Effects of Inclisiran in Patients With Atherosclerotic Cardiovascular Disease
Open accessAbstract
OBJECTIVE: To evaluate the efficacy, safety, and tolerability of inclisiran in participants with atherosclerotic cardiovascular disease (ASCVD) from ORION-10 and ORION-11 stratified by key patient characteristics. PATIENTS AND METHODS: Participants were randomized 1:1 to receive 300 mg inclisiran sodium (284 mg inclisiran) or placebo on days 1, 90, 270, and 450, alongside background lipid-lowering therapy. This pooled, post hoc analysis stratified participants with ASCVD by sex, age, race, kidney function, body mass index, and glycemic status. Co-primary endpoints were percentage changes in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510, and after day 90 and up to day 540 (time-adjusted). LDL-C goal attainment and safety were also assessed. RESULTS: This analysis of 2975 participants included: female, n=827; Black, n=213; 75 years of age or older, n=458; obese, n=1474; diabetes, n=1182; and moderate-to-severe chronic kidney disease, n=538. Mean baseline LDL-C levels in the total ASCVD population were balanced between treatment arms (inclisiran, 103.4 mg/dL; placebo, 102.0 mg/dL). With inclisiran, mean placebo-corrected percentage changes in LDL-C from baseline were -51.5% (95% CI, -54.0% to -49.0%) and -52.1% (95% CI, -53.9% to -50.4%) to day 510 and day 540 (time-adjusted), respectively; this was consistent across subgroups. LDL-C less than 55 mg/dL at 1 or more visits was reached by 87.6% of participants receiving inclisiran. The inclisiran safety profile was consistent across subgroups. CONCLUSION: Twice-yearly inclisiran (after initial and 3-month doses) was well-tolerated and provided significant, consistent LDL-C reductions for up to 18 months in participants with ASCVD independent of key patient characteristics (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]; NCT03399370 and ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]; NCT03400800).
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Inclisiran reduced LDL-C by 40-52% more than placebo in patients throughout a 540-day observation period.
“The studies showed Inclisiran reduced LDL-C by 40–52% more than placebo in patients throughout a 540-day observation period.”
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 [28]
The Efficacy section (page not provided) reports a 51.5% placebo-corrected LDL-C reduction at Day 510 and a 52.1% time-adjusted reduction after Day 90 through Day 540. It supports substantial, sustained lowering, but does not establish a 40–52% reduction throughout the full 540-day period; the time-adjusted measure excludes the first 90 days. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe effect of inclisiran did not change regardless of whether patients used background statins.
“The effects of Inclisiran did not change regardless of whether patients used background statins as part of their treatment.”
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 [28]
The Discussion (page not available in our copy) reports substantial LDL-C reductions with inclisiran in participants receiving maximally tolerated statins and/or other lipid-lowering therapy. But the paper's reported subgroup comparisons concern age, race, sex, glycemic status, BMI, and kidney function—not statin use. It therefore does not establish that inclisiran's effect was unchanged between patients who did and did not use background statins. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe effect of Inclisiran on LDL-C does not change regardless of whether patients use background statins as part of their treatment.
“of Inclisiran did not change regardless of whether patients used background statins as part of their treatment.”
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 [28]
The Efficacy section reports substantial LDL-C reductions with inclisiran, and the Study Design and Participants section says treatment was given with background statins and/or other oral lipid-lowering therapy. But the reported subgroup comparisons concern age, race, sex, kidney function, BMI, and glycemic status—not statin use. The paper therefore does not establish that the LDL-C effect was unchanged between patients who did and did not use background statins. (LLM, conf=0.82)
Experimental — accuracy not yet measuredORION-10 and ORION-11 included patients with established ASCVD or ASCVD risk equivalents for primary and secondary prevention.
“The patient population in ORION-10 and ORION-11 trials consisted of patients with established ASCVD or ASCVD risk equivalents for primary and secondary prevention [28].”
The effect size of Inclisiran does not diminish over time.
“Importantly, the effect size did not diminish over time”
The therapeutic response to Inclisiran is uniform across subgroups stratified by age, gender, ethnicity, and comorbidities.
“the therapeutic response was uniform across subgroups stratified by age, gender, ethnicity, and comorbidities [27–29].”
