A Pairwise and Network Meta-Analysis Comparing the Efficacy and Safety of Ribonucleic Acid Interference Therapeutics in the Management of Hypertension
Downloads
DOI:
https://doi.org/10.71079/ASIDE.IM.092125141Abstract
Background: Small interfering RNA (siRNA) and antisense agents targeting angiotensinogen are emerging antihypertensives. We synthesized their efficacy and safety.
Methods: We searched PubMed, Web of Science, Scopus, and CENTRAL through 25 Nov 2024. Eligible studies were randomized controlled trials in adults with hypertension comparing RNA-interference therapeutics with placebo. Primary outcomes were the change in ambulatory and office systolic/diastolic blood pressure. We conducted random-effects pairwise meta-analyses and a network meta-analysis with SUCRA ranking, and appraised certainty with GRADE.
Results: Four trials (n=486) met criteria. Versus placebo, RNA-interference therapy reduced ambulatory SBP (mean difference [MD] −15.46 mmHg; 95% CI −18.79 to −12.12) and DBP (MD −8.45 mmHg; −10.67 to −6.23), and lowered office SBP (MD −8.07 mmHg; −11.58 to −4.56) and DBP (MD −5.18 mmHg; −7.73 to −2.63). Injection-site reactions increased (risk ratio 5.26; 1.01–27.44); other adverse events, potassium, and eGFR were similar. In network analyses, zilebesiran 300 mg ranked highest for blood-pressure lowering; for AGT reduction, 800 mg ranked highest. GRADE certainty was high for blood-pressure outcomes and moderate for AGT, potassium, and eGFR. Few, short-term trials and sparse networks limit precision and generalizability; publication bias was not assessable.
Conclusion: siRNAs effectively reduced BP in hypertensive adults with an acceptable safety profile. Despite the indistinguishable efficacy or safety between the doses or types of siRNAs, Zilebesiran 300 mg best reduced BP compared to placebo.
Keywords:
Hypertension, Ribonucleic acid interference therapeutics, Blood pressure managementReferences
1. Kario K, Okura A, Hoshide S, Mogi M. The WHO Global report 2023 on hypertension warning the emerging hypertension burden in globe and its treatment strategy. Hypertens Res. 2024: 1099 [PMID: 38443614, https://doi.org/10.1038/s41440-024-01622-w] DOI: https://doi.org/10.1038/s41440-024-01622-w
2. Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018: 1736 [PMID: 30496103, https://doi.org/10.1016/S0140-6736(18)32203-7] DOI: https://doi.org/10.1016/S0140-6736(18)32203-7
3. Ranzani OT, Kalra A, Di Girolamo C, Curto A, Valerio F, Halonen JI, Basagana X, Tonne C. Urban-rural differences in hypertension prevalence in low-income and middle-income countries, 1990-2020: A systematic review and meta-analysis. PLoS Med. 2022: e1004079 [PMID: 36007101, https://doi.org/10.1371/journal.pmed.1004079] DOI: https://doi.org/10.1371/journal.pmed.1004079
4. Zhou B, Perel P, Mensah GA, Ezzati M. Global epidemiology, health burden and effective interventions for elevated blood pressure and hypertension. Nat Rev Cardiol. 2021: 785 [PMID: 34050340, https://doi.org/10.1038/s41569-021-00559-8] DOI: https://doi.org/10.1038/s41569-021-00559-8
5. Ranasinghe P, Addison ML, Webb DJ. Small Interfering RNA Therapeutics in Hypertension: A Viewpoint on Vasopressor and Vasopressor-Sparing Strategies for Counteracting Blood Pressure Lowering by Angiotensinogen-Targeting Small Interfering RNA. J Am Heart Assoc. 2022: e027694 [PMID: 36216481, https://doi.org/10.1161/JAHA.122.027694] DOI: https://doi.org/10.1161/JAHA.122.027694
6. Morgan ES, Tami Y, Hu K, Brambatti M, Mullick AE, Geary RS, Bakris GL, Tsimikas S. Antisense Inhibition of Angiotensinogen With IONIS-AGT-L(Rx): Results of Phase 1 and Phase 2 Studies. JACC Basic Transl Sci. 2021: 485 [PMID: 34222719, https://doi.org/10.1016/j.jacbts.2021.04.004] DOI: https://doi.org/10.1016/j.jacbts.2021.04.004
7. Desai AS, Webb DJ, Taubel J, Casey S, Cheng Y, Robbie GJ, Foster D, Huang SA, Rhyee S, Sweetser MT, Bakris GL. Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension. N Engl J Med. 2023: 228 [PMID: 37467498, https://doi.org/10.1056/NEJMoa2208391] DOI: https://doi.org/10.1056/NEJMoa2208391
8. Bakris GL, Saxena M, Gupta A, Chalhoub F, Lee J, Stiglitz D, Makarova N, Goyal N, Guo W, Zappe D, Desai AS, Group K-S. RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial. JAMA. 2024: 740 [PMID: 38363577, https://doi.org/10.1001/jama.2024.0728] DOI: https://doi.org/10.1001/jama.2024.0728
9. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catala-Lopez F, Gotzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015: 777 [PMID: 26030634, https://doi.org/10.7326/M14-2385] DOI: https://doi.org/10.7326/M14-2385
