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JAMA Cardiol. 2019 Sep 25. doi: 10.1001/jamacardio.2019.3502. [Epub ahead of print]

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.

Author information

Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, Charing Cross Hospital, London, England.
The Medicines Company, Parsippany, New Jersey.
Cardiovascular Medicine, Saga University, Nabeshima, Saga, Japan.
University of Toronto, Toronto, Ontario, Canada.
Charité-Universitats medizin Berlin, Berlin, Germany.
Department of Cardiology, Mayo Clinic, Rochester, Minnesota.
University of Amsterdam, Amsterdam, the Netherlands.



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.


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.


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.


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: identifier: NCT02597127.

[Available on 2020-09-25]

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