“Inclisiran first” strategy lowers LDL-C in real-world ASCVD patients: Results from the VICTORION-INITIATE trial

08 Jul 2024


A reduction in low-density lipoprotein-cholesterol (LDL-C) is associated with improvements in cardiovascular (CV) outcomes in patients with atherosclerotic cardiovascular disease (ASCVD).1 As such, multiple guidelines recommend LDL-C targets of <55mg/dL and <70mg/dL based on baseline risks.1 However, many patients fail their LDL-C goals due to clinical inertia, medication nonadherence, side effects, and/or poor healthcare access.1 Inclisiran is a first-in-class small interfering RNA (siRNA) that inhibits hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) production and increases LDL receptor expression and LDL-C clearance.1 In clinical studies, twice-yearly administration of inclisiran has been shown to achieve a 50% reduction in LDL-C.1

The VICTORION-INITIATE study is a prospective, randomized, open-label, phase 3b trial conducted to evaluate an “inclisiran first” implementation strategy compared to usual care in patients with ASCVD in representative US clinical settings.1 The study included adult patients with a history of ASCVD, LDL-C levels ≥70mg/dL or non-high density lipoprotein-cholesterol (non-HDL-C) levels ≥100mg/dL and fasting triglycerides <500mg/dL who were treated with maximally tolerated statin therapy or had documented statin intolerance.1 Participants were randomized 1:1 to receive “inclisiran first” (n=225) or the usual care (n=225).1 The “inclisiran first” implementation strategy is the immediate addition of inclisiran upon failure to achieve an LDL-C of <70mg/dL despite maximally tolerated statin therapy.1

The primary endpoints of the study were the percent change in LDL-C from baseline to day 330 and the discontinuation of statin (defined as no statin use ≥30 days before the end-of-study visit).1 Key secondary endpoints included the proportion of patients achieving the pre-specified LDL-C goals at day 330 and changes in background lipid-lowering therapy (LLT).1 A safety analysis was also performed at each follow-up visit.1


Primary endpoints:

  • The primary endpoints were the percent change in LDL-C from baseline to day 330 and statin discontinuation1
  • Patients in the “inclisiran first” group had a 60.0% reduction in LDL-C levels compared with a 7.0% reduction in the usual care group, resulting in a significantly greater LDL-C reduction at all time points (least square [LS] mean difference: -53.0%; 97.5% CI: -60.0 to -46.0; p<0.001)1
  • More patients receiving usual care discontinued statin therapy than those receiving “inclisiran first” (16.7% vs. 6.0%). The between-group difference in the rates of discontinuation were within the non-inferiority margin: -10.6% (97.5% CI: -18.3% to -3.0%)1

Secondary endpoints:

  • The key secondary endpoints were the proportion of patients reaching an LDL-C of <70mg/dL or <55mg/dL at day 330 and the changes in background LLT1
  • The percentage of patients achieving an LDL-C of <70mg/dL was 81.8% and 22.2% in the “inclisiran first” and the usual care arm, respectively1
  • The percentage of patients achieving an LDL-C of <55mg/dL was 71.6% and 8.9% in the “inclisiran first” and the usual care arm, respectively1
  • In the “inclisiran first” group, background LLT remained similar between baseline and day 330, with the majority receiving statin only (89.8% vs. 88.4%) or statin combination therapy (0.4% vs. 1.4%)1
  • In the usual care group, the proportion of patients who received statin only as background LLT decreased from baseline to day 330 (88.0% vs. 73.4%). Compared to baseline, more patients had PCSK9 monoclonal antibody without statins (0% vs. 2.5%) or statin combination therapy (1.8% vs. 12.6%) as background LLT at day 3301


The safety profile of the “inclisiran first” implementation strategy was comparable to usual care1
62.8% and 53.7% of the “inclisiran first” group and the usual care group experienced ≥1 treatment-emergent adverse event (TEAE), respectively1
Injection-site TEAEs were more common in the “inclisiran first” group than the usual care group (10.3% vs. 0.0%), where almost all cases were mild with only 1 case of moderate injection-site TEAE1


"Results from VICTORION-INITIATE trial demonstrate the clinical value of initiating inclisiran earlier in the treatment pathway"

Dr. Michael J. Koren
Department of Cardiology,
Jacksonville Center for Clinical Research,
Jacksonville, United States

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