTL3, including small interfering RNA (siRNA) and monoclonal antibody (mAb) treatments. A Phase I trial with zodasiran (formerly ARO-ANG3) reported potent and sustained reductions in ANGPTL3 coupled with significant falls in apoB and LDL cholesterol levels.11 An interim analysis of a Phase II study,12 ARCHES-2, in people with residual HTG on statin therapy has shown more potent reductions in TG, non-HDL cholesterol, apoB, remnant cholesterol, and LDL cholesterol than the vupanorsen study summarized earlier. Unlike the TRANSLATE-TIMI 70 trial, zodasiran was also not associated with an increase in hepatic fat based on magnetic resonance imaging.11,12 The differences between zodasiran and vupanorsen trials may relate to several factors, including modes of intracellular inhibition of the mRNA transcript of ANGPTL3 (ASO acting within the nucleus vs. siRNA acting via RNA-induced silencing complex in the cytoplasm), as well as the selection of patients for the study, LDL cholesterol being higher in the ARCHES-2 trial. The impact of vupanorsen on HFF may be a consequence of a specific off-target drug effect rather than a direct consequence of hepatic inhibition of ANGPTL3,13 although recent cellular work appears to suggest otherwise.14 Another method for inhibiting ANGPTL3 in the circulation is the use of a fully human IgG mAb (evinacumab) that has shown potent TG-lowering effects in patients with moderate HTG and elevated LDL cholesterol.15 It is clear that ANGPTL3 inhibition, using these alternative approaches, has a role not only in lowering TRLs but also LDL cholesterol. In our opinion, further Phase III trials in selected patients with mixed hyperlipidaemia or residual HTG using siRNA therapeutics targeted ANGPTL3 are justified on the basis of the extant evidence. TRLs and plasma TG may also be effectively lowered by inhibiting APOC3 with RNA-based therapeutics.6 Olezarsen, an ASO, has been shown to potently lower plasma TG and prevent the development of severe chylomicronaemia,16 with evidence also showing marked reductions in plasma TG and TRL remnants by 60%, with a lesser reduction in apoB concentration and minimal changes in LDL cholesterol in subjects with moderate HTG.17 These data support a coronary imaging study that will provide additional insights into the potential role of inhibiting APOC3 for ASCVD prevention in patients with residual moderate HTG (NCT05610280). However, the results of the PROMINENT trial with pemafibrate (a selective peroxisome proliferator-activated receptor-alpha agonist that modestly inhibits apoC3) suggest that TRL lowering without LDL cholesterol (or apoB) reduction does not have an impact on ASCVD events.18 Lack of significant change in LDL cholesterol, and even an increase in apoB, may account for the null outcomes in fibrate trials, with the exception of some studies using gemfibrozil.19 Whether apoC3 inhibition improves cardiovascular outcomes in the absence of a reduction in LDL or apoB remains to be demonstrated, a question that, by contrast to the use of fibrates, can only in our opinion be addressed by RNA therapeutics that have potent and sustained effects in lowering apoC3. The mechanism of action of gene silencing targeted at ANGPTL3 or APOC3 are important for two reasons. The reduction in TRLs with ANGPTL3 inhibition is related to an increase in LPL activity that enhances the clearance of both chylomicrons and VLDL particles, and also reduces VLDL remnant particle concentrations and the subsequent intracirculatory production of LDL. This may be seen with both ASO and siRNA and may be more potent with zodasiran than with vupanorsen, although formal lipoprotein kinetic tracer studies are required to assess such subtle differences. With apoC3 inhibition, reduction in TRLs involves the stimulation of LPL activity, which results in increased lipolytic clearance of these particles; increased TRL clearance via hepatic remnant receptors and possibly decreased direct secretion of VLDL from the liver may also be involved. A downside of apoC3 inhibition is that the production rate of LDL may be increased in subjects with residual HTG, as evidence by the more modest effects on plasma total apoB and LDL cholesterol concentration reductions compared with ANGPTL3 inhibition; such potentially adverse sequalae may be offset by marked upregulation of LDL receptors with statins, ezetimibe and possibly PCSK9 inhibitors. Beyond