{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T02:28:09Z","timestamp":1786328889921,"version":"build-2736575974"},"reference-count":77,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T00:00:00Z","timestamp":1786147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research, Development, and Innovation Fund of Hungary","award":["NKFI-K-146929"],"award-info":[{"award-number":["NKFI-K-146929"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Hypertension remains a major global health burden, and control rates remain suboptimal because of poor medication adherence and limitations of existing therapies, including escape within the renin\u2013angiotensin\u2013aldosterone system. Zilebesiran, a first-in-class, subcutaneously administered small interfering RNA therapeutic, represents a promising advance in hypertension management. Through N-acetylgalactosamine-mediated hepatic delivery, zilebesiran selectively silences angiotensinogen (AGT) messenger RNA, the transcript encoding the common precursor of all angiotensin peptides. This upstream intervention reduces AGT production and produces durable blood pressure lowering that can persist for up to 6 months after a single dose. This review summarizes the mechanism of action of zilebesiran, its pharmacokinetic and pharmacodynamic properties, and the available phase 1 and phase 2 clinical evidence, including the KARDIA program. We also place zilebesiran within the evolving antihypertensive landscape by comparing it with aldosterone synthase inhibitors, dual endothelin receptor antagonists, and brain aminopeptidase A inhibitors. Finally, we discuss translational challenges, including reversal strategies for emergency situations, monitoring considerations, and potential roles for personalized dosing. Early-phase and phase 2 trials show dose-dependent and durable reductions in serum AGT and blood pressure with infrequent dosing; however, long-term safety, cardiovascular outcome benefit, and generalizability in diverse high-risk populations remain to be established, and zilebesiran remains investigational while phase 3 outcome testing is underway.<\/jats:p>","DOI":"10.3390\/life16081301","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T01:20:03Z","timestamp":1786324803000},"page":"1301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Zilebesiran, a Small Interfering RNA Therapeutic Targeting Angiotensinogen: Mechanism, Clinical Evidence, Safety, and Implementation Considerations"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3207-4280","authenticated-orcid":false,"family":"Jawaria","sequence":"first","affiliation":[{"name":"Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering-C (NIBGE), Faisalabad 38000, Pakistan"},{"name":"Pakistan Institute of Engineering and Applied Sciences (PIEAS), Islamabad 45650, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Areeba","family":"Noor","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8744-2255","authenticated-orcid":false,"given":"Yusra","family":"Zarlashat","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3535-1814","authenticated-orcid":false,"given":"Muhammad Ebad Asif","family":"Khan","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9804-8835","authenticated-orcid":false,"given":"Enrique Mandado","family":"Loureiro","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2984-2642","authenticated-orcid":false,"given":"Edit","family":"D\u00f3sa","sequence":"additional","affiliation":[{"name":"Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/s41581-019-0244-2","article-title":"The global epidemiology of hypertension","volume":"16","author":"Mills","year":"2020","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.phrs.2017.11.003","article-title":"Hypertension and cardiovascular risk: General aspects","volume":"129","author":"Kjeldsen","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1161\/HYPERTENSIONAHA.124.24137","article-title":"Closing the Gap in Global Disparities in Hypertension Control","volume":"82","author":"Mishra","year":"2025","journal-title":"Hypertension"},{"key":"ref_4","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2021). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: A pooled analysis of 1201 population-representative studies with 104 million participants. Lancet, 398, 957\u2013980. Erratum in Lancet\u00a02022, 399, 520."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e008220","DOI":"10.1161\/CIRCOUTCOMES.121.008220","article-title":"Helping Patients Manage Their Own Blood Pressures: A Strategy to Address Hypertension Control in the United States","volume":"14","author":"Haff","year":"2021","journal-title":"Circ. Cardiovasc. Qual. Outcomes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jash.2011.01.001","article-title":"Adherence and persistence with taking medication to control high blood pressure","volume":"5","author":"Hill","year":"2011","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1097\/HJH.0000000000002398","article-title":"Nonadherence to antihypertensive medications is related to pill burden in apparent treatment-resistant hypertensive individuals","volume":"38","author":"Lawson","year":"2020","journal-title":"J. Hypertens."