Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial
Open accessAbstract
OBJECTIVE: To evaluate the efficacy and safety of inclisiran by diabetes status. RESEARCH DESIGN AND METHODS: ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C–lowering therapies, to one or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared. RESULTS: Inclisiran was associated with marked declines in LDL-C (median −28% to −52%, P < 0.0001 and −28% to −55%, P < 0.005 for all doses in the without- and with-diabetes groups, respectively) and PCSK9. The inclisiran-treated groups also had lower apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL cholesterol. Inclisiran had an adverse profile similar to that of placebo, and adverse events were proportionally balanced in the baseline with- and without-diabetes groups. CONCLUSIONS: PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option for managing dyslipidemia in the presence and absence of diabetes.
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The 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 [38]
The Abstract and Results describe ORION-1, a placebo-controlled trial that randomized 501 participants and found significant LDL-C reductions with inclisiran. This paper can support the trial’s contribution to the cited synthesis, but it does not report an analysis of 11 RCTs or more than 13,000 participants. (LLM, conf=0.88)
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- Authors
- Leiter, L. A., Teoh, H., Kallend, D., Wright, R. S., Landmesser, U., Wijngaard, P. L. J., Kastelein, J. J. P., & Ray, K. K.
- Affiliations
- St. Michael's Hospital (CA)
- Medicines Company (United States) (US)
- Mayo Clinic (US)
- German Centre for Cardiovascular Research (DE)
- Amsterdam UMC Location University of Amsterdam (NL)
- Imperial College London (GB)
- Corresponding author
- Leiter, Lawrence A.
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2018-11-28
- Volume
- 42
- Issue
- 1
- Pages
- 173-176
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2903347258
- Cited by
- 117
- References
- 5
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 17 · 2023: 21 · 2022: 15 · 2021: 12 · 2020: 15 · 2019: 13
- FWCI
- 10.47
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- The 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 › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- inclisiran, PCSK9, LDL cholesterol lowering, diabetes mellitus, siRNA, atherosclerotic cardiovascular disease, dyslipidemia, apolipoprotein B, lipoprotein(a), non-HDL cholesterol, HDL cholesterol, lipid-lowering therapy
- MeSH terms
- Proprotein Convertase 9, Apolipoproteins B, Diabetes Mellitus, Dose-Response Relationship, Drug, Female, Humans, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Risk Factors, RNA, Small Interfering, Dyslipidemias, Atherosclerosis
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