Dual PCSK9 Inhibition With Inclisiran and Alirocumab in Secondary Prevention

Summary

This study will evaluate the effectiveness and safety of combining two different types of PCSK9 inhibitors, inclisiran and alirocumab, in patients with high cardiovascular risk who are unable to tolerate statins. Lowering low-density lipoprotein cholesterol (LDL-C) is essential to reduce the risk of cardiovascular events. While PCSK9 inhibitors are effective, many patients treated with a single agent do not reach recommended LDL-C targets, especially those who cannot take statins. Inclisiran and alirocumab reduce LDL-C through different mechanisms. Inclisiran decreases the production of PCSK9 in the liver, while alirocumab binds circulating PCSK9 in the blood. Combining these therapies may lead to a greater reduction in LDL-C levels. In this randomized, open-label clinical trial, approximately 60 patients in secondary prevention will be assigned to one of three groups: inclisiran alone, alirocumab alone, or a combination of both treatments. Patients will be followed for 9 months with regular clinical and laboratory assessments. The main goal of the study is to determine whether combination therapy leads to greater LDL-C reduction compared to each treatment alone. Secondary objectives include assessing the proportion of patients achieving target LDL-C levels and evaluating treatment safety and tolerability.

Timeline

Start

2026-05-18

Primary completion

2027-05

Completion

2027-06

Publications

• Background Kafol J, Fras Z, Novakovic M, Sperling LS, Cevc M, Krevel B, Kafol L, Kelenc A, Kepic K, Vrbinc K, Svarc M, Groselj U, Jug B. Real-world effectiveness and cardiovascular outcomes of PCSK9 inhibitor therapy: a prospective registry study. Lipids Health Dis. 2026 Mar 5;25(1):106. doi: 10.1186/s12944-026-02897-3.
• Background Mach F, Koskinas KC, Roeters van Lennep JE, Tokgozoglu L, Badimon L, Baigent C, Benn M, Binder CJ, Catapano AL, De Backer GG, Delgado V, Fabin N, Ference BA, Graham IM, Landmesser U, Laufs U, Mihaylova B, Nordestgaard BG, Richter DJ, Sabatine MS; ESC/EAS Scientific Document Group. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2025 Nov 7;46(42):4359-4378. doi: 10.1093/eurheartj/ehaf190. No abstract available.
• Background Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455. No abstract available.
• Background Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489-99. doi: 10.1056/NEJMoa1501031. Epub 2015 Mar 15.
• Background Wright RS, Raal FJ, Koenig W, Landmesser U, Leiter LA, Vikarunnessa S, Lesogor A, Maheux P, Talloczy Z, Zang X, Schwartz GG, Ray KK. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial. Cardiovasc Res. 2024 Oct 14;120(12):1400-1410. doi: 10.1093/cvr/cvae109.
• Background Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP; ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387. Epub 2020 Mar 18.

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