Leqvio Shows Clinically Meaningful LDL-C Goal Attainment in Patients with Hypercholesterolemia in Phase IV Trial

Results from the Phase IV V-DIFFERENCE trial (NCT05192941) showed that Novartis’ Leqvio (inclisiran) achieved rapid and clinically meaningful low-density lipoprotein cholesterol (LDL-C) goal attainment in patients with hypercholesterolemia.

The company noted that these outcomes were achieved when Leqvio was administered in addition to optimized lipid-lowering therapy (LLT). Full data were presented at the 2025 European Society of Cardiology Congress.¹

“V-DIFFERENCE is the largest LDL-C lowering study with Leqvio to read out to date, and the first to focus on patient-centered outcomes,” said Ulf Landmesser, MD, chairman, department of cardiology, angiology and intensive care medicine, German Heart Center of Charité and Charité University Medicine Berlin, in a press release. “These findings are significant as they demonstrate effective options for lipid management improvement in patients at risk, a majority of whom continue to remain above recommended LDL-C levels.”

V-DIFFERENCE Trial Design and Patient Population

• The randomized, double-blind, placebo-controlled V-DIFFERENCE trial is comparing the efficacy, safety, and quality-of-life (QoL) outcomes of Leqvio vs. placebo, on top of individually optimized LLT in 1,770 hypercholesterolemia patients with high and very high cardiovascular risk who have not achieved guideline-recommended LDL-C goals.
• Patients were randomly assigned in a 1:1 ratio to receive Leqvio plus LLT or placebo plus LLT.
• The primary endpoint of the trial was the number of patients achieving their individual LDL-C target after 90 days of treatment.
• Key secondary endpoints assessed after 360 days included the percentage change in mean LDL-C, incidence of muscle-related adverse events (MRAEs), and patient-reported outcomes such as pain occurrence and pain-related QoL measured by the Short-Form Brief Pain Inventory (SF-BPI).^1,2

Key Results

• Results showed that at 90 days, 84.9% of patients receiving Leqvio achieved guideline-recommended LDL-C targets compared with 31% in the placebo group (p<0.0001).
• Time-averaged mean LDL-C reductions at 360 days were −59.5% for Leqvio compared to −24.3% for placebo plus LLT, representing a significant treatment difference of 35.1% (p<0.0001).
• Leqvio demonstrated a favorable safety profile, with 11.9% experiencing MRAEs compared to 19.2% in the placebo group.
• Treatment-related adverse events were comparable between groups.³

Clinical Implications

“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,” V-DIFFERENCE trial principal investigator Ulf Landmesser, Deutsches Herzzentrum der Charité, Berlin, Germany, said in a press release. “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.”³

Background on Hypercholesterolemia

• According to the Centers for Disease Control and Prevention, the prevalence of adults with hypercholesterolemia was 11.3% between 2021 and 2023.
• Women had a slightly higher prevalence (11.9%) compared to men (10.6%).
• Around 13.8% of adults had low levels of high-density lipoprotein cholesterol, with the condition more common in men at 21.5% compared to 6.6% in women, and the prevalence decreased as age increased.⁴

Novartis Perspective

“Novartis is dedicated to tackling the most challenging problems in cardiovascular disease,” said Ruchira Glaser, MD, global head, Cardiovascular, Renal and Metabolic Development Unit, Novartis, in the press release. “These results highlight the potential of Leqvio to transform cardiovascular care by improving meaningful patient outcomes. V-DIFFERENCE has provided evidence that early use of Leqvio is an effective way to help patients reach their LDL-C goals faster without the need to add other therapies or maximize statin doses.”

References

1. Novartis Leqvio® shows statistically significant and clinically meaningful early LDL-C goal achievement with less muscle pain. Novartis. August 30, 2025. Accessed September 3, 2025. https://www.novartis.com/news/media-releases/novartis-leqvio-shows-statistically-significant-and-clinically-meaningful-early-ldl-c-goal-achievement-less-muscle-pain
2. Study of Efficacy, Safety, Tolerability and Quality of Life of Inclisiran (KJX839) vs Placebo, on Top of Ongoing Individually Optimized Lipid-lowering Therapy, in Participants With Hypercholesterolemia (V-DIFFERENCE). Clinicaltrials.gov. Accessed September 3, 2025. https://www.clinicaltrials.gov/study/NCT05192941?term=NCT05192941&rank=1
3. Early and sustained LDL-C goal achievement with inclisiran in patients at high cardiovascular risk. ESC. 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?utm_source=chatgpt.com#
4. Total and High-density Lipoprotein Cholesterol in Adults: United States, August 2021–August 2023. CDC. Accessed September 3, 2025. https://www.cdc.gov/nchs/products/databriefs/db515.htm