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Cited by 1Lipoproteins and Cardiovascular HealthLipid metabolism and disordersCholesterol and Lipid Metabolism

Comparative efficacy and safety of novel Lp(a)-lowering therapies for ASCVD prevention: A network meta-analysis

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Wu, An-xin, Wang, Xing-jin, Zhao, Chen, Hu, Jia-qiang, Li, Jin-wei, Xu, Ying, Li, Yi, Liu, Song·2026·Pharmacological Research
DOI 10.1016/j.phrs.2026.108178
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Abstract

Elevated lipoprotein(a) [Lp(a)] is a genetically determined and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) that is largely resistant to conventional lipid-lowering therapies. Novel Lp(a)-targeted agents, including small interfering RNA (siRNA), antisense oligonucleotides (ASO), and the oral small-molecule inhibitor muvalaplin, have shown potent efficacy in early trials. We conducted a systematic review and network meta-analysis to comprehensively compare their efficacy and safety. A total of 25 randomized controlled trials (RCTs) involving 7715 participants were included, evaluating six siRNA agents, four ASO agents, and one small-molecule inhibitor. The primary outcome was percentage change from baseline in Lp(a). Secondary outcomes included absolute change in Lp(a), percentage changes in apolipoprotein B (apoB) and low-density lipoprotein cholesterol (LDL-C), and adverse events. SiRNA therapies achieved the greatest Lp(a) reductions (olpasiran: mean difference [MD] -92.1%, 95% CI -100.1 to -84.0%; zerlasiran: -80.6%, 95% CI -87.7 to -73.5%), followed by muvalaplin (-76.8%, 95% CI -90.3 to -63.2%) and ASO therapy (pelacarsen: -54.2%, 95% CI -72.2 to -36.2%; all P < 0.001). Most agents achieved absolute Lp(a) reductions exceeding 105 nmol/L, suggesting clinically meaningful benefit. Baseline Lp(a) levels significantly modified treatment response (P < 0.001), and concomitant proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor use further enhanced LDL-C reduction (P = 0.024). All therapies were well tolerated, with injection-site reactions most frequent for injectables, while muvalaplin was well tolerated. These findings indicate that targeted Lp(a)-lowering therapies substantially reduce circulating Lp(a), with siRNA showing the greatest potency and muvalaplin offering a convenient oral alternative for personalized ASCVD risk reduction.

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Authors
Wu, A.-X., Wang, X.-J., Zhao, C., Hu, J.-Q., Li, J.-W., Xu, Y., Li, Y., & Liu, S.
Affiliations
  • Third People's Hospital of Chengdu (CN)
  • Heidelberg University (DE)
  • Capital Medical University (CN)
  • Chengdu Medical College (CN)
  • Southwest Medical University (CN)
Corresponding author
  • Li, Yi
  • Liu, Song
Venue
Pharmacological Research
Publisher
Elsevier BV
Published
2026-05
Volume
227
Pages
108178
ISSN
1043-6618 (ISSN-L)
DOI
10.1016/j.phrs.2026.108178
OpenAlex
W7148987344
Semantic Scholar
3493b61979f708864defc3fdfebf9647fa790d11
Cited by
1
References
62
Citations by year
2026: 1
FWCI
6.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Pharmacological Research (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Southwest Medical University (2025JC087)
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
lipoprotein(a), Lp(a)-lowering therapy, atherosclerotic cardiovascular disease prevention, siRNA, antisense oligonucleotides, olpasiran, pelacarsen, apolipoprotein B, LDL cholesterol, PCSK9 inhibitors, treatment response, injection site reactions, drug safety
MeSH terms
Network Meta-Analysis as Topic, Hypolipidemic Agents, Humans, Randomized Controlled Trials as Topic, Oligonucleotides, Antisense, Treatment Outcome, Lipoprotein(a), RNA, Small Interfering, Atherosclerosis

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