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2256","DOI":"10.1161\/ATVBAHA.123.319897","article-title":"Targeting Angiotensinogen with N-Acetylgalactosamine-Conjugated Small Interfering RNA to Reduce Blood Pressure","volume":"43","author":"Ye","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_9","first-page":"9","article-title":"The renin-angiotensin aldosterone system: Pathophysiological role and pharmacologic inhibition","volume":"13","author":"Atlas","year":"2007","journal-title":"J. Manag. Care Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1161\/HYPERTENSIONAHA.117.09755","article-title":"Blood Pressure Lowering and Safety Improvements with Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury","volume":"70","author":"Mullick","year":"2017","journal-title":"Hypertension"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1161\/HYPERTENSIONAHA.119.12703","article-title":"Strong and Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen","volume":"73","author":"Uijl","year":"2019","journal-title":"Hypertension"},{"key":"ref_12","first-page":"420","article-title":"Zilebesiran and Hypertension: A Systematic Review and Meta-analysis","volume":"36","author":"Lemine","year":"2024","journal-title":"J. Saudi Heart Assoc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1056\/NEJMoa2208391","article-title":"Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension","volume":"389","author":"Desai","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1007\/s11906-003-0087-9","article-title":"RAAS escape: A real clinical entity that may be important in the progression of cardiovascular and renal disease","volume":"5","author":"Lakkis","year":"2003","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nrneph.2011.29","article-title":"Limitations of angiotensin inhibition","volume":"7","author":"Nobakht","year":"2011","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11906-025-01325-8","article-title":"Small Interfering RNA Therapy for the Management and Prevention of Hypertension","volume":"27","author":"Ren","year":"2025","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1080\/17512433.2023.2277330","article-title":"Emerging insights and future prospects for therapeutic application of siRNA targeting angiotensinogen in hypertension","volume":"16","author":"Addison","year":"2023","journal-title":"Expert. Rev. Clin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/s41392-020-0207-x","article-title":"Therapeutic siRNA: State of the art","volume":"5","author":"Hu","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"114432","DOI":"10.1016\/j.bcp.2021.114432","article-title":"The growth of siRNA-based therapeutics: Updated clinical studies","volume":"189","author":"Zhang","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1056\/NEJMcibr1613559","article-title":"Targeting Therapeutic Oligonucleotides","volume":"376","author":"Levin","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1093\/cvr\/cvae140","article-title":"Zilebesiran, a ribonucleic acid interference agent targeting angiotensinogen, proves a promising approach in hypertension","volume":"120","author":"Webb","year":"2024","journal-title":"Cardiovasc. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1097\/MNH.0000000000000586","article-title":"Targeting angiotensinogen with RNA-based therapeutics","volume":"29","author":"Ren","year":"2020","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1124\/jpet.122.001234","article-title":"RNAi-Based Therapeutics and Novel RNA Bioengineering Technologies","volume":"384","author":"Traber","year":"2023","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Chen, H., Hong, L., Wang, H., Li, B., Zhang, M., Li, J., Yang, L., and Liu, F. (2023). Inclisiran: A new generation of lipid-lowering siRNA therapeutic. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1260921"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2217\/nmt-2018-0033","article-title":"Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis","volume":"9","author":"Kristen","year":"2019","journal-title":"Neurodegener. Dis. Manag."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1001\/jama.2024.0728","article-title":"RNA Interference with Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial","volume":"331","author":"Bakris","year":"2024","journal-title":"JAMA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16958","DOI":"10.1021\/ja505986a","article-title":"Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing","volume":"136","author":"Nair","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2697","DOI":"10.1111\/bph.15972","article-title":"Small interfering RNA: Discovery, pharmacology and clinical development\u2014An introductory review","volume":"180","author":"Ranasinghe","year":"2023","journal-title":"Br. