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Cited by 13Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

Inclisiran-based treatment strategy in hypercholesterolaemia: the VICTORION-difference trial

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Landmesser, Ulf, Laufs, Ulrich, Schatz, Ulrike, Winzer, Ephraim B, Nowak, Bernd, Kassner, Ursula, Gouni-Berthold, Ioanna, Esteban, Alicia +7 more·2026·European Heart Journal
DOI 10.1093/eurheartj/ehaf685PMC PMC13318417
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Abstract

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 randomized clinical trial included adults with hypercholesterolaemia at high- or very high CV risk. Participants were randomized 1:1 to receive inclisiran sodium (300 mg subcutaneous injections; equivalent to 284 mg inclisiran) or placebo together with individually optimized 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. Overall, 1770 individuals (mean age, 63.7 years) were randomized 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 < .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 < .001]. Fewer participants receiving inclisiran vs ioLLT reported a MRAE (11.9% vs 19.2%; OR 0.57, P < .001). The mean reduction in Short Form-Brief Pain Inventory pain severity and interference scores favoured inclisiran over ioLLT (LSMTD = −0.11, P = .039; LSMTD = −0.11, P = .029, respectively). No new safety concerns were identified. Results: Overall, 1770 individuals (mean age, 63.7 years) were randomized 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.

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  • Randomized controlled trials including VICTORION-Mono, VICTORION-Difference, ORION-10, ORION-11, and other Phase III trials have consistently demonstrated that inclisiran reduces LDL-C compared with placebo in primary and secondary prevention settings.

    “Randomized controlled trials, including the VICTORION-Mono and VICTORION-Difference trials, as well as ORION -10, -11, and other Phase III trials, have consistently demonstrated that inclisiran reduces LDL-C compared with placebo in primary and secondary prevention settings.5, 6, 7”

    From Small Interfering RNA for LDL-Cholesterol Reduction (2026) · cites this paper as [6]

    The Methods (Trial design; page unavailable) identify VICTORION-Difference as a randomized, placebo-controlled trial, and the Results (Efficacy; page unavailable) report a significantly greater LDL-C reduction with inclisiran than with placebo, both added to individually optimized therapy. This paper identifies VICTORION-Difference as phase 4, not phase III, and its own results do not establish the sentence’s broader claim across all the named trials and primary and secondary prevention settings. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • VICTORION Difference program demonstrates inclisiran superiority over placebo even when both arms receive intensive background lipid-lowering therapies, including high-intensity statins and ezetimibe.

    “VICTORION Difference program further substantiates inclisiran’s potent LDL-C lowering effect, demonstrating superiority over placebo even when both arms receive intensive background lipid-lowering therapies, including high-intensity statins and ezetimibe.”

    From Small Interfering RNA for LDL-Cholesterol Reduction (2026) · cites this paper as [6]

    The Results > Efficacy and Discussion report significantly greater LDL-C reduction with inclisiran than with placebo, with both arms receiving individually optimized lipid-lowering therapy (page not specified in our copy). But Methods > Trial design says rosuvastatin began at 5 or 10 mg/day and was titrated as needed, with other therapies added sequentially; it does not establish that both arms received high-intensity statins and ezetimibe as background treatment. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • VICTORION Difference confirms inclisiran's additive efficacy beyond standard lipid-lowering regimens and highlights its potential as a valuable treatment option for patients who remain above LDL-C targets despite optimized therapy.

    “This confirms inclisiran’s additive efficacy beyond standard lipid-lowering regimens and highlights its potential as a valuable treatment option for patients who remain above LDL-C targets despite optimized therapy.6”

    From Small Interfering RNA for LDL-Cholesterol Reduction (2026) · cites this paper as [6]

  • Mean LDL-C reduction on Day 360 was −59.5% with inclisiran versus −24.3% with individually optimized lipid-lowering therapy (LSMTD −35.14%, P < 0.001).

    “Mean LDL-C reduction on Day 360 was − 59.5% with Inclisiran versus − 24.3% with ioLLT (LSMTD − 35.14%, P < 0.001).”

    From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [35]

  • On Day 90, 84.9% of inclisiran-treated participants achieved their individualized LDL-C goals versus 31.0% with individually optimized lipid-lowering therapy (OR 12.09, P < 0.001).

    “On Day 90, 84.9% of Inclisiran-treated participants achieved their individualized LDL-C goals versus 31.0% with ioLLT (OR 12.09, P < 0.001).”

    From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [35]

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Authors
Landmesser, U., Laufs, U., Schatz, U., Winzer, E. B., Nowak, B., Kassner, U., Gouni-Berthold, I., Esteban, A., Lubyayi, L., Krueger, A., Hentschke, C., Wilke, A., Winkelmann, B. R., Achouba, A., & Banach, M.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • University Hospital Leipzig (DE)
  • University Hospital Carl Gustav Carus (DE)
  • Herzzentrum Dresden Universitätsklinik (DE)
  • Cardiovascular Center Bethanien (DE)
  • Center for Endocrinology, Diabetes and Preventive Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne , Cologne ,
  • Novartis (Switzerland) (CH)
  • Novartis (United Kingdom) (GB)
  • Novartis (Germany) (DE)
  • Kardiologie Frankfurt-Sachsenhausen (DE)
  • Cardiovascular Center Frankfurt (DE)
  • John Paul II Catholic University of Lublin (PL)
Corresponding author
Landmesser, Ulf
ORCID
Venue
European Heart Journal
Publisher
Oxford University Press (OUP)
Published
2025-08-30
Volume
47
Issue
25
Pages
3241-3253
ISSN
  • 0195-668X (ISSN-L)
  • 1522-9645
DOI
10.1093/eurheartj/ehaf685
PMC
PMC13318417
OpenAlex
W4413849322
Cited by
13
References
3
Citations by year
2026: 13
FWCI
12.23
Type
journal article
Language
en
Open access
Licence
Locations
  • European Heart Journal (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Novartis Pharma AG (NCT05192941)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
inclisiran, hypercholesterolemia, LDL cholesterol lowering, PCSK9 inhibition, siRNA, rosuvastatin, LDL-C goal attainment, atherosclerotic cardiovascular disease, statin intolerance
MeSH terms
Rosuvastatin Calcium, Proprotein Convertase 9, Aged, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Small Interfering

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