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References 56 · Cited by 25
Research works printed but not linked: 38
- Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Com- mittee. J Am Coll Cardiol. 2022;80(14):1366-1418.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AA CVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Associa- tion task force on clinical practice guidelines. Circulation. 2019; 139(25):e1082-e1143.
- Wong ND, Zhao Y, Xiang P, Coll B, López JAG. Five-year re- sidual atherosclerotic cardiovascular disease rsk prediction model for statin treated patients with known cardiovascular dis- ease. Am J Cardiol. 2020;137:7-11.
- Marx N, Federici M, Schütt K, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes: developed by the task force on the management of cardiovascular disease in patients with diabetes of the Eu- ropean Society of Cardiology (ESC). Eur Heart J. 2023; 44(39):4043-4140.
- Authors/Task Force Members, ESC Committee for Practice Guidelines (CPG), ESC National Cardiac Societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis. 2019; 290:140-205.
- Cannon CP, de Lemos JA, Rosenson RS, et al. Use of lipid- lowering therapies over 2 years in GOULD, a registry of pa- tients with atherosclerotic cardiovascular disease in the US. JAMA Cardiol. 2021;6(9):1-9.
- Gu J, Sanchez RJ, Chauhan A, Fazio S, Wong ND. Lipid treat- ment status and goal attainment among patients with athero- sclerotic cardiovascular disease in the United States: a 2019 update. Am J Prev Cardiol. 2022;10:100336.
- Ray KK, Haq I, Bilitou A, et al. Treatment gaps in the implemen- tation of LDL cholesterol control among high-and very high- risk patients in Europe between 2020 and 2021: The multina- tional observational SANTORINI study. Lancet Reg Health Eur. 2023;29:100624.
- Peters SAE, Muntner P, Woodward M. Sex differences in the prevalence of, and trends in, cardiovascular risk factors, treat- ment, and control in the United States, 2001 to 2016. Circula- tion. 2019;139(8):1025-1035.
- Khvorova A. Oligonucleotide therapeutics d a new cass of cholesterol-lowering drugs. N Engl J Med. 2017;376(1):4-7.
- Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021;77(9):1182-1193.
- National Institutes of Health, National Heart Lung and Blood Institute. The American Association for the Study of Obesity. NHLBI Obesity Education Initiative. National Institute of Health; 2000:11. https://www.nhlbi.nih.gov/files/docs/guidelines/prctgd_ c.pdf. Accessed 29 April 2024.
- Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376(15):1430-1440.
- Ray KK, Kallend D, Leiter LA, et al. Effect of inclisiran on lipids in primary prevention: the ORION-11 trial. Eur Heart J. 2022; 43(48):5047-5057.
- Underberg J, Toth PP, Rodriguez F. LDL-C target attainment in secondary prevention of ASCVD in the United States: barriers, consequences of nonachievement, and strategies to reach goals. Postgrad Med. 2022;134(8):752-762.
- Schroff P, Gamboa CM, Durant RW, Oikeh A, Richman JS, Safford MM. Vulnerabilities to health disparities and statin use in the REGARDS (Reasons for Geographic and Racial Differ- ences in Stroke) study. J Am Heart Assoc. 2017;6(9):e005449.
- Jankowski J, Floege J, Fliser D, Böhm M, Marx N. Cardiovascular disease in chronic kidney disease. Circulation. 2021;143(11): 1157-1172.
- Schofield JD, Liu Y, Rao-Balakrishna P, Malik RA, Soran H. Dia- betes dyslipidemia. Diabetes Ther. 2016;7(2):203-219.
- Valdivielso JM, Rodríguez-Puyol D, Pascual J, et al. Atheroscle- rosis in chronic kidney disease. Arterioscler Thromb Vasc Biol. 2019;39(10):1938-1966.
- Mathew RO, Rosenson RS, Lyubarova R, et al. Concepts and controversies: Lipid management in patients with chronic kid- ney disease. Cardiovasc Drugs Ther. 2021;35(3):479-489.
- Bays HE, Toth PP, Kris-Etherton PM, et al. Obesity, adiposity, and dyslipidemia: a consensus statement from the National Lipid Association. J Clin Lipidol. 2013;7(4):304-383.
- Karalis DG, Wild RA, Maki KC, et al. Gender differences in side effects and attitudes regarding statin use in the Understanding Statin Use in America and Gaps in Patient Education (USAGE) study. J Clin Lipidol. 2016;10(4):833-841.