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.ymthe.2017.12.021","article-title":"Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates","volume":"26","author":"Foster","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhang, L., Liang, Y., Liang, G., Tian, Z., Zhang, Y., Liu, Z., and Ji, X. (2022). The therapeutic prospects of N-acetylgalactosamine-siRNA conjugates. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1090237"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16259","DOI":"10.1021\/acsomega.1c01755","article-title":"Liver-Targeted Delivery of Oligonucleotides with N-Acetylgalactosamine Conjugation","volume":"6","author":"Cui","year":"2021","journal-title":"ACS Omega"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/hr.2013.155","article-title":"Targeting of hepatic angiotensinogen using chemically modified siRNAs results in significant and sustained blood pressure lowering in a rat model of hypertension","volume":"37","author":"Olearczyk","year":"2014","journal-title":"Hypertens. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1161\/HYPERTENSIONAHA.122.19430","article-title":"Novel Pharmacological Approaches in the Treatment of Hypertension: A Focus on RNA-Based Therapeutics","volume":"80","author":"Addison","year":"2023","journal-title":"Hypertension"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e75","DOI":"10.1161\/HYP.0000000000000227","article-title":"Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring Cardiovascular Health Across the Life Course: Moving the Field Forward: A Scientific Statement From the American Heart Association","volume":"80","author":"Alexander","year":"2023","journal-title":"Hypertension"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1001\/jama.2025.6681","article-title":"Add-On Treatment with Zilebesiran for Inadequately Controlled Hypertension: The KARDIA-2 Randomized Clinical Trial","volume":"334","author":"Desai","year":"2025","journal-title":"JAMA"},{"key":"ref_36","unstructured":"Pagidipati, N., Weber, M., Saxena, M., Williams, B., Goodman, S., Xiang, Z., Daga, S., Bengus, M., Zappe, D., and Bhan, I. (September, January 29). KARDIA-3: Zilebesiran as add-on therapy in adults with hypertension who have established cardiovascular disease or are at high cardiovascular risk. Presented at the European Society of Cardiology (ESC) Congress, Madrid, Spain."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Pagidipati, N., Weber, M., Saxena, M., Williams, B., Goodman, S.G., Xiang, Z., Daga, S., Bengus, M., Zappe, D., and Bhan, I. (2025, January 7\u201310). KARDIA-3: A randomized trial of zilebesiran versus placebo on top of standard care for patients with hypertension and established cardiovascular disease or high cardiovascular risk with or without chronic kidney disease. Presented at the American Heart Association (AHA) Scientific Sessions, New Orleans, LA, USA.","DOI":"10.1097\/01.hjh.0001197492.36993.cc"},{"key":"ref_38","unstructured":"ClinicalTrials.gov (2026, May 21). Zilebesiran in Patients with Hypertension Not Adequately Controlled and with Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease (ZENITH). ClinicalTrials.gov Identifier NCT07181109, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07181109."},{"key":"ref_39","unstructured":"Alnylam Pharmaceuticals (2026, May 21). Alnylam Announces First Patient Dosed in ZENITH Global Phase 3 Cardiovascular Outcomes Trial of Zilebesiran. Available online: https:\/\/investors.alnylam.com\/press-release?id=29321."},{"key":"ref_40","unstructured":"National Institute of Diabetes and Digestive and Kidney Diseases (2026, May 21). Lumasiran, LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet], Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK588653\/."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ymgme.2022.01.002","article-title":"Givosiran in acute intermittent porphyria: A personalized medicine approach","volume":"135","author":"Poli","year":"2022","journal-title":"Mol. Genet. