Reviews
31 December 2025
Vol. 3 No. 4 (2025)
Aldosterone synthase inhibitors in cardio-renal diseases: a state-of-the-art review
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
21
Views
4
Downloads
Authors
Aldosterone plays a pivotal role in the progression of cardio-renal diseases by driving myocardial fibrosis, vascular dysfunction, and renal injury through both genomic and non-genomic mechanisms. While mineralocorticoid receptor antagonists have long served as the cornerstone of pharmacologic intervention, their use is limited by adverse effects such as hyperkalemia, gynecomastia, and incomplete suppression of aldosterone-mediated pathology. Aldosterone synthase inhibitors, a novel class of therapeutics, offer a promising alternative by targeting the enzymatic production of aldosterone at its source, thereby circumventing receptor-level limitations. This narrative review comprehensively explores the physiological role of aldosterone, critiques existing RAAS-targeted therapies, and provides an in-depth evaluation of the pharmacology, efficacy, and safety of emerging ASIs including baxdrostat, lorundrostat, and osilodrostat. Evidence from recent clinical trials such as BrigHTN, HALO, Target-HTN, and FIONE is synthesized to assess their clinical potential. In addition, the review highlights novel mechanistic frontiers including the role of ASIs in overcoming aldosterone escape, attenuating cardio-renal fibrosis, modulating neurohormonal dysregulation, and enabling precision therapy through pharmacogenomic stratification. Future directions emphasize drug design innovations such as adrenal-specific prodrugs and nanoparticle-based formulations. Overall, ASIs represent a mechanistically robust and clinically promising advancement in the treatment of heart failure, chronic kidney disease, and primary aldosteronism. Their integration into multidrug regimens and personalized treatment frameworks may redefine the therapeutic landscape of cardio-renal-metabolic disease.
Altmetrics
Downloads
Download data is not yet available.
Citations
1. Ksiazek SH, Hu L, Andò S, et al. Renin-angiotensin-aldosterone system: from history to practice of a secular topic. Int J Mol Sci 2024;25:4035. DOI: https://doi.org/10.3390/ijms25074035
2. Shrestha A, Che RC, Zhang AH. Role of aldosterone in renal fibrosis. Adv Exp Med Biol 2019;1165:325-46. DOI: https://doi.org/10.1007/978-981-13-8871-2_15
3. Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol 2013;9:459-69. DOI: https://doi.org/10.1038/nrneph.2013.110
4. Ames MK, Atkins CE, Pitt B. The renin-angiotensin-aldosterone system and its suppression. J Vet Intern Med 2019;33:363-82. DOI: https://doi.org/10.1111/jvim.15454
5. Schmidt BMW, Sammer U, Fleischmann I, et al. Rapid Nongenomic Effects of Aldosterone on the Renal Vasculature in Humans. Hypertension. 2006;47(4):650-5. DOI: https://doi.org/10.1161/01.HYP.0000205224.58715.cc
6. Buffolo F, Tetti M, Mulatero P, Monticone S. Aldosterone as a mediator of cardiovascular damage. Hypertension 2022;79:1899-911. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.122.17964
7. El Mouhayyar C, Chhikara M, Tang M, Nigwekar SU. Clinical implications of mineralocorticoid receptor overactivation. Clin Kidney J 2025;18:sfae346. DOI: https://doi.org/10.1093/ckj/sfae346
8. Jonsson A, Norberg H, Bergdahl E, Lindmark K. Obstacles to mineralocorticoid receptor antagonists in a community-based heart failure population. Cardiovasc Ther 2018;36:e12459. DOI: https://doi.org/10.1111/1755-5922.12459
9. Brixius-Anderko S, Scott EE. Structural and functional insights into aldosterone synthase interaction with its redox partner protein adrenodoxin. J Biol Chem 2021;296:100794. DOI: https://doi.org/10.1016/j.jbc.2021.100794
10. Bogman K, Schwab D, Delporte M-L, et al. Preclinical and early clinical profile of a highly selective and potent oral inhibitor of aldosterone synthase (CYP11B2). Hypertension 2017;69:189-96. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.116.07716
11. Mazzieri A, Timio F, Patera F, et al. Aldosterone synthase inhibitors for cardiorenal protection: ready for prime time? Kidney Blood Press Res 2024;49:1041-56. DOI: https://doi.org/10.1159/000542621
12. Bollag WB. Regulation of aldosterone synthesis and secretion. Compr Physiol 2014;4:1017-55. DOI: https://doi.org/10.1002/j.2040-4603.2014.tb00565.x
