Inclisiran-based strategy achieves LDL-C goals in patients at high CV risk

Treatment with inclisiran, on top of individually optimized lipid-lowering therapy (ioLLT), resulted in the achievement of guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets among patients with hypercholesterolaemia at high or very high risk of cardiovascular (CV) events, according to the VICTORION-Difference trial presented at ESC 2025.

“The study met its primary endpoint, demonstrating the superiority of an inclisiran-based strategy vs ioLLT to attain LDL-C goals at day 90 (p<0.0001) in patients at high or very high CV risk,” said lead author Dr Ulf Landmesser from Deutsches Herzzentrum der Charité, Berlin, Germany.

This phase IV, double-blind, placebo-controlled trial involved 1,770 patients (mean age 63.7 years, 70 percent male) with hypercholesterolaemia at high/very high CV risk recruited from 133 sites across eight European countries. Participants were randomized in a 1:1 ratio to receive subcutaneous inclisiran sodium 300 mg (inclisiran-based strategy arm, n=898) or placebo (ioLLT arm, n=872) in addition to ioLLT and up-titration with rosuvastatin (starting dose: 5 or 10 mg/day) until they reached their individual LDL-C goals or maximally tolerated statin dose.

In this study, the guideline-recommended individual LDL-C goals for 2019 were <70 mg/dL (<1.8 mmol/L) for patients at high CV risk and <55 mg/dL (<1.4 mmol/L) for those at very high CV risk.

On day 90, a significantly higher proportion of patients in the inclisiran-based strategy arm achieved their individual LDL-C goals compared with those in the ioLLT arm (84.9 percent vs 31 percent; odds ratio [OR], 12.09; p<0.0001). [Landmesser U, et al, ESC 2025]

This benefit was consistently observed across various subgroups, including age, gender, and the degree of CV risk, as noted by Landmesser.

From baseline to day 360, the mean percentage change in LDL-C levels was significantly reduced by 59.4 percent in patients treated with inclisiran, whereas only a 24.3-percent reduction was observed in those treated with ioLLT (least squares mean treatment difference, -35.14 percent; p<0.0001).

Additionally, the proportion of patients in the inclisiran arm who achieved their LDL-C goals was evident as early as day 30 (80.8 percent vs 11.3 percent) and remained consistent through day 330 (92.7 percent vs 62.8 percent) compared with those in the ioLLT arm.

Although more than half of the ioLLT recipients achieved the guideline-recommended LDL-C goal by day 330, the inclisiran recipients still achieved a notably higher percentage (approximately 90 percent) reaching the same target, noted Landmesser.

This further demonstrates the “clear superiority over time for the inclisiran-based strategy,” Landmesser said.

In terms of safety, significantly fewer patients in the inclisiran-based strategy arm experienced muscle-related adverse events (AEs) from days 1–360 than those in the ioLLT arm (11.9 percent vs 19.2 percent; OR, 0.57; p<0.0001).

Landmesser said this maybe because fewer patients in the inclisiran arm required up-titration to the maximally tolerated statin dose than those in the ioLLT arm (mean rosuvastatin dose, 13.2 vs 25.4 mg/day).

Taken together, “the study met both key secondary endpoints, demonstrating that an inclisiran-based treatment strategy vs ioLLT led to a greater and sustained mean LDL-C reduction from day 1 to day 360, with significantly fewer muscle-related AEs,” noted Landmesser.

Overall, “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,” according to Landmesser.

“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,” he added.