July 24, 2026European Journal of Preventive Cardiology
Longer-Term Efficacy and Safety of Zodasiran in Patients with Mixed Hyperlipidaemia
Key result
Zodasiran sustains ~55% triglyceride reduction over 21 months in mixed hyperlipidemia.
- 95% CI -64 to -43
- n=156
Why the study?
Mixed hyperlipidaemia increases ASCVD risk, and following significant lipid lowering in the Phase 2b ARCHES-2 trial, the longer-term safety and efficacy of the ANGPTL3 siRNA zodasiran needed evaluation.
Does zodasiran provide sustained lipid lowering and safety over 24 months in adults with mixed hyperlipidaemia?
Key Points
- This research aims to assess the long-term safety and efficacy of zodasiran in adults with mixed hyperlipidaemia.
- Adults with mixed hyperlipidaemia who completed 9 months of randomised treatment were eligible for the open-label extension (OLE).
- The study included multiple zodasiran doses administered subcutaneously every 3 months.
- Lipid parameters were assessed through 21 months of the OLE with a total follow-up of 24 months.
- By Month 21, median triglycerides reduced by 55% (95% CI, 64, 43).
- Median remnant cholesterol reduced by 57% (SD: 32), LDL-C decreased by 5% (SD: 40), and ApoB decreased by 13% (SD: 21).
- Zodasiran was generally well tolerated, with only 3.2% of participants discontinuing due to adverse events.
Study Design
Type
RCT (n=156)
Blinding
Open-label
Randomization
Randomized
Structured PICO
Does zodasiran provide sustained lipid lowering and safety over 24 months in adults with mixed hyperlipidaemia?
P
Population
156 adults with mixed hyperlipidaemia who completed 9 months of a randomized trial, followed for an additional 21 months in an open-label extension.
I
Intervention
Zodasiran (50-, 100-, or 200-mg subcutaneously every 3 months) in an open-label extension.
O
Outcome
Lipid parameters (percent change in median triglycerides, remnant cholesterol, LDL-C, ApoB) assessed through 21 months of the open-label extension (total follow-up 24 months).surrogate
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“For patients with mixed hyperlipidemia and persistent elevations in LDL cholesterol and non-HDL cholesterol, zodasiran could expand the opportunities for lowering “bad” cholesterol beyond conventional therapies such as statins, potentially leading to more favorable outcomes for patients.”
“It's our contention that based on these promising results, further studies are warranted to determine the potential of zodasiran, an investigational drug has the potential to reduce the risk of cardiovascular events in a broad range of patients through a single therapy that targets all the lipoprotein fractions.”
“Results from clinical studies of zodasiran, including those for the ARCHES-2 study in patients with mixed hyperlipidemia presented today at EAS and published in the New England Journal of Medicine, continue to support ANGPTL3 as an exciting target for an RNAi-based gene silencing strategy.”
Implication
Zodasiran produced sustained reductions in triglycerides and atherogenic lipoproteins over 24 months and was well tolerated in patients with mixed hyperlipidaemia.
Abstract
BACKGROUND: Mixed hyperlipidaemia, characterized by elevated cholesterol and triglyceride levels, is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). Angiopoietin-like protein 3 (ANGPTL3) regulates lipid metabolism through inhibition of lipoprotein and endothelial lipases. Loss-of-function variants in ANGPTL3 are associated with lower plasma triglycerides, cholesterol, and reduced ASCVD risk. Zodasiran, a hepatocyte-targeted small interfering RNA (siRNA) against ANGPTL3, demonstrated significant lipid lowering in the Phase 2b ARCHES-2 trial. AIMS: To evaluate the long-term safety and efficacy of zodasiran in adults with mixed hyperlipidaemia participating in the open-label extension (OLE) of ARCHES-2 (NCT04832971). METHODS: Adults with mixed hyperlipidaemia (fasting triglycerides 1.7-5.6 mmol/L and LDL-C ≥ 1.8 mmol/L or non-HDL-C ≥ 2.59 mmol/L) who completed 9 months of randomised treatment with placebo or zodasiran (50-, 100-, or 200-mg subcutaneously Q3 M) were eligible for the OLE. The primary endpoint in the randomised doubleblind study was percent change in median triglycerides from baseline to Month 6. Here, lipid parameters were assessed through 21 months of the OLE; with total follow-up of 24 months. RESULTS: Of 191 participants completing randomised treatment, 156 (82%) enrolled in the OLE. Over 24 months, zodasiran was generally well tolerated; five participants (3.2%) discontinued due to adverse events; one (0.6%) death, not considered treatment-related, occurred. Injection site reactions were mild. By Month 21, median triglycerides were reduced by -55% (95% CI, 64, 43); remnant cholesterol by -57% (SD: 32); LDL-C by -5% (SD: 40); and ApoB by -13% (SD: 21). CONCLUSIONS: Zodasiran produced sustained reductions in triglycerides and atherogenic lipoproteins over 30 months and was well tolerated, supporting its potential as a long-term therapeutic option for mixed hyperlipidaemia.
Discussion
No takes yet. Share an insight, caveat, or question.
Cite This Study
Rosenson et al. (2026) conducted an RCT in Mixed hyperlipidaemia (n=156). Zodasiran vs. Placebo was evaluated on Percent change in median triglycerides (95% CI -64 to -43). In an open-label extension, zodasiran produced sustained reductions in median triglycerides by 55% (95% CI, -64 to -43) over 21 months in adults with mixed hyperlipidaemia.