Inclisiran in the Spotlight: The VICTORION-Mono Trial Shakes Up Primary Prevention
Breaking New Ground in LDL-C Management
A landmark study, VICTORION‑Mono (V‑Mono), reveals that inclisiran—a twice-yearly, small interfering RNA (siRNA) designed to inhibit PCSK9—is significantly more effective than both placebo and ezetimibe in lowering LDL‑cholesterol (LDL‑C) in individuals without atherosclerotic cardiovascular disease (ASCVD)
Who Was Studied?
- Population: Adults aged 18–75 years, free of ASCVD, diabetes, or familial hypercholesterolemia.
- Risk Profile: Primary prevention cohort with 10-year ASCVD risk below 7.5%, LDL‑C between 100 and 190 mg/dL.
- Study Design: A 6-month, double-blind, multicenter, Phase III trial with a 2:1:1 randomization to inclisiran, ezetimibe, or placebo
Results That Turn Heads
- LDL‑C Reduction at Day 150:
- Inclisiran: – 46.5% from baseline
- Ezetimibe: – 11.2%
- Placebo: +1.4%
- Relative Difference:
- Inclisiran vs. Placebo: – 47.9%
- Inclisiran vs. Ezetimibe: – 35.4% (both p < 0.0001)
- Lipoprotein(a) and PCSK9 levels also fell significantly with inclisiran compared to both controls
Safety & Tolerability
- Well tolerated, with no new safety concerns identified.
- Adverse event rates were similar across groups (inclisiran ~31%, placebo ~29%, ezetimibe ~30%)
- A few cases of new-onset diabetes occurred in patients receiving inclisiran (mainly those with prediabetes), but none in other groups.
- Rare hepatic adverse events (1%) were equally distributed among inclisiran and ezetimibe recipients.
Why It Matters
- Convenience meets power: Inclisiran’s twice-yearly dosing regimen could dramatically improve adherence in primary prevention—many patients hesitate to daily statin use due to side-effect concerns or perceived low benefit.
- Efficacy: The LDL‑C reduction (– 46.5%) rivals or surpasses that of monoclonal PCSK9 inhibitors, which typically show ~48‑57% LDL‑C drops but often require more frequent dosing
- Diverse cohort: With 62.6% women, ~10.6% Black, and ~40% Hispanic participants, V‑Mono stands out for inclusivity in lipid-lowering research
Limitations & Next Steps
- Short duration: Only a 6-month follow-up—long-term outcomes, including cardiovascular event reduction, remain unknown.
- Comparator gap: No head-to-head comparison with statins, bempedoic acid, or other PCSK9 monoclonal antibodies.
- Ezetimibe performance: The relatively modest LDL‑C reduction (~ –11%) is lower than in some prior studies—possibly due to unmeasured nonadherence
Understanding how inclisiran stacks up against established therapies and whether it translates to real-world cardiovascular benefit will require further trials.
Bottom Line
The VICTORION‑Mono trial is a compelling proof-of-concept: Inclisiran monotherapy achieves robust LDL‑C reduction, significantly outperforming placebo and ezetimibe, with a favorable safety profile, in individuals not yet receiving lipid-lowering therapy.
Its infrequent dosing, strong efficacy, and tolerability make it a potential game-changer in the preventive cardiology landscape, especially for those unwilling or unable to use daily pills.
References
- Taub PR et al., J Am Coll Cardiol, “Safety and Lipid‑Lowering Efficacy of Inclisiran Monotherapy in Patients Without ASCVD: The VICTORION‑Mono Randomized Clinical Trial”, Epub May 5 2025; Print Jul 22 2025; DOI: 10.1016/j.jacc.2025.04.049