The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia
Abstract
BACKGROUND: Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase. METHODS: We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24. RESULTS: A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose. CONCLUSIONS: In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.).
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In the citing paper
“Mild elevations in aminotransferase levels as well as small increases in glycated hemoglobin levels have also been seen with plozasiran 18,23,29 and are similar to the now well-established safety profile of statins. 30,31”
From Targeting APOC3 with Olezarsen in Moderate Hypertriglyceridemia (2025) · cites this paper as [23]
In the citing paper
“In MUIR [119] and SHASTA-2 [120], plozasiran similarly reduced TG by 50–60% and improved remnant cholesterol, non–HDL-C, and apoB, while modest, dose-dependent LDL-C increases were observed at higher doses.”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [119]
In the citing paper
“Ultimately, four RCTs met al.l eligibility criteria and were included in the final analysis [16, 17, 22, 23].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“The meta-analysis included data from 4 clinical trials [16, 17, 22, 23], encompassing a total of 1,514 participants—534 assigned to various doses and treatment durations of plozasiran, and 980 receiving placebo.”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“At 24 weeks, the analysis showed significant heterogeneity (P = 0.02, I² = 60%), which was resolved by excluding the study by Ballantyne et al. (2024) [16] (50 mg, H) (P = 0.15, I² = 38%).”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“which was resolved after excluding Ballantyne et al., 2024 [16] (50 mg, H) (P = 0.35, I² = 10%)”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“which was resolved by excluding Ballantyne et al., 2024 [16] (50 mg, Q) (P = 0.35, I² = 10%)”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“Concerning safety findings for plozasiran, we observed slight increases in HbA1c, AST, and ALT levels, along with a higher incidence of headaches.”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“Moreover, the rises seen in liver transaminases were considered non-serious and associated with higher and more frequent doses of plozasiran, which trials mitigated by changing dosing and frequency [16, 22].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“Moreover, the rises seen in liver transaminases were considered non-serious and associated with higher and more frequent doses of plozasiran, which trials mitigated by changing dosing and frequency [16, 22].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“Ballantyne et al. (2024) included patients with mixed dyslipidemia to explore whether plozasiran’s lipid-lowering effects could extend to individuals at risk for ASCVD and support the rationale for a dedicated cardiovascular outcomes trial [16].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
In the citing paper
“Subgroup analyses confirmed that changes in HbA1c, ALT, and AST levels were dose- and regimen-dependent.”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [16]
Citations
Cites
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Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials
Sattar, N., Preiss, D., Murray, H. M., Welsh, P., Buckley, B. M., de Craen, A. J., Seshasai, S. R. K., McMurray, J. J., Freeman, D. J., Jukema, J. W., et al. (2010) · The Lancet · doi:10.1016/s0140-6736(09)61965-6 · Cited by 2,436
Therapeutic siRNA: state of the art
Hu, B., Zhong, L., Weng, Y., Peng, L., Huang, Y., Zhao, Y., & Liang, X.-J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0207-x · Cited by 1,586
Triglycerides and cardiovascular disease
Nordestgaard, B. G., & Varbo, A. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61177-6 · Cited by 1,419
Preiss, D. (2011) · JAMA · doi:10.1001/jama.2011.860 · Cited by 1,390
Nordestgaard, B. G. (2016) · Circulation Research · doi:10.1161/circresaha.115.306249 · Cited by 1,116
Remnant Cholesterol as a Causal Risk Factor for Ischemic Heart Disease
Varbo, A., Benn, M., Tybjærg-Hansen, A., Jørgensen, A. B., Frikke-Schmidt, R., & Nordestgaard, B. G. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.08.1026 · Cited by 1,115
Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
The TG and HDL Working Group of the Exome Sequencing Project, N. H. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1307095 · Cited by 1,071
Research works printed but not linked: 1
- Jacobsen A Duffy E Blumenthal RS Martin SS. Clinical review on triglycerides. Washington DC: American College of Cardiology March 4 2020 (https://www.acc.org/Latest-in-Cardiology/Articles/2020/03/03/15/08/Clinical-Review-on-Triglycerides).
Cited by
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2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias
Mach, F., Koskinas, K. C., Roeters van Lennep, J. E., Tokgözoğlu, L., Badimon, L., Baigent, C., Benn, M., Binder, C. J., Catapano, A. L., De Backer, G. G., et al. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf190 · Cited by 688
Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia
Rosenson, R. S., Gaudet, D., Hegele, R. A., Ballantyne, C. M., Nicholls, S. J., Lucas, K. J., San Martin, J., Zhou, R., Muhsin, M., Chang, T., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2404147 · Cited by 213
Self-citation2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias
Mach, F., Koskinas, K. C., van Lennep, J. E. R., Tokgözoğlu, L. S., Badimón, L., Baigent, C., Benn, M., Binder, C. J., Catapano, A. L., Backer, G. D., et al. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.120479 · Cited by 190
Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk
Watts, G. F., Rosenson, R. S., Hegele, R. A., Goldberg, I. J., Gallo, A., Mertens, A., Baass, A., Zhou, R., Muhsin, M., Hellawell, J., et al. (2025) · New England Journal of Medicine · doi:10.1056/nejmoa2409368 · Cited by 178
Self-citationRomeo, S., Vidal‐Puig, A., Husain, M., Ahima, R. S., Arca, M., Bhatt, D. L., Diehl, A. M., Fontana, L., Foo, R., Frühbeck, G., et al. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf314 · Cited by 93
Metadata
- Authors
- Ballantyne, C. M., Vasas, S., Azizad, M., Clifton, P., Rosenson, R. S., Chang, T., Melquist, S., Zhou, R., Mushin, M., Leeper, N. J., Hellawell, J., & Gaudet, D.
- Affiliations
- Royal Adelaide Hospital (AU)
- From the Baylor College of Medicine and the Texas Heart Institute, Houston (C.M.B.); Borbánya Praxis, Nyíregyháza, Hungary (S.V.); Valley Clinical Trials, Northridge (M.A.), Arrowhead Pharmaceuticals, Pasadena (T.C., S.M., R.Z., M.M., J.H.), and the Stanford School of Medicine, Stanford (N.J.L.) — all in California; the Royal Adelaide Hospital, Adelaide, SA, Australia (P.C.); the Icahn School of Medicine at Mount Sinai, New York (R.S.R.); and the Department of Medicine, Université de Montréal and Ecogene-21, Quebec, QC, Canada (D.G.).
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2024-09-12
- Volume
- 391
- Issue
- 10
- Pages
- 899-912
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W4399087766
- Semantic Scholar
- c67a77a19492dfb8d4608c1ccc2c06e5e7c68abe
- Cited by
- 210
- References
- 44
- Citations by year
- 2026: 73 · 2025: 106 · 2024: 30
- FWCI
- 55.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Arrowhead Pharmaceuticals
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- plozasiran, apolipoprotein C-III, siRNA, mixed dyslipidemia, triglyceride-rich lipoproteins, remnant cholesterol, non-HDL cholesterol, lipoprotein lipase inhibition, triglyceride lowering, atherosclerotic cardiovascular disease, dose comparison, safety and tolerability, subcutaneous injection
- MeSH terms
- RNAi Therapeutics, Adult, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Hyperlipidemias, Cholesterol, LDL, Male, Middle Aged, Triglycerides, RNA, Small Interfering, Apolipoprotein C-III
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