10. EndNote. EndNote - The Best Citation & Reference Management Tool.
11. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016: 210 [PMID: 27919275, https://doi.org/10.1186/s13643-016-0384-4] DOI: https://doi.org/10.1186/s13643-016-0384-4
12. Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM, Emberson JR, Hernan MA, Hopewell S, Hrobjartsson A, Junqueira DR, Juni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019: l4898 [PMID: 31462531, https://doi.org/10.1136/bmj.l4898] DOI: https://doi.org/10.1136/bmj.l4898
13. RevMan C. RevMan: Systematic review and meta-analysis tool for researchers worldwide.
14. Jackson D, Turner R. Power analysis for random-effects meta-analysis. Res Synth Methods. 2017: 290 [PMID: 28378395, https://doi.org/10.1002/jrsm.1240] DOI: https://doi.org/10.1002/jrsm.1240
15. Griffin J. 2020: https://doi.org/10.32614/CRAN.package.metapower] DOI: https://doi.org/10.32614/CRAN.package.metapower
16. Team RC. R: The R Project for Statistical Computing.
17. Schunemann HJ, Mustafa RA, Brozek J, Steingart KR, Leeflang M, Murad MH, Bossuyt P, Glasziou P, Jaeschke R, Lange S, Meerpohl J, Langendam M, Hultcrantz M, Vist GE, Akl EA, Helfand M, Santesso N, Hooft L, Scholten R, Rosen M, Rutjes A, Crowther M, Muti P, Raatz H, Ansari MT, Williams J, Kunz R, Harris J, Rodriguez IA, Kohli M, Guyatt GH, Group GW. GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy. J Clin Epidemiol. 2020: 129 [PMID: 32060007, https://doi.org/10.1016/j.jclinepi.2019.12.020] DOI: https://doi.org/10.1016/j.jclinepi.2019.12.020
18. Schunemann HJ, Mustafa RA, Brozek J, Steingart KR, Leeflang M, Murad MH, Bossuyt P, Glasziou P, Jaeschke R, Lange S, Meerpohl J, Langendam M, Hultcrantz M, Vist GE, Akl EA, Helfand M, Santesso N, Hooft L, Scholten R, Rosen M, Rutjes A, Crowther M, Muti P, Raatz H, Ansari MT, Williams J, Kunz R, Harris J, Rodriguez IA, Kohli M, Guyatt GH, Group GW. GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables. J Clin Epidemiol. 2020: 142 [PMID: 32058069, https://doi.org/10.1016/j.jclinepi.2019.12.021] DOI: https://doi.org/10.1016/j.jclinepi.2019.12.021
19. Gradepro. GRADEpro GDT: GRADEpro Guideline Development Tool Hamilton, ON, Canada: McMaster University; 2015 [cited 21 Jan 2025]. Available from: https://www.gradepro.org/
20. Kandzari DE, Mahfoud F, Weber MA, Townsend R, Parati G, Fisher NDL, Lobo MD, Bloch M, Bohm M, Sharp ASP, Schmieder RE, Azizi M, Schlaich MP, Papademetriou V, Kirtane AJ, Daemen J, Pathak A, Ukena C, Lurz P, Grassi G, Myers M, Finn AV, Morice MC, Mehran R, Juni P, Stone GW, Krucoff MW, Whelton PK, Tsioufis K, Cutlip DE, Spitzer E. Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium. Circulation. 2022: 847 [PMID: 35286164, https://doi.org/10.1161/CIRCULATIONAHA.121.057687] DOI: https://doi.org/10.1161/CIRCULATIONAHA.121.057687
21. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016: 957 [PMID: 26724178, https://doi.org/10.1016/S0140-6736(15)01225-8] DOI: https://doi.org/10.1016/S0140-6736(15)01225-8
22. Blood Pressure Lowering Treatment Trialists C. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet. 2021: 1625 [PMID: 33933205, https://doi.org/10.1016/S0140-6736(21)00590-0] DOI: https://doi.org/10.1016/S0140-6736(21)00590-0
23. Nobakht N, Kamgar M, Rastogi A, Schrier RW. Limitations of angiotensin inhibition. Nat Rev Nephrol. 2011: 356 [PMID: 21502972, https://doi.org/10.1038/nrneph.2011.29] DOI: https://doi.org/10.1038/nrneph.2011.29
24. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH. Efficacy and safety of dual blockade of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013: f360 [PMID: 23358488, https://doi.org/10.1136/bmj.f360] DOI: https://doi.org/10.1136/bmj.f360
25. Investigators O, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008: 1547 [PMID: 18378520, https://doi.org/10.1056/NEJMoa0801317] DOI: https://doi.org/10.1056/NEJMoa0801317
26. Uijl E, Mirabito Colafella KM, Sun Y, Ren L, van Veghel R, Garrelds IM, de Vries R, Poglitsch M, Zlatev I, Kim JB, Hoorn EJ, Foster D, Danser AHJ. Strong and Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen. Hypertension. 2019: 1249 [PMID: 31030610, https://doi.org/10.1161/HYPERTENSIONAHA.119.12703] DOI: https://doi.org/10.1161/HYPERTENSIONAHA.119.12703
