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Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial
Open accessAbstract
Importance: Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes. Objective: To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen. Design, Setting, and Participants: Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017. Interventions: One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo. Main Outcomes and Measures: Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year. Results: At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year. Conclusions and Relevance: Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing. Trial Registration: ClinicalTrials.gov identifier: NCT02597127.
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“Clinical trials demonstrate that LDL-C levels decrease by 50% and maintain this reduction for at least 18 months of treatment [25, 26].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The analysis of 11 RCTs for quantitative synthesis included more than 13,000 participants showed inclisiran produces significant LDL-C reduction versus placebo treatment [24, 25, 38–44, 46, 49].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The initial injections of inclisiran at Day 1 and 90 followed by biannual maintenance resulted in a long-term average LDL-C reduction of − 44% to − 48% across ORION-1 and ORION-10 and ORION-11 [25, 44].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The ORION-1 biannual 300 mg dosing regimen maintained a 46.4% LDL-C reduction from Day 1 and Day 90 through Day 360 [25].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [25]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The studies presented demonstrated sustained maximum LDL-C reduction levels that persisted throughout six months following the last administered dose [25, 42, 70].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [25]
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Citations
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“At days 180, 240 and 360, the greatest LDL-C reductions were observed in patients who received two doses of inclisiran 300 mg (53%, 47% and 31%, respectively) [17, 18].”
Background
Metadata
- Authors
- Ray, K. K., Stoekenbroek, R. M., Kallend, D., Nishikido, T., Leiter, L. A., Landmesser, U., Wright, R. S., Wijngaard, P. L. J., & Kastelein, J. J. P.
- Affiliations
- Charing Cross Hospital (GB)
- Medicines Company (United States) (US)
- Saga University (JP)
- University of Toronto (CA)
- Charité – Universitätsmedizin Berlin (DE)
- Mayo Clinic (US)
- University of Amsterdam (NL)
- Corresponding author
- Ray, Kausik K.
- ORCID
- Venue
- JAMA Cardiology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-11-01
- Volume
- 4
- Issue
- 11
- Pages
- 1067
- ISSN
- 2380-6583 (ISSN-L)
- PMC
- PMC6763983
- OpenAlex
- W2976144989
- Cited by
- 172
- References
- 17
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 33 · 2023: 25 · 2022: 19 · 2021: 20 · 2020: 34 · 2019: 5
- FWCI
- 18.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Cardiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Medicines Company
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- inclisiran, LDL cholesterol, PCSK9, siRNA, single-dose regimen, dosing frequency, statin-resistant hypercholesterolemia, lipid-lowering therapy, PCSK9 inhibition, patient adherence, familial hypercholesterolemia, atherosclerotic cardiovascular disease
- MeSH terms
- Aged, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Hypercholesterolemia, Injections, Subcutaneous, Cholesterol, LDL, Male, Middle Aged, Severity of Illness Index, Time Factors, Treatment Outcome, Risk Assessment, RNA, Small Interfering, Patient Safety
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