Inclisiran Demonstrates Significant LDL-C Reduction in New Trial

A recent clinical trial has shown that inclisiran significantly reduces low-density lipoprotein cholesterol (LDL-C) levels in patients at high and very high risk of cardiovascular events. The results of the VICTORION-Difference trial, presented at the European Society of Cardiology Congress 2025, highlight inclisiran’s effectiveness when combined with optimized lipid-lowering therapy compared to a placebo.

The VICTORION-Difference trial was a double-blind, placebo-controlled, randomized phase 4 study conducted across 133 centers in Europe. Participants were selected based on their high or very high cardiovascular risk status, as defined by the 2019 European Society of Cardiology/European Atherosclerosis Society guidelines. All subjects had elevated LDL-C levels despite being on a maximally tolerated dose of statins, which are the most commonly prescribed medications for lowering LDL-C.

Given the established link between high LDL-C levels and the risk of atherosclerotic cardiovascular disease (ASCVD), reducing LDL-C is crucial for patient health. Unfortunately, many individuals on statin therapy do not achieve their LDL-C targets. Inclisiran, a small interfering ribonucleic acid that targets PCSK9 messenger RNA, has emerged as a promising treatment option. Administered biannually after initial doses, it has shown consistent LDL-C reduction.

The VICTORION-Difference trial aimed to evaluate the impact of inclisiran on LDL-C goal achievement and assess its safety profile, including muscle-related adverse events and pain-related quality of life. Professor Ulf Landmesser, director of the department of cardiology at the Deutsches Herzzentrum der Charité in Berlin, emphasized the study’s design to reflect real-world clinical practice.

In total, 1,770 participants were enrolled and randomly assigned to receive either 300mg of subcutaneous inclisiran sodium or a placebo. Patients who did not reach their LDL-C goals received an open-label titration of rosuvastatin to the highest tolerated dose. Notably, 92.3% of participants were classified as having very high cardiovascular risk.

The primary endpoint of the trial was the proportion of participants achieving the recommended LDL-C levels, defined as <55 mg/dl for very high-risk individuals and <70 mg/dl for high-risk individuals, measured at day 90. Results showed that a significantly higher percentage of participants in the inclisiran group reached these goals, with 84.9% achieving their targets compared to just 31% in the placebo group. The odds ratio was calculated at 12.09 with a confidence interval of 95% (9.59 to 15.24), and the statistical significance was confirmed with a p-value of P < 0.0001.

Over a 360-day period, the mean percentage reduction in LDL-C from baseline was -59.45% for those receiving inclisiran, compared to -24.31% for the placebo group, resulting in a treatment difference of 35.14% (P < 0.0001). Additionally, adverse muscle events were lower in the inclisiran cohort, with 11.9% reporting such issues compared to 19.2% in the placebo group (P < 0.0001). The trial also indicated that patients in the inclisiran group experienced greater improvements in pain-related severity and interference scores, with both showing statistical significance. “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,” said Professor Landmesser. He noted that these findings position inclisiran as a convenient and effective treatment for the many at-risk patients who do not adequately respond to existing lipid-lowering therapies. With the publication of these results, inclisiran is being recognized as a critical addition to the management of hypercholesterolemia. The implications for clinical practice are significant, especially as health professionals strive to meet LDL-C goals for their patients effectively.