Inclisiran found Safe and Effective for Lowering LDL in Low-Risk Patients: Study

Inclisiran is a small interfering RNA (siRNA) therapy that lowers LDL cholesterol by inhibiting the generation of PCSK9 in the liver. Even though it has already been approved in the US and Europe to be used together with statin in patients with higher risk, its efficacy as monotherapy in lower-risk groups was not clear. The VICTORION-Mono trial filled this gap, and valuable information on the promise of inclisiran in •who refuse or cannot tolerate statins has been generated.

The VICTORION-Mono trial was a double-blind, randomized clinical trial that recruited 350 adults (mean age 46.1 years; 62.6% women) with no history of ASCVD, diabetes, or FH. All subjects had an estimated 10-year ASCVD risk of <7.5% and LDL cholesterol between 100 and 190 mg/dL (median risk of 2.2%; mean LDL cholesterol of 135.4 mg/dL).

Subjects were randomly assigned to one of the following groups:

• Inclisiran Arm: Subcutaneous injections of inclisiran 284 mg (twice a year) and oral placebo.

• Ezetimibe Arm: Subcutaneous placebo injections and oral ezetimibe 10 mg daily.

• Placebo Arm: Subcutaneous placebo injections and oral placebo.

Inclisiran and placebo injections were administered on day 1 and day 90. The study’s primary goal was to assess the reduction in LDL cholesterol levels at day 150.

Key Findings

LDL Cholesterol Reduction:

• Inclisiran reduced LDL cholesterol by 46.5% from baseline.

• Ezetimibe lowered LDL cholesterol by 11.2%.

• LDL cholesterol in the placebo group rose by 1.4%.

Absolute decreases in LDL cholesterol:

• Inclisiran: 64.9 mg/dL.

• Ezetimibe: 17.6 mg/dL.

• Placebo: 1.3 mg/dL.

Safety Profile:

• Adverse events were comparable across all three groups.

• Four patients (2.3%) in the inclisiran group had new-onset diabetes, but they were already prediabetic.

• No diabetes cases were seen in the ezetimibe or placebo groups.

Diverse Participant Population:

• 40% Hispanic/Latino, 11% African American, and >50% female, a multigenerational patient population.

The VICTORION-Mono trial showed that twice-yearly inclisiran is a safe and effective treatment for reducing LDL cholesterol in low-risk patients who are not on any other lipid-lowering therapy. These findings bring inclisiran into the picture as a possible alternative for patients who refuse or cannot utilize statins, offering a new solution to cholesterol management in this group.

Reference:

Taub, P. R., Gutierrez, A., Wewers, D., Cantu, E. G., Cao, H., Deck, C., Lesogor, A., Ott, D., Mena-Madrazo, J., Zang, X., & Wright, R. S. (2025). Safety and lipid-lowering efficacy of inclisiran monotherapy in patients without ASCVD: The VICTORION-mono randomized clinical trial. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2025.04.049