changes in lipoprotein metabolism, inhibition of ANGPLT3 or apoC3 may exhibit pleiotropic effects, such as direct inhibition of plaque growth, improvement in endothelial dysfunction, and decrease in vascular inflammation,5 but their precise contributions to a possible reduction in ASCVD events need further investigation. Elevated plasma TG concentrations are associated with increased risk of ASCVD. The consensus among international guidelines for the secondary prevention of ASCVD is that in patients on maximally tolerated statins, who achieved LDL cholesterol goals and have residual HTG, consideration should be given to the use of high-dose EPA, as suggested by the REDUCE-IT trial.1,2 This study showed that the reduction in major ASCVD events was not significantly associated with change in plasma TG, but instead was related to the baseline level of plasma TG (a biomarker of increased ASCVD risk) and in the main to the increase in plasma concentration of EPA,20 suggesting a direct pleiotropic effect of EPA on the progression of atherosclerosis. Many patients in Phase II studies of ANGPTL3 and APOC3 inhibitors are overweight or obese with diabetes and may benefit from the use of EPA. The value of employing a glucagon-like peptide 1 (GLP-1) receptor agonist in obese, diabetic, and non-diabetic patients with cardiovascular disease has recently been well emphasised.21,22 Glucagon-like peptide 1 receptor agonists not only lower plasma TG but also significantly decrease body weight, blood pressure, hyperglycaemia, and markers of inflammation, such as c-reactive protein. Whether there is additional benefit from inhibiting ANGPTL3 and apoC3 in high-risk patients treated with EPA and/or GLP-1 receptor agonist remains open to further investigation. The apparent disappointing findings of the TRANSLATE-TIMI 70 trial and the discontinuation of the vupanorsen development programme should not be viewed as the beginning of the end, but as the end of the beginning of the development of other ANGPTL3 inhibitors, as exemplified by zodasiran and even the inception of a new therapeutic programme targeted at the ANGPTL3/8 complex.23 In aggregate, therapeutic inhibition of ANGPTL3 stands as a safe and promising option for correcting a broad spectrum of atherogenic dyslipidaemias, characterized by elevated TRLs, LDL cholesterol, apoB, and possibly lipoprotein(a).12 Despite the potent and durable therapeutic properties of ANGPLT3 inhibitors, their role in clinical practice ultimately rests on demonstration of long-term safety, acceptability, and cost-effectiveness in on-going and future clinical trials in appropriated selected sample populations. No new data were generated or analysed in support of this editorial.","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38446991","pmcid":null,"openalex_id":"https://openalex.org/W4392502027","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":1}],"oa_status":"bronze","license":"cc-by","oa_locations":[{"url":"https://academic.oup.com/eurjpc/advance-article-pdf/doi/10.1093/eurjpc/zwae095/56975380/zwae095.pdf","host_type":"journal"},{"url":"https://academic.oup.com/eurjpc/advance-article-pdf/doi/10.1093/eurjpc/zwae095/56975380/zwae095.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/eurjpc/article-pdf/31/10/1224/58778494/zwae095.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/eurjpc/zwae095","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38446991","host_type":"repository"},{"url":"https://research-repository.uwa.edu.au/en/publications/6f2bca28-548d-4399-8aba-ce96b73cfbec","host_type":"repository"},{"url":"https://www.scopus.com/pages/publications/85201029568","host_type":"repository"}],"fields_of_study":["Lipid metabolism and disorders","Diabetes, Cardiovascular Risks, and Lipoproteins","Lipoproteins and Cardiovascular Health","Humans","Hypertriglyceridemia","Angiopoietin-Like Protein 3","Risk Factors","Hypolipidemic Agents","Biomarkers","Risk Assessment"],"mesh_terms":["Angiopoietin-Like Protein 3","Hypolipidemic Agents","Humans","Risk Factors","Hypertriglyceridemia","Biomarkers","Risk Assessment"],"keywords":["Medicine","Residual risk","Angiopoietin 2","Internal medicine","Residual","Endocrinology","Bioinformatics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Zero hunger"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T06:44:15.289874Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}