Key take-aways
- Many patients at high risk of cardiovascular events do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals with available lipid-lowering therapies.
- The VICTORION-Difference trial evaluated efficacy, safety and quality-of-life outcomes with subcutaneous inclisiran every 3–6 months vs. placebo on top of individually optimised lipid-lowering therapy in patients with hypercholesterolaemia at high/very high risk of cardiovascular events.
- Inclisiran brought more patients to early and sustained LDL-C goals with significantly fewer adverse muscle events compared with placebo, providing a treatment strategy that may help address the current gap in LDL-C goal achievement.
Madrid, Spain – 30 August 2025: More patients with hypercholesterolaemia at high/very high risk of cardiovascular (CV) events achieved low-density lipoprotein cholesterol (LDL-C) goals with inclisiran compared with placebo, when given on top of individually optimised lipid-lowering therapy, according to a late-breaking trial presented in a Hot Line session today at ESC Congress 2025.1
Elevated LDL-C is causal for the development and progression of atherosclerotic cardiovascular disease; however, most patients do not achieve guideline-recommended LDL-C goals with available lipid-lowering therapies2 due to suboptimal treatment escalation, nonadherence or concerns about safety, such as muscle pain.
Principal Investigator, Professor Ulf Landmesser from the Deutsches Herzzentrum der Charité, Berlin, Germany, explained the aims of the VICTORION-Difference trial: “When given as a subcutaneous injection every 3 or 6 months, inclisiran interferes with the production of proprotein convertase subtilisin/kexin type 9 (PCSK9), lowering LDL-C levels. The purpose of the VICTORION-Difference study was to compare inclisiran with placebo, on top of individually optimised 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.”
This double-blind, placebo-controlled, randomised phase IV trial was conducted at 133 centres in Bulgaria, Czechia, Estonia, France, Germany, Latvia, Poland and Spain. Eligible patients were at high or very high CV risk according to 2019 European Society of Cardiology/European Atherosclerosis Society guidelines3 and had elevated LDL-C despite being treated with an individualised maximally tolerated statin dose. Participants were randomised 1:1 to receive either subcutaneous injections of inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) or placebo. In addition to inclisiran/placebo, open-label rosuvastatin (starting dose of 5 mg/day or 10 mg/day) was sequentially and optimally titrated to the maximally tolerated dose if individual LDL-C goals were not achieved. The primary endpoint was the proportion of participants achieving 2019 guideline-recommended individual LDL-C goals (very high CV risk: <55 mg/dl [<1.4 mmol/l]; high CV risk: <70 mg/dl [<1.8 mmol/l])3 at day 90.
A total of 1,770 individuals were randomised who had a mean age of 63.7 years and 30.2% were female. Most participants (92.3%) were classified as having very high CV risk.
Regarding the primary endpoint, a significantly higher proportion of participants in the inclisiran vs. the standard-of-care arm achieved their individual guideline-recommended LDL-C goals at 90 days (84.9% vs. 31.0%; odds ratio [OR] 12.09; 95% confidence interval [CI] 9.59 to 15.24; p<0.0001).
Time-averaged mean percentage LDL-C reductions from baseline to day 360 were −59.45% and −24.31% in the inclisiran and the standard-of-care groups, respectively (least squares mean treatment difference 35.14%; p<0.0001).
Fewer participants in the inclisiran vs. standard-of-care arms experienced a muscle-related adverse event (11.9% vs. 19.2%; p<0.0001). In addition, numerically larger time-averaged reductions were noted with inclisiran vs. standard-of-care for pain-related severity (−0.11; p=0.0389) and interference scores (−0.11; p=0.0285) using the Short-Form Brief Pain Inventory, which did not reach statistical significance.
The incidence of treatment-emergent adverse events was comparable between the inclisiran and standard-of-care arms (71.3% and 75.9%, respectively).
In conclusion, Professor Landmesser commented: “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. 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.”
ENDS