- Laville SM, Gras-Champel V, Moragny J, et al. Adverse drug re- actions in patients with CKD. Clin J Am Soc Nephrol. 2020;15(8): 1090-1102.
- Sinnaeve PR, Schwartz GG, Wojdyla DM, et al. Effect of aliro- cumab on cardiovascular outcomes after acute coronary syn- dromes according to age: an ODYSSEY OUTCOMES trial analysis. Eur Heart J. 2020;41(24):2248-2258.
- Sever P, Gouni-Berthold I, Keech A, et al. LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in pa- tients in the FOURIER trial. Eur J Prev Cardiol. 2021;28(8):805-812.
- Tuñón J, Steg PG, Bhatt DL, et al. Effect of alirocumab on major adverse cardiovascular events according to renal function in pa- tients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial. Eur Heart J. 2020;41(42):4114-4123.
- Ferdinand KC, Jacobson TA, Koren A, Elassal J, Thompson D, Deedwania P. Alirocumab efficacy and safety by race and ethnicity: Analysis from 3 ODYSSEY phase 3 trials. J Clin Lipidol. 2019;13(4):586-593.e5.
- Hunt NB, Emmens JE, Irawati S, et al. Sex disparities in the effect of statins on lipid parameters: the PharmLines Initiative. Medi- cine. 2022;101(2):e28394.
- Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-1278.
- Wilson DP, Jacobson TA, Jones PH, et al. Use of Lipoprotein(a) in clinical practice: A biomarker whose time has come. A scien- tific statement from the National Lipid Association. J Clin Lipidol. 2022;16(5):e77-e95.
- Reyes-Soffer G, Ginsberg HN, Berglund L, et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42(1):e48-e60.
- Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a Eu- ropean Atherosclerosis Society consensus statement. Eur Heart J. 2022;43(39):3925-3946.
- Tsimikas S, Stroes ESG. The dedicated "Lp(a) clinic": a concept whose time has arrived? Atherosclerosis. 2020;300:1-9.
- Khera AV, Everett BM, Caulfield MP, et al. Lipoprotein(a) con- centrations, rosuvastatin therapy, and residual vascular risk: An analysis from the JUPITER Trial (Justification for the Use of Sta- tins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129(6):635-642.
- Varvel S, McConnell JP, Tsimikas S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol. 2016;36(11):2239- 2245.
- Patel AP, Wang M, Pirruccello JP, et al. Lp(a) (lipoprotein [a]) concentrations and incident atherosclerotic cardiovas- cular disease. Arterioscler Thromb Vasc Biol. 2021;41(1): 465-474.
- Arora P, Kalra R, Callas PW, et al. Lipoprotein(a) and risk of ischemic stroke in the REGARDS study. Arterioscler Thromb Vasc Biol. 2019;39(4):810-818.
- Nissen SE, Wolski K, Cho L, et al. Lipoprotein(a) levels in a global population with established atherosclerotic cardiovascu- lar disease. Open Heart. 2022;9(2):e002060.
- Authors
- Wright, R. S., Ray, K. K., Landmesser, U., Koenig, W., Raal, F. J., Leiter, L. A., Conde, L. G., Han, J., & Schwartz, G. G.
- Affiliations
- Mayo Clinic (US)
- Imperial College London (GB)
- Deutsches Herzzentrum der Charité (DE)
- University of the Witwatersrand (ZA)
- St. Michael's Hospital (CA)
- Novartis (Switzerland) (CH)
- Novartis (United States) (US)
- University of Colorado Anschutz (US)
- Corresponding author
- Wright, R. Scott
- ORCID
- Venue
- Mayo Clinic Proceedings
- Publisher
- Elsevier BV
- Published
- 2024-08
- Volume
- 99
- Issue
- 8
- Pages
- 1222-1235
- ISSN
- 0025-6196 (ISSN-L)
- OpenAlex
- W4401226305
- Cited by
- 25
- References
- 56
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 2
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Mayo Clinic Proceedings (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Novartis Pharmaceuticals Corp
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- inclisiran, atherosclerotic cardiovascular disease, LDL cholesterol lowering, PCSK9 inhibition, subgroup analysis, chronic kidney disease, diabetes mellitus, obesity, sex differences, race, lipid-lowering therapy, safety and tolerability, LDL-C goal attainment, hypercholesterolemia, hypertriglyceridemia
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