The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial
Open accessAbstract
INTRODUCTION: Whether long-term treatment with the twice-yearly, siRNA therapeutic inclisiran, which reduces hepatic production of proprotein convertase subtilisin/kexin type 9 (PCSK9), results in sustained reductions in LDL cholesterol with an acceptable safety profile is not known. The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol. METHODS: ORION-3 was a 4-year open-label extension study of the placebo-controlled, phase 2 ORION-1 trial, conducted at 52 sites across five countries. Patients with prevalent atherosclerotic cardiovascular disease or high-risk primary prevention and elevated LDL cholesterol despite maximally tolerated statins or other LDL-lowering treatments, or with documented statin intolerance, who had completed the ORION-1 trial were eligible. Patients receiving inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm), whereas patients receiving placebo in ORION-1 first received subcutaneous evolocumab 140 mg every 2 weeks until day 360 thereafter transitioning to inclisiran twice-yearly for the remainder of ORION-3 study (switching arm). The primary efficacy endpoint was the percentage change in LDL cholesterol with inclisiran from the start of ORION-1 through to day 210 of the open label extension phase in the inclisiran-only arm (approximately 570 days of total inclisiran exposure in the modified intention-to-treat population). Secondary and exploratory endpoints included changes in LDL-C cholesterol and PCSK9 concentrations levels up to day 1440 (4 years) in each arm, and safety. ORION-3 is registered with ClinicalTrials.gov, NCT03060577. FINDINGS: Of the original ORION-1 cohort of 497 patients, 290 of 370 patients allocated to drug continued into the inclisiran-only arm and 92 of 127 patients allocated to placebo entered the switching-arm in the ORION-3 extension study conducted between March 24, 2017, and Dec 17, 2021. In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7-44·3) at day 210 and sustained over 1440 days. The 4-year averaged mean reduction of LDL-C cholesterol was 44·2% (95% CI: 47·1-41·4), with reductions in PCSK9 ranging from 62·2% to 77·8%. Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm. The incidence of treatment-emergent serious adverse events possibly related to the study drug was 1% (three of 284) in the inclisiran-only arm and 1% (one of 87) in the switching arm. INTERPRETATION: Twice-yearly inclisiran provided sustained reductions in LDL cholesterol and PCSK9 concentrations and was well tolerated over 4 years in the extension study. This is the first prospective long-term study to assess repeat hepatic exposure to inclisiran. FUNDING: Novartis Pharma.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The 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 research findings demonstrate that Inclisiran functions as a safe and effective treatment for lipid reduction among diverse patient groups [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 [70]
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 [70]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“It is important to note that of the ORION-3 participants, 23% had diabetes and 33% were not taking statin therapy.”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [133]
The cited source says what the claim attributes to it.
In the citing paper
“Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol [ORION-3]), where an LDL cholesterol reduction of ∼45% was maintained through the end of year 4 (133).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [133]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961
Self-citationEvolocumab and Clinical Outcomes in Patients with Cardiovascular Disease
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615664 · Cited by 6,138
Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome
Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1801174 · Cited by 3,634
CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis
Gillmore, J. D., Gane, E., Taubel, J., Kao, J., Fontana, M., Maitland, M. L., Seitzer, J., O’Connell, D., Walsh, K. R., Wood, K., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2107454 · Cited by 1,801
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1912387 · Cited by 1,665
Self-citationNair, J. K., Willoughby, J. L. S., Chan, A., Charisse, K., Alam, M. R., Wang, Q., Hoekstra, M., Kandasamy, P., Kel’in, A. V., Milstein, S., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja505986a · Cited by 1,141
Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol
Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas, M., Hall, T., Troquay, R. P. T., Turner, T., Visseren, F. L. J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615758 · Cited by 992
Self-citationFerence, B. A., Yoo, W., Alesh, I., Mahajan, N., Mirowska, K. K., Mewada, A., Kahn, J., Afonso, L., Williams, K. A., & Flack, J. M. (2012) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2012.09.017 · Cited by 898
Ray, K. K., Molemans, B., Schoonen, W. M., Giovas, P., Bray, S., Kiru, G., Murphy, J., Banach, M., De Servi, S., Gaita, D., et al. (2021) · European Journal of Preventive Cardiology · doi:10.1093/eurjpc/zwaa047 · Cited by 839
Self-citationInclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia
Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L. J., Curcio, D., Jaros, M. J., Leiter, L. A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913805 · Cited by 818
Self-citation
Cited by
Sorted by citations
Items 301–329 of 329
Sokolova, I. V., Averina, I. A. A., Konovalchuk, N. A., Chernigovskiy, R. A., & Larkina, M. V. (2026) · Russian Journal of Cardiology and Cardiovascular Surgery · doi:10.17116/kardio20261902158
The role of PCSK9 in cancer risk: Population-level evidence and mechanistic insights
Liu, H., Zhou, T., Wang, L., Liu, F., & Gu, D. (2026) · Oncology and Translational Medicine · doi:10.1097/ot9.0000000000000141
Baldini, G., Serio, L., Pinto, R. D., & Ferri, C. (2026) · World Journal of Cardiovascular Diseases · doi:10.4236/wjcd.2026.165028
Yao, J., Sun, Q., Liu, D., Lin, J., & Wang, W. (2026) · BMC Cardiovascular Disorders · doi:10.1186/s12872-026-05931-5
An, L., Ren, Y., Yang, J., & Pei, Z. (2026) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd13050214
Liu, Z., Liu, R., Ying, Y., & Nie, J. (2026) · Biomedicines · doi:10.3390/biomedicines14051142
A narrative review of PCSK9 inhibitors: from evolocumab to novel discoveries
Liu, H., Li, S. N., & Li, J. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1800502
Martín, A., García-Escudero, M. D., García, H. M., Bañares, I., Fontal, N., Eguia, J., Gallastegui, P. G., Benito, A. V., SÁEZ, F. J., Crende, O., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.26.727886
Effects of inclisiran therapy on metabolomic and lipoproteomic profiles in dyslipidemic patients
Patrussi, J., Vignoli, A., Tenori, L., Sorrentino, A., Berteotti, M., Lotti, E., Crudele, F., Taranta, G. C., Rogolino, A. A., Barbieri, G., et al. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1824522
Martin, A., García, H. M., Bañares, I., Khatib, A., & Badiola, I. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105429
Calcaterra, I. L., Luca, C. D., Valletta, L., D’Errico, G., Ferrandino, M., Cardiero, G., Taranto, M. D. D., Fortunato, G., Iannuzzo, G., Tufano, A., et al. (2026) · Internal and Emergency Medicine · doi:10.1007/s11739-026-04417-8
Inclisiran—will it fulfill its promise?
Zadeh, S. S. T., Fogacci, F., & Hadaegh, F. (2026) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2026.104848
Huo, Y., Dejmek, J. S., Yuan, Z., Peng, D., Mena-Madrazo, J. A., Liu, K. X., Zhang, M., Ji, Y., Xing, X., Yao, Z., et al. (2026) · Journal of clinical lipidology · doi:10.1016/j.jacl.2026.06.016
Pan, Y., Golwala, H. S., Shenoy, V. V., & Kostner, K. (2026) · JACC Case Reports · doi:10.1016/j.jaccas.2026.109196
