VICTORION-Difference: Inclisiran Achieves Primary Endpoint of LDL-C Reduction Versus Placebo

More patients with hypercholesterolemia at high and very high risk of cardiovascular (CV) events achieved low-density lipoprotein cholesterol (LDL-C) goals with inclisiran on top of individually optimized lipid-lowering therapy than with placebo, according to the VICTORION-Difference trial.1

Presented at the European Society of Cardiology Congress 2025, the VICTORION-Difference trial was a double-blind, placebo-controlled, randomized phase 4 trial conducted at 133 centers across Europe. For inclusion, patients were required to be at high or very high CV risk according to the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines and have elevated LDL-C despite being treated with an individualized, maximally tolerated statin dose.1

Given the causal relationship between persistently high levels of LDL-C and the risk of atherosclerotic cardiovascular disease (ASCVD), global clinical guidelines have long emphasized the importance of reducing cumulative exposure to LDL-C. However, many patients on statins, the most recommended therapy for LDL-C reduction, fail to achieve the recommended goals.2

Inclisiran, a small interfering ribonucleic acid targeting PCSK9 messenger RNA, provides a consistent reduction in LDL-C when given twice yearly after initial doses. In the last decade, the ORION and VICTORION programs have provided the basis for the ascension of inclisiran from investigational agent to approved agent with multiple indications, including as a first-line therapy in the management of ASCVD in July 2025. The latest trial in the VICTORION program, VICTORION-Difference was undertaken to examine its impact when used on top of ongoing lipid-lowering therapy.

“The purpose of the VICTORION-Difference study was to compare inclisiran with placebo, on top of individually optimized lipid-lowering therapies, for LDL-C goal achievement and novel endpoints related to muscle-related adverse events and pain-related quality of life (QoL) in a population that mirrors real-world practice,” Professor Ulf Landmesser, MD, PhD, director of the department of cardiology, angiology, and intensive care medicine at the Deutsches Herzzentrum der Charité in Berlin, said in a statement.1

Investigators included a total of 1770 participants, who were randomly assigned in a 1:1 ratio to either subcutaneous inclisiran sodium 300mg or placebo. Additionally, open-label rosuvastatin was titrated to the maximally tolerated dose if individual LDL-C goals were not achieved. Most patients (92.3%) included in the study had very high CV risk.1

The trial’s primary endpoint was the proportion of participants achieving the 2019 guideline-recommended individual LDL-C goals (very high CV risk: <55 mg/dl; high CV risk: <70 mg/dl at day 90). Ultimately, a substantially higher proportion of participants in the inclisiran group achieved individual guideline-recommended goals at 90 days (84.9% versus 31%; odds ratio [OR], 12.09; 95% CI, 9.59 to 15.24; P <.0001). Time-averaged mean percentage LDL-C reductions from baseline to day 360 were -59.45% and -24.31% in the inclisiran and placebo groups, respectively (least mean squares mean treatment difference 35.14%; P <.0001).1

Additionally, investigators noted a lower number of participants in the inclisiran group experiencing a muscle-related adverse event (11.9% versus 19.2%; P <.0001). Numerically larger time-averaged reductions were also seen among the inclisiran group in both pain-related severity (-0.11; P = .0389) and interference scores (-0.11; P = .0285).1

“This large study demonstrated the effectiveness of an inclisiran-based treatment strategy over current usual care in bringing patients to early and sustained LDL-C goals, with significantly fewer adverse muscle symptoms,” Landmesser said. “These findings indicate that inclisiran represents a convenient, effective and well-tolerated treatment option for the high number of at-risk patients who currently do not respond adequately to other lipid-lowering therapies.”1

References

1. European Society of Cardiology. Early and sustained LDL-C goal achievement with inclisiran in patients at high cardiovascular risk. August 30, 2025. Accessed September 3, 2025. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Early-and-sustained-LDL-C-goal-achievement-with-inclisiran-in-patients-at-high-cardiovascular-risk

2. Landmesser U, Laufs U, Schatz U, et al. Inclisiran-based treatment strategy in hypercholesterolaemia: the VICTORION-Difference trial. Eur Heart J. Published online August 30, 2025. doi:10.1093/eurheartj/ehaf685