Safety and Lipid-Lowering Efficacy of Inclisiran Monotherapy in Patients Without ASCVD

BACKGROUND: Inclisiran administration twice-yearly (after initial and 3-month doses) effectively reduces low-density lipoprotein cholesterol (LDL-C) in patients on maximally tolerated statins with atherosclerotic cardiovascular disease (ASCVD), risk equivalents, or heterozygous familial hypercholesterolemia. OBJECTIVES: In this study, the authors sought to evaluate whether inclisiran is superior as monotherapy over placebo and ezetimibe in reducing LDL-C in a primary prevention population without ASCVD. METHODS: VICTORION-Mono (V-Mono), a 6-month, randomized, double-blind, multicenter, placebo- and active-comparator controlled phase 3 trial, assessed inclisiran monotherapy in adult participants (aged 18-75 years) without prior ASCVD, diabetes, or familial hypercholesterolemia, with a fasting LDL-C of 100-190 mg/dL and 10-year predicted ASCVD risk of <7.5% according to pooled cohort equation, who were not receiving any lipid-lowering therapy. Participants were randomized (2:1:1) to inclisiran, ezetimibe, or placebo. The primary endpoint was percentage change in LDL-C from baseline, and key secondary endpoints included absolute change in LDL-C and percentage change in proprotein convertase subtilisin/kexin type 9 (PCSK9) from baseline to day 150. The study did not evaluate twice-yearly inclisiran dosing beyond the first 180 days. Safety was also assessed. RESULTS: , and median 10-year predicted ASCVD risk score was 2.2%. The mean percentage change in LDL-C from baseline at day 150 for placebo was 1.4%, for ezetimibe -11.2%, and inclisiran -46.5%. The difference in the change from baseline with inclisiran vs placebo was -47.9% and vs ezetimibe was -35.4% (both P < 0.0001). Inclisiran treatment also demonstrated favorable improvements in other lipid and lipoprotein(a) levels. Inclisiran was well tolerated, with no new safety concerns. CONCLUSIONS: V-Mono demonstrates for the first time that in patients not receiving lipid-lowering therapy, inclisiran as monotherapy, is superior to both placebo and ezetimibe in reducing LDL-C levels over a 6-month follow-up period and was well tolerated. These findings are consistent with previous observations in statin-treated patients. (Efficacy and Safety of Inclisiran as Monotherapy in Patients With Primary Hypercholesterolemia Not Receiving Lipid-Lowering Therapy [VICTORION-Mono]; NCT05763875).