Ahn, C., Jeong, H., Yim, H. W., Kim, N. J., Han, S., & Oh, I. (2026) · Frontiers in Drug Safety and Regulation · doi:10.3389/fdsfr.2026.1855572
Pätzold, D., Vonbank, A., Clodi, M., Sourij, H., Hübner, D., Ebenbichler, C. F., Fagan, A., Farries, G., Hofstätter, E., Nitzlader, M., et al. (2026) · Journal of clinical lipidology · doi:10.1016/j.jacl.2026.07.025
A scalable platform for dumbbell siRNA production using engineered Td PIE in probiotic E. coli
Huang, Z., Wang, S., Liu, J., Lin, Y., Xiao, Z., Chen, T., Shi, B., Gu, S., Zhou, R., Yao, Z., et al. (2026) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2026.103030
Wu, X., & Zhang, J. (2026) · Reviews in Cardiovascular Medicine · doi:10.31083/rcm48237
Mohamed, A. A., Rached, R., Kantsø, L. R., Honoré, E. T., Lauridsen, B. K., Fijolek, A., & Gislason, G. (2026) · Open Heart · doi:10.1136/openhrt-2026-004265
Baharani, J., & Ramachandran, S. (2026) · Lipidology · doi:10.3390/lipidology3030025
Causas y evolución del colesterol LDL tras la suspensión del inclisirán en prevención secundaria
González, E. F., Matos, F. R., Piro, V., Marco, M. D. V. G., Ruíz, M. G., & Quintana, A. G. (2026) · REC CardioClinics · doi:10.1016/j.rccl.2026.09.003
Liu, W., Zou, Q., Liu, W., & Huang, Z. (2026) · Pharmacological Reviews · doi:10.1016/j.pharmr.2026.100164
Hu, Y., Yuan, S., 陈兴娟, Yu, W., Liu, F., Dong, X., Cui, M., Zhao, N., & Dong, H. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1916672
Zhang, E., Zheng, W., LI, Y., Cheng, Z., Cai, Y., Cheng, Y., Zhang, X., Hou, Q., Liu, Y., Bingxue, M., et al. (2026) · Journal of drug targeting · doi:10.1080/1061186x.2026.2721709
Stamatopoulou, V., Kouvela, A., Ahtypi, K., Douka, E., Kominatou, C., Meimaroglou, A., Spyropoulou, K., Taxari, S., Theodoridou, S., & Plotas, P. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1935318
Nzobokela, J., Choolwe, S. C., & Masenga, S. K. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1987811
Shahid, R. S., Habib, S. M., Awan, M., Usman, M. A., & Mushtaq, M. (2026) · Journal of clinical lipidology · doi:10.1016/j.jacl.2026.10.011
Ciobanu, D. M., Berchisan, A., Mălan, C., Rusu, A., Craciun, A. E., Inceu, G., Tholvay, D.-M., & Bala, C. G. (2026) · Romanian Journal of Internal Medicine · doi:10.2478/rjim-2026-0025
Pederiva, C., Capra, M. E., Galimberti, F., Buonuomo, P. S., Fornari, E., Iughetti, L., Zambon, A., Tarugi, P., Arca, M., Averna, M. R., et al. (2026) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2026.105038
Metadata
- Authors
- Ray, K. K., Troquay, R. P. T., Visseren, F. L. J., Leiter, L. A., Scott Wright, R., Vikarunnessa, S., Talloczy, Z., Zang, X., Maheux, P., Lesogor, A., & Landmesser, U.
- Affiliations
- Imperial College London (GB)
- VieCuri Medisch Centrum (NL)
- University Medical Center Utrecht (NL)
- St. Michael's Hospital (CA)
- Novartis (Switzerland) (CH)
- German Centre for Cardiovascular Research (DE)
- Corresponding author
- Ray, Kausik K
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2023-02
- Volume
- 11
- Issue
- 2
- Pages
- 109-119
- ISSN
- 2213-8587 (ISSN-L)
- OpenAlex
- W4313554841
- Cited by
- 328
- References
- 28
- Citations by year
- 2026: 55 · 2025: 102 · 2024: 103 · 2023: 67
- FWCI
- 87.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet Diabetes & Endocrinology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, cc-by)
- Funders
- Novartis
- NIHR Imperial Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- inclisiran, PCSK9 inhibition, siRNA therapeutics, LDL cholesterol lowering, high cardiovascular risk, atherosclerotic cardiovascular disease, statin intolerance, long-term efficacy, safety
- MeSH terms
- Proprotein Convertase 9, Heart Disease Risk Factors, Anticholesteremic Agents, Cardiovascular Diseases, Humans, Cholesterol, LDL, Prospective Studies, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Small Interfering
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
