BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for atherosclerotic cardiovascular (CV) disease development and progression. The European Society of Cardiology guidelines recommend combination treatment to achieve CV risk-based LDL-C treatment goals. Inclisiran, a small interfering ribonucleic acid (siRNA) that targets hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA, can provide sustained and effective LDL-C reduction.
METHODS: VICTORION-Difference, a phase 4 double-blind, placebo-controlled randomised clinical trial included adults with hypercholesterolaemia at high- or very high CV risk. Participants were randomised 1:1 to receive inclisiran sodium (300 mg subcutaneous injections; equivalent to 284 mg inclisiran) or placebo together with individually optimised lipid-lowering therapy (ioLLT), including up-titration with rosuvastatin (open-label) until either their individual LDL-C goal or maximally tolerated statin dose (open-label rosuvastatin) was achieved. The primary objective was assessment of LDL-C goal achievement at Day 90. Key secondary objectives were muscle-related adverse events (MRAEs) and mean LDL-C reduction.
RESULTS: Overall, 1770 individuals (mean age, 63.7 years) were randomised to receive inclisiran (n=898) or ioLLT (n=872). At Day 90, a significantly higher proportion of participants receiving inclisiran vs. ioLLT achieved their individual LDL-C goals (84.9% vs. 31.0%; odds ratio [OR] 12.09, p<0.001). The mean percentage reduction in LDL-C from baseline to Day 360 was -59.5% and -24.3% in the inclisiran and ioLLT arms, respectively (least squares mean treatment difference [LSMTD]=-35.14%, p<0.001). Fewer participants receiving inclisiran vs. ioLLT reported a MRAE (11.9% vs. 19.2%; OR 0.57, p<0.001). The mean reduction in Short Form-Brief Pain Inventory pain severity and interference scores favoured inclisiran over ioLLT (LSMTD=-0.11, p=0.039; LSMTD=-0.11, p=0.029, respectively). No new safety concerns were identified.
CONCLUSIONS: An inclisiran-based treatment strategy was superior to ioLLT in LDL-C goal achievement, delivering early and sustained LDL-C reduction, with fewer MRAEs in individuals with hypercholesterolaemia. cholesterol, muscle-related adverse events, quality of life, statins.
| Discipline Area | Score |
|---|---|
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Internal Medicine | |
| Cardiology |  |
The VICTORION-Difference trial provides compelling evidence supporting inclisiran as an effective lipid-lowering strategy in patients at high or very high cardiovascular risk. Compared with optimized lipid-lowering therapy, inclisiran achieved a markedly higher LDL-C goal attainment (85% vs 31%) and a sustained ~60% LDL-C reduction over 12 months, with fewer muscle-related adverse events. These results reinforce the role of inclisiran as a cornerstone in combination lipid-lowering therapy, offering potent efficacy, excellent tolerability, and the convenience of twice-yearly dosing.
This study looks at adding in a small interfering ribonucleic acid (siRNA) that targets hepatic proprotein PCSK9 messenger RNA to lipid optimizing therapy vs placebo and finds more patients reach target LDL at apparent lower muscle adverse effect rates. Other studies have shown that a target maximizing approach isn't clinically that different from a maximum statin dose approach for clinical outcomes, not surrogate markers, so one does need to think about where this fits in exactly. Certainly, the drug itself looks promising.
Important study of an effective drug to help optimise secondary prevention in real-life clinical care when optimal lipid levels are not possible to achieve due to intolerance / potential nocebo effects.