CONFERENCE UPDATES: ESC 2025

Inclisiran-based strategy improves LDL-C goal attainment and safety: Results from the phase 4 VICTORION-Difference trial

CARDIOLOGY
20 Sep 2025

STUDY DESIGN

Atherosclerotic cardiovascular disease (ASCVD) remains a substantial health burden, with low-density lipoprotein cholesterol (LDL-C) established as a causal risk factor in both its development and progression.1 Despite maximally tolerated dose (MTD) of statin therapy and further therapy escalation, many patients do not achieve recommended LDL-C targets, often due to tolerability concerns.1

Inclisiran is a small interfering ribonucleic acid (siRNA) targeting hepatic proprotein convertase subtilisin/kexin type 9 messenger ribonucleic acid (PCSK9 mRNA) that is administered twice yearly and offers sustained and effective LDL-C reductions.1 The VICTORION-Difference trial assessed the efficacy, safety, tolerability, and quality-of-life (QoL) outcomes of an inclisiran-based strategy vs. individually optimized lipid-lowering therapy (ioLLT) in patients with high or very high cardiovascular (CV) risk who fail to achieve guideline-recommended LDL-C targets despite statin MTD.1

This phase 4, double-blind, placebo-controlled study enrolled a total of 1,770 patients across 133 sites in 8 European countries.1 Prior to randomization, patients underwent a statin run-in period during which they were switched to rosuvastatin and up-titrated to MTD if guideline-recommended LDL-C levels were not attained.1 Eligible patients were ≥18 years old with high or very high CV risk, with fasting triglyceride level <400mg/dL and on a stable statin dose for ≥30 days.1 At randomization, participants were assigned 1:1 to either inclisiran sodium 300mg subcutaneous (SC) injection + rosuvastatin + ioLLT (inclisiran-based strategy) or placebo + rosuvastatin + ioLLT (ioLLT strategy).1 Baseline demographics and clinical characteristics were well-balanced between arms.1 Patients were followed up for 360 days with assessments at multiple timepoints.1

The primary endpoint was the proportion of patients achieving LDL-C goals at day 90.1 Key secondary endpoints included the percentage change in mean LDL-C from baseline to day 360 and the proportion of patients with muscle-related adverse events (AEs) over the same period.1 Additional endpoints assessed patient-reported outcomes (PROs), including changes in pain severity, interference scores, and the annualized number of days during which patients experienced pain.1

FINDINGS

 Primary endpoint :
  • The primary endpoint was the proportion of patients achieving guideline-recommended LDL-C goals at day 901
  • At day 90, a significantly higher proportion of patients receiving the inclisiran-based strategy achieved LDL-C goals vs. the ioLLT group (84.9% vs. 31.0%; odds ratio [OR]=12.09; 95% CI: 9.59-15.24; p<0.0001)1
  • The treatment effect was consistent across all prespecified subgroups1
 Key efficacy endpoint :
  • The key secondary endpoint was the percentage change in mean LDL-C from baseline to day 3601
  • Inclisiran-based strategy achieved a superior reduction in LDL-C (-59.5%) vs. ioLLT arm (-24.3%), corresponding to a treatment difference of -35.1% (p<0.0001)1
 Key safety endpoint :
  • The key safety endpoint was the proportion of patients with at least one muscle-related adverse event (AE) from baseline to day 3601
  • The inclisiran-based strategy arm had fewer muscle-related AEs (11.9%) vs. the ioLLT arm (19.2%) (OR=0.57; 95% CI: 0.43-0.74; p<0.0001)1
  • The proportion of treatment-related AEs (TRAEs) was similar between the two arms (71.3% vs. 75.9%) with no new safety signals reported1
 Patient-reported outcomes :
  • Additional endpoints assessed included PROs on changes in pain severity, interference scores, and the annualized number of days during which patients experienced pain1
  • Changes from baseline in Short-Form Brief Pain Inventory (SF-BPI) pain severity and interference were slightly greater with inclisiran vs. ioLLT (mean change=-0.11; 95% CI: -0.23 to 0.01; 1-sided p=0.0389 for severity; -0.22 to 0.0; 1-sided p=0.0285 for interference), but neither reached statistical significance, likely reflecting greater QoL impairment in a minority of patients on statin MTD1
  • Annualized pain days from baseline to day 360 were lower with inclisiran vs. ioLLT (198.63 days vs. 214.51 days; OR=0.93; 95% CI: 0.81-1.06; p=0.1349), but the difference was not statistically significant1
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