13. Hattangady NG, Olala LO, Bollag WB, Rainey WE. Acute and chronic regulation of aldosterone production. Mol Cell Endocrinol 2012;350:151-62. DOI: https://doi.org/10.1016/j.mce.2011.07.034
14. Fisher A, Davies E, Fraser R, Connell JM. Structure-function relationships of aldosterone synthase and 11 beta-hydroxylase enzymes: implications for human hypertension. Clin Exp Pharmacol Physiol Suppl 1998;25:S42-6. DOI: https://doi.org/10.1111/j.1440-1681.1998.tb02299.x
15. Rösler A, White PC. Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. J Steroid Biochem Mol Biol 1993;45:99-106. DOI: https://doi.org/10.1016/0960-0760(93)90128-J
16. Nishimoto K, Nakagawa K, Li D, et al. Adrenocortical zonation in humans under normal and pathological conditions. J Clin Endocrinol Metab 2010;95:2296-305. DOI: https://doi.org/10.1210/jc.2009-2010
17. Takeda Y, Demura M, Yoneda T, et al. Epigenomic alterations of the human CYP11B gene in adrenal zonation. Int J Mol Sci 2024;25:11956. DOI: https://doi.org/10.3390/ijms252211956
18. Tsilosani A, Gao C, Zhang W. Aldosterone-regulated sodium transport and blood pressure. Front Physiol 2022;13:770375. DOI: https://doi.org/10.3389/fphys.2022.770375
19. Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol 2004;217):67-74. DOI: https://doi.org/10.1016/j.mce.2003.10.011
20. Lefebvre H, Thomas M, Duparc C, et al. Role of ACTH in the interactive/paracrine regulation of adrenal steroid secretion in physiological and pathophysiological conditions. Front Endocrinol (Lausanne) 2016;7:98. DOI: https://doi.org/10.3389/fendo.2016.00098
21. Sainz JM, Reche C, Rábano MA, et al. Effects of nitric oxide on aldosterone synthesis and nitric oxide synthase activity in glomerulosa cells from bovine adrenal gland. Endocrine 2004;24:61-71. DOI: https://doi.org/10.1385/ENDO:24:1:061
22. Hanke CJ, O’Brien T, Pritchard KA, Campbell WB. Inhibition of adrenal cell aldosterone synthesis by endogenous nitric oxide release. Hypertension 2000;35:324-8. DOI: https://doi.org/10.1161/01.HYP.35.1.324
23. Natarajan R, Lanting L, Bai W, et al. The role of nitric oxide in the regulation of aldosterone synthesis by adrenal glomerulosa cells. J Steroid Biochem Mol Biol 1997;61:47-53. DOI: https://doi.org/10.1016/S0960-0760(97)00004-6
24. Otsuka H, Abe M, Kobayashi H. The effect of aldosterone on cardiorenal and metabolic systems. Int J Mol Sci 2023;24:5370. DOI: https://doi.org/10.3390/ijms24065370
25. Rogerson FM, Brennan FE, Fuller PJ. Mineralocorticoid receptor binding, structure and function. Mol Cell Endocrinol 2004;217:203-12. DOI: https://doi.org/10.1016/j.mce.2003.10.021
26. Hermidorff MM, de Assis LV, Isoldi MC. Genomic and rapid effects of aldosterone: what we know and do not know thus far. Heart Fail Rev 2017;22:65-89. DOI: https://doi.org/10.1007/s10741-016-9591-2
27. Bauersachs J, Jaisser F, Toto R. Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases. Hypertension 2015;65:257-63. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.114.04488
28. McCurley A, Jaffe IZ. Mineralocorticoid receptors in vascular function and disease. Mol Cell Endocrinol 2012;350:256-65. DOI: https://doi.org/10.1016/j.mce.2011.06.014
29. Jaffe IZ, Jaisser F. Endothelial cell mineralocorticoid receptors. Hypertension 2014;63:915-7. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.114.01997
30. Barrera-Chimal J, Jaisser F. Vascular mineralocorticoid receptor activation and disease. Exp Eye Res 2019;188:107796. DOI: https://doi.org/10.1016/j.exer.2019.107796
31. Brem AS, Morris DJ, Gong R. Aldosterone-induced fibrosis in the kidney: questions and controversies. Am J Kidney Dis 2011;58:471-9. DOI: https://doi.org/10.1053/j.ajkd.2011.03.029
32. Mihailidou AS, Tzakos AG, Ashton AW. Non-genomic effects of aldosterone. Vitam Horm 2019;109:133-49. DOI: https://doi.org/10.1016/bs.vh.2018.12.001
33. Checa J, Aran JM. Reactive oxygen species: drivers of physiological and pathological processes. J Inflamm Res 2020;13:1057-73. DOI: https://doi.org/10.2147/JIR.S275595
34. Ruhs S, Nolze A, Hübschmann R, Grossmann C. 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor. J Endocrinol 2017;234:T107-T24. DOI: https://doi.org/10.1530/JOE-16-0659
35. Nehme A, Zibara K. Efficiency and specificity of RAAS inhibitors in cardiovascular diseases: how to achieve better end-organ protection? Hypertens Res 2017;40:903-9. DOI: https://doi.org/10.1038/hr.2017.65
36. Alshahrani S. Renin-angiotensin-aldosterone pathway modulators in chronic kidney disease: A comparative review. Front Pharmacol 2023;14:1101068.