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1474-4422(20)30368-9","article-title":"Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study","volume":"20","author":"Adams","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lin, Y.C., Lin, J.W., Wu, M.S., Chen, K.C., Peng, C.C., and Kang, Y.N. (2017). Effects of calcium channel blockers comparing to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension and chronic kidney disease stage 3 to 5 and dialysis: A systematic review and meta-analysis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188975"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e001353","DOI":"10.1136\/openhrt-2020-001353","article-title":"Renin-angiotensin-aldosterone system inhibitors and the risk of mortality in patients with hypertension hospitalised for COVID-19: Systematic review and meta-analysis","volume":"7","author":"Ssentongo","year":"2020","journal-title":"Open Heart"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.hipert.2023.11.005","article-title":"Renin-angiotensin-aldosterone system blockers effect in chronic kidney disease progression in hypertensive elderly patients without proteinuria: PROERCAN trial","volume":"41","author":"Verdalles","year":"2024","journal-title":"Hipertens. Riesgo Vasc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.amjmed.2014.07.011","article-title":"Angiotensin-converting enzyme inhibitor-induced angioedema","volume":"128","author":"Bezalel","year":"2015","journal-title":"Am. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1586\/erc.09.127","article-title":"Recent changes in the landscape of combination RAS blockade","volume":"7","author":"Epstein","year":"2009","journal-title":"Expert. Rev. Cardiovasc. Ther."},{"key":"ref_48","first-page":"e77607","article-title":"Safety and Efficacy of Novel RNA Interference Therapeutic Agent Zilebesiran in People with Hypertension: A Systematic Review and Meta-Analysis","volume":"17","author":"Singh","year":"2025","journal-title":"Cureus"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/978-1-0716-1298-9_7","article-title":"Synthesis of GalNAc-Oligonucleotide Conjugates Using GalNAc Phosphoramidite and Triple-GalNAc CPG Solid Support","volume":"2282","author":"Ulashchik","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1002\/cbic.201500023","article-title":"Hepatocyte-specific delivery of siRNAs conjugated to novel non-nucleosidic trivalent N-acetylgalactosamine elicits robust gene silencing in vivo","volume":"16","author":"Rajeev","year":"2015","journal-title":"Chembiochem"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1089\/nat.2018.0736","article-title":"GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics","volume":"28","author":"Springer","year":"2018","journal-title":"Nucleic Acid. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ymthe.2016.10.019","article-title":"Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate","volume":"25","author":"Zimmermann","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11827","DOI":"10.1093\/nar\/gkaa670","article-title":"Investigating the pharmacodynamic durability of GalNAc-siRNA conjugates","volume":"48","author":"Brown","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1161\/CIRCRESAHA.118.313220","article-title":"Adherence in Hypertension","volume":"124","author":"Burnier","year":"2019","journal-title":"Circ. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e120","DOI":"10.1097\/01.hjh.0001020524.16638.68","article-title":"KARDIA-3 study design: Zilebesiran as add-on therapy in patients with high cardiovascular risk and hypertension inadequately controlled by standard of care antihypertensives","volume":"42","author":"Havasi","year":"2024","journal-title":"J. Hypertens."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"El-Garawani, I.M., Shaheen, E.M., El-Seedi, H.R., Khalifa, S.M.A., Mersal, G.A.M., Emara, M.M., and Kasemy, Z.A. (2021). Angiotensinogen Gene Missense Polymorphisms (rs699 and rs4762): The Association of End-Stage Renal Failure Risk with Type 2 Diabetes and Hypertension in Egyptians. Genes, 12.","DOI":"10.3390\/genes12030339"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Shahid, M., Rehman, K., Akash, M.S.H., Suhail, S., Kamal, S., Imran, M., and Assiri, M.A. (2022). Genetic Polymorphism in Angiotensinogen and Its Association with Cardiometabolic Diseases. Metabolites, 12.","DOI":"10.3390\/metabo12121291"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1001\/jama.2023.16029","article-title":"Aldosterone Synthase Inhibition with Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial","volume":"330","author":"Laffin","year":"2023","journal-title":"JAMA"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1016\/S0140-6736(22)02034-7","article-title":"Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): A multicentre, blinded, randomised, parallel-group, phase 3 trial","volume":"400","author":"Schlaich","year":"2022","journal-title":"Lancet"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"sfad251","DOI":"10.1093\/ckj\/sfad251","article-title":"New trials in resistant hypertension: Mixed blessing stories","volume":"17","author":"Zoccali","year":"2023","journal-title":"Clin. Kidney J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1161\/CIRCULATIONAHA.123.067373","article-title":"RNA Therapeutics for the Cardiovascular