{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:42:40Z","timestamp":1792006960163,"version":"4.4.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2018,9,25]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin\/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo. Participants with elevated low-density lipoprotein cholesterol despite receiving maximally tolerated statin therapy received a single-dose (200, 300, or 500 mg) or 2-dose starting regimen (100, 200, or 300 mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non\u2013high-density lipoprotein cholesterol (non\u2013HDL-C), apolipoprotein (apo) B, very-low-density lipoprotein cholesterol, lipoprotein(a), triglycerides, HDL-C, and apo A1 at the primary efficacy time point (day 180) with mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, interindividual variation in response, and lipid goal attainment.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              The mean age of the 501 participants was 63 years, 65% were male, 69% had atherosclerotic cardiovascular disease, 73% used statins, and mean low-density lipoprotein cholesterol was 128 mg\/dL. A single dose of inclisiran reduced apo B, non\u2013HDL-C, and very-low-density lipoprotein cholesterol over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non\u2013HDL-C was lowered dose-dependently: by 25% from 148\u00b143 to 110\u00b145 mg\/dL in the 200-mg single-dose group and by 46% from 161\u00b158 to 91\u00b158 mg\/dL in the 2-dose 300-mg group. For the same dosing regimens, apo B was reduced by 23% from 101\u00b123 to 78\u00b129 mg\/dL and by 41% from 106\u00b131 to 65\u00b133 mg\/dL (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non\u2013HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non\u2013HDL-C &lt;100 and &lt;130 mg\/dL.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin\/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin\/kexin type 9.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Registration:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              . Unique identifier: NCT02597127.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.034710","type":"journal-article","created":{"date-parts":[[2018,5,7]],"date-time":"2018-05-07T17:20:47Z","timestamp":1525713647000},"page":"1304-1316","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":150,"title":["Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins"],"prefix":"10.1161","volume":"138","author":[{"given":"Kausik K.","family":"Ray","sequence":"first","affiliation":[{"name":"Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, UK (K.K.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Stoekenbroek","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands (R.M.S., J.J.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kallend","sequence":"additional","affiliation":[{"name":"The Medicines Company, Parsippany, NJ (D.K., P.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence A.","family":"Leiter","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital, University of Toronto, Canada (L.A.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Landmesser","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin Institute of Health and German Center for Cardiovascular Research, Partner Site Berlin, Germany (U.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Scott","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Mayo Clinic, Rochester, MN (R.S.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wijngaard","sequence":"additional","affiliation":[{"name":"The Medicines Company, Parsippany, NJ (D.K., P.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.P.","family":"Kastelein","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands (R.M.S., J.J.P.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-015-0358-8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1500858"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehx450"},{"key":"e_1_3_4_5_2","volume-title":"Paper presented at: American College of Cardiology Annual Meeting","author":"Steg PG","unstructured":"Steg, PG, ODYSSEY OUTCOMES Investigators and Committees. ODYSSEY Outcomes: CV outcomes with alirocumab after ACS. Paper presented at: American College of Cardiology Annual Meeting; March 10\u201312, 2018; Orlando, FL."},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1615758"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.301621"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000133684.77013.88"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.025080"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.025253"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.112.250043"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv043"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2014.02.615"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.05.030"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw046"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1614062"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2012.05.007"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.288.4.462"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.25.3104"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(17)33548-9"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.02.017"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.005873"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.10.055"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2016.264515"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.713438"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.366"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2012.07.007"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1567-5688(17)30021-1"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehw272"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2016-013255"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61374-X"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.P002816"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706628"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907569"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2010.11.015"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.299.13.1547"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.5551\/jat.1719"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R071233"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.P065334"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehu058"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.118.034710","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T07:59:48Z","timestamp":1715587188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.118.034710"}},"subtitle":["Prespecified Secondary End Points in ORION 1"],"short-title":[],"issued":{"date-parts":[[2018,9,25]]},"references-count":39,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2018,9,25]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.118.034710"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.118.034710","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,25]]},"assertion":[{"value":"2018-03-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-04-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-07-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}