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.
“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]
The Conclusions (page not available) state that a 50% LDL-C reduction can be maintained for at least 6 months after two 300-mg doses of inclisiran. The trial followed participants for a maximum of 360 days, so it does not demonstrate that the reduction persists for at least 18 months. (LLM, conf=0.92)
Experimental — accuracy not yet measuredThe analysis of 11 RCTs for quantitative synthesis included more than 13,000 participants and showed inclisiran produces significant LDL-C reduction versus placebo treatment.
“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]
The Abstract reports that inclisiran significantly reduced LDL-C in the placebo-controlled ORION-1 trial (P < .001 between groups). But this paper is a prespecified analysis of one trial with 501 participants, not a quantitative synthesis of 11 RCTs involving more than 13,000 participants. (LLM, conf=0.91)
Experimental — accuracy not yet measuredInitial 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, ORION-10, and ORION-11.
“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]
The Time-Averaged Biomarker Reductions Over 1 Year section reports a 46.4% average LDL-C reduction after two doses in ORION-1, within the claimed range. The Discussion describes twice-yearly maintenance as a proposed regimen, not one tested in this study. The Limitations section says longer-term results from ORION-10 and ORION-11 were still needed, so this source does not establish the claimed reduction across all three trials. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe ORION-1 biannual 300 mg dosing regimen maintained a 46.4% LDL-C reduction from Day 1 and Day 90 through Day 360.
“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]
The “Time-Averaged Biomarker Reductions Over 1 Year” section (page not provided) reports a 46.4% time-averaged LDL-C reduction for the two-dose 300-mg regimen, not a reduction maintained at 46.4% through day 360. The Discussion (page not provided) says twice-yearly maintenance dosing was proposed after doses on days 1 and 90; ORION-1 did not test that maintenance regimen. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe studies presented demonstrated sustained maximum LDL-C reduction levels that persisted throughout six months following the last administered dose.
“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]
The Discussion reports a median 50% LDL-C reduction over the 180 days after a second 300-mg dose, supporting sustained lowering for six months. The Rationale for Dosing Interval section describes this as a time-averaged reduction, not a maximum maintained throughout that period; it also says reductions after a single dose steadily declined. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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BackgroundMethodEmerging lipid lowering agents targeting LDL cholesterol
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Inclisiran—Silencing the Cholesterol, Speaking up the Prognosis
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“27 The mean half-life of inclisiran is ∼ 7 h, and the drug is cleared from circulation within 12–24 h, but its LDL cholesterol-lowering effect lasts 6–12 months.”
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Self-citationTargeting PCSK9 and Beyond for the Management of Low-Density Lipoprotein Cholesterol
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“Data from the ORION 1 trial, in patients at high risk for ASCVD, showed a reduction in LDL-C levels of up to 42% and 53% after a single dose and second dose, respectively at 6 months, with observations at one-year follow-up showing that the two-dose 300 mg regimen produced the highest proportion of responders and the…”
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“RNA silencing drugs injected once or twice a year are efficacious and appear to be safe (45); regulatory approval is expected soon.”
BackgroundLDL-Cholesterol-Lowering Therapy
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State of Gene Therapy for Monogenic Cardiovascular Diseases
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Self-citationNovel RNA-Based Therapies in the Management of Dyslipidemias
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“In the one-year follow-up of the ORION-1 trial (2019), it was demonstrated that a 50% LDL-C reduction was maintained for at least 6 months after two doses of 300 mg of inclisiran on days 1 and 90 [15].”
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“Inclisiran blocks the expression of a specific gene by selectively silencing the translation of PCSK9 messenger RNA (mRNA) [88], leading to a long-lasting reduction in LDL-C even up to 12 months [89,90].”
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“A one-year follow-up of the ORION-1 participants showed an LDL-C reduction of 31.4% at 360 days, signifying a sustained but waning effect over time [54].”
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“A one-year follow-up study of the ORION-1 trial showed that inclisiran produced durable reductions in LDL-C over one year [38].”
Familial Hypercholesterolaemia as a Predisposing Factor for Atherosclerosis
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“Targeting only the liver has many limitations, and the targeting of normal liver cells is stronger than that of diseased liver cells [25,26] Thiophosphoric acid skeleton modification, methoxyl modification, fluoro modification By changing the structure of the RNA, the stability of the RNA is…”
BackgroundDevelopment of siRNA Therapeutics for the Treatment of Liver Diseases
Holm, A., Løvendorf, M. B., & Kauppinen, S. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1298-9_5 · Cited by 13 · see citing works
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“56,91,92,96,97 No signi fi cant increase in risk for AEs of hepatic transaminase elevation was reported in a prespec-i fi ed secondary analysis of the FOURIER trial with evolocu-mab.”
BackgroundReducing residual cardiovascular risk with novel therapies
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“23 At the end of the study, the most significant decrease in LDL cholesterol levels was noted when using two yearly doses of 300 mg, with a reduction of 52.6% from base-line at day 240.”
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Self-citationFrom clinical development to real-world outcomes with inclisiran
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Self-citation
- 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 › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › 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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