27. Han M, Li Q, Liu L, Zhang D, Ren Y, Zhao Y, Liu D, Liu F, Chen X, Cheng C, Guo C, Zhou Q, Tian G, Qie R, Huang S, Wu X, Liu Y, Li H, Sun X, Zhang M, Hu D. Prehypertension and risk of cardiovascular diseases: a meta-analysis of 47 cohort studies. J Hypertens. 2019: 2325 [PMID: 31335511, https://doi.org/10.1097/HJH.0000000000002191] DOI: https://doi.org/10.1097/HJH.0000000000002191
28. Miura K, Daviglus ML, Dyer AR, Liu K, Garside DB, Stamler J, Greenland P. Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases, and all causes in young adult men: the Chicago Heart Association Detection Project in Industry. Arch Intern Med. 2001: 1501 [PMID: 11427097, https://doi.org/10.1001/archinte.161.12.1501] DOI: https://doi.org/10.1001/archinte.161.12.1501
29. Kokubo Y, Kamide K, Okamura T, Watanabe M, Higashiyama A, Kawanishi K, Okayama A, Kawano Y. Impact of high-normal blood pressure on the risk of cardiovascular disease in a Japanese urban cohort: the Suita study. Hypertension. 2008: 652 [PMID: 18725580, https://doi.org/10.1161/HYPERTENSIONAHA.108.118273] DOI: https://doi.org/10.1161/HYPERTENSIONAHA.108.118273
30. Ma J, Stafford RS. Screening, treatment, and control of hypertension in US private physician offices, 2003-2004. Hypertension. 2008: 1275 [PMID: 18347229, https://doi.org/10.1161/HYPERTENSIONAHA.107.107086] DOI: https://doi.org/10.1161/HYPERTENSIONAHA.107.107086
31. Nelson CR, Knapp DA. Trends in antihypertensive drug therapy of ambulatory patients by US office-based physicians. Hypertension. 2000: 600 [PMID: 11040242, https://doi.org/10.1161/01.hyp.36.4.600] DOI: https://doi.org/10.1161/01.HYP.36.4.600
32. Hill MN, Miller NH, Degeest S, American Society of Hypertension Writing G, Materson BJ, Black HR, Izzo JL, Jr., Oparil S, Weber MA. Adherence and persistence with taking medication to control high blood pressure. J Am Soc Hypertens. 2011: 56 [PMID: 21320699, https://doi.org/10.1016/j.jash.2011.01.001] DOI: https://doi.org/10.1016/j.jash.2011.01.001
33. Group GRADEW. GRADE handbook.
34. Collaboration C. Cochrane Handbook for Systematic Reviews of Interventions.
35. Lin L, Chu H, Murad MH, Hong C, Qu Z, Cole SR, Chen Y. Empirical Comparison of Publication Bias Tests in Meta-Analysis. J Gen Intern Med. 2018: 1260 [PMID: 29663281, https://doi.org/10.1007/s11606-018-4425-7] DOI: https://doi.org/10.1007/s11606-018-4425-7
Data Availability Statement
All data generated or analyzed during this study are included in this published article and its supplementary file.
License
Copyright (c) 2025 Mohamed E. Haseeb, Zeyad Bady, Hazem E. Mohammed, George Hanen, Mohamed Nasser, Nada S. Jibril, Mohamed Khalafalla Darwish, Heba Aboeldahab
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright and Licensing
All articles published in ASIDE Internal Medicine are open access and freely available online immediately upon publication, without embargo.
This journal applies the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). Under this license, anyone may copy, redistribute, remix, transform, and build upon the material for any purpose, even commercially, provided that proper credit is given to the original author(s), a link to the license is provided, and any changes made are indicated.
-
License link: https://creativecommons.org/licenses/by/4.0/
-
Machine-readable license metadata is embedded in each article and its DOI record.
Copyright Holder
Copyright in all articles remains with the author(s). By submitting a manuscript, authors agree to grant the publisher (American Society for Inclusion, Diversity, and Equity in Healthcare – ASIDE) a non-exclusive license to publish and distribute the work under the terms of the CC BY 4.0 license.
Third-party Material
Any material (e.g., images, figures, or tables) not covered by CC BY 4.0 will be clearly indicated in the article. Users must obtain permission directly from the copyright holder for reuse of such third-party material.
Author Rights and Self-Archiving
Authors are permitted to deposit all versions of their work (preprint, author’s accepted manuscript, and version of record) in institutional or subject repositories of their choice immediately upon publication, without embargo, provided that the DOI and license information are included.
Downloads
Published
How to Cite
Article history
- Received
- 20 Jun 2025
- Received in revised form
- 17 Aug 2025
- Accepted
- 31 Aug 2025
- Published
- 21 Sep 2025