System","volume":"149","author":"Dzau","year":"2024","journal-title":"Circulation"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e70080","DOI":"10.1111\/bcpt.70080","article-title":"Blood Pressure-Lowering Effects of Aldosterone Synthase Inhibitors\u2014A Systematic Review","volume":"137","author":"Rasmussen","year":"2025","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1080\/17474086.2025.2500607","article-title":"Revolutionizing hypertension treatment: Aprocitentan\u2019s dual action against resistant hypertension","volume":"18","author":"Sahebkar","year":"2025","journal-title":"Expert. Rev. Hematol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Forzano, I., Mone, P., Varzideh, F., Jankauskas, S.S., Kansakar, U., De Luca, A., and Santulli, G. (2022). The selective aldosterone synthase inhibitor Baxdrostat significantly lowers blood pressure in patients with resistant hypertension. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.1097968"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1001\/jama.2025.9413","article-title":"Lorundrostat in Participants with Uncontrolled Hypertension and Treatment-Resistant Hypertension: The Launch-HTN Randomized Clinical Trial","volume":"334","author":"Saxena","year":"2025","journal-title":"JAMA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1097\/HJH.0000000000004055","article-title":"Breaking down resistance: Novel aldosterone synthase inhibitors in the management of resistant hypertension","volume":"43","author":"Hung","year":"2025","journal-title":"J. Hypertens."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1097\/CRD.0000000000000595","article-title":"Baxdrostat: An Aldosterone Synthase Inhibitor for the Treatment of Systemic Hypertension","volume":"33","author":"Dey","year":"2025","journal-title":"Cardiol. Rev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1056\/NEJMoa2507109","article-title":"Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension","volume":"393","author":"Flack","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_69","unstructured":"U.S. Food and Drug Administration (2026, May 21). Novel Drug Approvals for 2026: Baxfendy (Baxdrostat), Available online: https:\/\/www.fda.gov\/drugs\/novel-drug-approvals-fda\/novel-drug-approvals-2026."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1097\/01.hjh.0000939452.95549.48","article-title":"Effects of the dual endothelin antagonist aprocitentan on ambulatory blood pressure indices in patients with resistant hypertension. Results from the PRECISION study","volume":"41","author":"Schlaich","year":"2023","journal-title":"J. Hypertens."},{"key":"ref_71","unstructured":"U.S. Food and Drug Administration (2026, May 21). TRYVIO (Aprocitentan) Tablets, for Oral Use: Prescribing Information. Revised April 2025, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2025\/217686s004lbl.pdf."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1172\/JCI99417","article-title":"RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models","volume":"130","author":"Haase","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.2147\/TCRM.S150434","article-title":"Angiotensin II: A new therapeutic option for vasodilatory shock","volume":"14","author":"Bussard","year":"2018","journal-title":"Ther. Clin. Risk Manag."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"f360","DOI":"10.1136\/bmj.f360","article-title":"Efficacy and safety of dual blockade of the renin-angiotensin system: Meta-analysis of randomised trials","volume":"346","author":"Makani","year":"2013","journal-title":"BMJ"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1161\/HYPERTENSIONAHA.124.22878","article-title":"Counteracting Angiotensinogen Small-Interfering RNA-Mediated Antihypertensive Effects with REVERSIR","volume":"81","author":"Ye","year":"2024","journal-title":"Hypertension"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e026426","DOI":"10.1161\/JAHA.122.026426","article-title":"Conventional Vasopressor and Vasopressor-Sparing Strategies to Counteract the Blood Pressure-Lowering Effect of Small Interfering RNA Targeting Angiotensinogen","volume":"11","author":"Uijl","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nbt.4136","article-title":"Reversal of siRNA-mediated gene silencing in vivo","volume":"36","author":"Zlatev","year":"2018","journal-title":"Nat. Biotechnol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/8\/1301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T01:32:25Z","timestamp":1786325545000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/8\/1301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,8]]},"references-count":77,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["life16081301"],"URL":"https:\/\/doi.org\/10.3390\/life16081301","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,8]]}}}