Key result
Inclisiran-based therapy increases 1-year LDL-C goal attainment by ~27 percentage points over optimized lipid therapy alone.
Why the study?
Following demonstrated improvements in lipid management with inclisiran-based therapy in the VICTORION-Difference trial, the specific patterns of lipid-lowering therapy escalation, LDL-C goal attainment, and muscle-related adverse events across treatment subgroups required further assessment.
Does inclisiran-based therapy improve LDL-C goal attainment and reduce the need for lipid-lowering therapy escalation and muscle-related adverse events compared to placebo with individually optimized lipid-lowering therapy in patients with hypercholesterolaemia at high or very high cardiovascular risk?
RCT (n=1,770)
Double-blind
1:1
Does inclisiran-based therapy improve LDL-C goal attainment and reduce the need for lipid-lowering therapy escalation and muscle-related adverse events compared to placebo with individually optimized lipid-lowering therapy in patients with hypercholesterolaemia at high or very high cardiovascular risk?
In high or very high cardiovascular risk patients with hypercholesterolaemia, an inclisiran-based strategy achieved superior and earlier LDL-C goal attainment while reducing the need for high-dose statins or non-statin therapy escalation and lowering rates of muscle-related adverse events.
Inclisiran-based regimens may improve LDL-C goal attainment with lower statin doses; extends prior trial data but remains exploratory.
Background Inclisiran-based therapy improved lipid management in individuals at high/very high cardiovascular (CV) risk in the VICTORION-Difference trial. Purpose This exploratory analysis assessed lipid-lowering therapy (LLT) escalation, low-density lipoprotein cholesterol (LDL-C) goal attainment, and muscle-related adverse events (AEs) over 360 days. Methods In this Phase 4, double-blind, placebo-controlled trial, participants (N=1770) with hypercholesterolaemia at high/very high CV risk on maximally tolerated statins were randomised 1:1 to inclisiran sodium 300 mg (284 mg inclisiran) or placebo, each with individually optimized LLT (ioLLT), on Days (D) 1, 90, and 270. All participants switched to open-label rosuvastatin at randomisation and were managed to LDL-C goals by rosuvastatin uptitration (20 or 40 mg QD) and LLT escalation through D360; those not at goal had full LLT escalation access without inclisiran. Results More participants achieved LDL-C goals with inclisiran-based therapy vs ioLLT (D90: 85.1% vs 31.0%; D360: 89.5% vs 62.2%). Odds of goal attainment were higher with inclisiran-based therapy across LLT subgroups (Figure). Goal attainment remained lower in the ioLLT arm despite access to protocol-guided LLT escalation. By D360, LLT regimens in the inclisiran vs ioLLT arms were: statin (without ezetimibe/bempedoic acid [BPA]; 72.9% vs 22.6%), statin and ezetimibe (without BPA; 21.5% vs 52.9%), no statin (± ezetimibe/BPA; 2.9% vs 2.3%), and statin and BPA (± ezetimibe; 2.7% vs 22.1%). By D360, 64.8% of those on inclisiran-based therapy vs 12.5% on ioLLT had ≤10 mg rosuvastatin; fewer required >20 mg (12.5% vs 52.8%; Table). LDL-C goal attainment at D90 with inclisiran-based therapy was 45.8%, 89.4%, 77.9%, and 75.6% vs 0%, 38.3%, 34.6%, and 25.4% with ioLLT for rosuvastatin 0, ≤10, >10 to ≤20, and >20 mg. Mean percentage LDL-C reductions from D1 (averaged over all post-baseline visits) were significantly greater with inclisiran-based therapy across rosuvastatin doses. Significantly fewer muscle-related AEs occurred with inclisiran-based therapy vs ioLLT among those on no rosuvastatin (33.3% vs 60.5%; odds ratio [OR], 0.34; 95% confidence interval [CI], 0.13–0.85), ≤10 mg (10.8% vs 35.9%; OR, 0.22; 95% CI, 0.14–0.36), >10 to ≤20 mg (13.5% vs 25.5%; OR, 0.46; 95% CI, 0.27–0.80), and no statin ± ezetimibe/BPA (24.0% vs 57.9%; OR, 0.25; 95% CI, 0.07–0.89; safety set). Additional patient-reported outcomes will be presented with the data above. Conclusion Inclisiran-based therapy provided superior and earlier LDL-C goal attainment with less need for LLT escalation and fewer muscle-related AEs overall and in specific LLT subgroups. Despite full access to LLT options as part of ioLLT, most participants did not achieve their LDL-C goals by D360 without inclisiran. Inclisiran-based therapy offers an effective approach in achieving guideline-recommended LDL-C goals in at-risk patients with hypercholesterolaemia.FigureTable
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Banach et al. (2026) conducted an RCT in Hypercholesterolaemia at high or very high cardiovascular risk (n=1,770). Inclisiran sodium plus individually optimized lipid-lowering therapy vs. Placebo plus individually optimized lipid-lowering therapy was evaluated on LDL-C goal attainment at Day 360. Inclisiran-based therapy achieved higher LDL-C goal attainment than individually optimized lipid-lowering therapy alone at Day 90 (85.1% vs 31.0%) and Day 360 (89.5% vs 62.2%).
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