37. Gromotowicz-Poplawska A, Szoka P, Kolodziejczyk P, et al. New agents modulating the renin-angiotensin-aldosterone system-Will there be a new therapeutic option? Exp Biol Med (Maywood) 2016;241:1888-99. DOI: https://doi.org/10.1177/1535370216660211
38. Schrier RW. Aldosterone 'escape' vs 'breakthrough'. Nat Rev Nephrol 2010;6:61. DOI: https://doi.org/10.1038/nrneph.2009.228
39. Verma S, Pandey A, Pandey AK, et al. Aldosterone and aldosterone synthase inhibitors in cardiorenal disease. Am J Physiol Heart Circ Physiol 2024;326:H670-H88. DOI: https://doi.org/10.1152/ajpheart.00419.2023
40. Mentz RJ, Bakris GL, Waeber B, et al. The past, present and future of renin-angiotensin aldosterone system inhibition. Int J Cardiol 2013;167:1677-87. DOI: https://doi.org/10.1016/j.ijcard.2012.10.007
41. Upadhyay A, Haider L. Mineralocorticoid receptor antagonists in diabetic kidney disease: clinical evidence and potential adverse events. Clin Diabetes 2024;43:43-52. DOI: https://doi.org/10.2337/cd24-0036
42. Cuculi F, Suter A, Erne P. Spironolactone-induced gynecomastia. CMAJ 2007;176:620. DOI: https://doi.org/10.1503/cmaj.061286
43. Bădilă E. The expanding class of mineralocorticoid receptor modulators: New ligands for kidney, cardiac, vascular, systemic and behavioral selective actions. Acta Endocrinol (Buchar) 2020;16:487-96. DOI: https://doi.org/10.4183/aeb.2020.487
44. Savarese G, Lindberg F, Filippatos G, et al. Mineralocorticoid receptor overactivation: targeting systemic impact with non-steroidal mineralocorticoid receptor antagonists. Diabetologia 2024;67:246-62. DOI: https://doi.org/10.1007/s00125-023-06031-1
45. Agarwal A, Cheung AK. Mineralocorticoid receptor antagonists in ESKD. Clin J Am Soc Nephrol 2020;15:1047-9. DOI: https://doi.org/10.2215/CJN.13221019
46. Arici M, Altun B, Araz M, et al. The significance of finerenone as a novel therapeutic option in diabetic kidney disease: a scoping review with emphasis on cardiorenal outcomes of the finerenone phase 3 trials. Front Med (Lausanne) 2024;11:1384454. DOI: https://doi.org/10.3389/fmed.2024.1384454
47. Shaikh A, Ray J, Campbell KN. Role of finerenone in the treatment of diabetic kidney disease: patient selection and clinical perspectives. Ther Clin Risk Manag 2022;18:753-60. DOI: https://doi.org/10.2147/TCRM.S325916
48. Ando H. Inhibition of aldosterone synthase: Does this offer advantages compared with the blockade of mineralocorticoid receptors? Hypertens Res 2023;46:1056-7. DOI: https://doi.org/10.1038/s41440-023-01188-z
49. Pitt B, Williams GH. Aldosterone synthase inhibitors and mineralocorticoid receptor antagonists: competitors or collaborators? Circulation 2024;149:414-6. DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.066314
50. Zhu W, Chen Z, Li Q, et al. Inhibitors of 11β-Hydroxylase (CYP11B1) for treating diseases related to excess cortisol. Curr Med Chem 2016;23:623-33. DOI: https://doi.org/10.2174/0929867323666160122114947
51. Andersen K, Hartman D, Peppard T, et al. The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study. J Clin Hypertens 2012;14:580-7.
52. Schumacher CD, Steele RE, Brunner HR. Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy. J Hypertens 2013;31:2085-93. DOI: https://doi.org/10.1097/HJH.0b013e328363570c
53. Khan MS, Butler J, Khan LA, Anker MS. Advanced cancer as a heart failure like syndrome due to cardiac wasting cardiomyopathy: facts and numbers. Global Cardiology 2024;2:58. DOI: https://doi.org/10.4081/cardio.2024.58
54. Valentín-Goyco J, Liu J, Peng HM, et al. Selectivity of osilodrostat as an inhibitor of human steroidogenic cytochromes P450. J Steroid Biochem Mol Biol 2023;231:106316. DOI: https://doi.org/10.1016/j.jsbmb.2023.106316
55. Brixius-Anderko S, Scott EE. Aldosterone synthase structure with cushing disease drug LCI699 highlights avenues for selective CYP11B drug design. Hypertension 2021;78:751-9. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.121.17615
56. Amar L, Azizi M, Menard J, et al. Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. Hypertension 2010;56:831-8. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.110.157271
57. Calhoun DA, White WB, Krum H, et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: results of a randomized, double-blind, placebo- and active-controlled phase 2 trial. Circulation 2011;124:1945-55. DOI: https://doi.org/10.1161/CIRCULATIONAHA.111.029892
58. Karns AD, Bral JM, Hartman D, et al. Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J Clin Hypertens (Greenwich) 2013;15:186-92. DOI: https://doi.org/10.1111/jch.12051
59. Andersen K, Hartman D, Peppard T, et al. The effects of aldosterone synthase inhibition on aldosterone and cortisol in patients with hypertension: a phase II, randomized, double-blind, placebo-controlled, multicenter study. J Clin Hypertens (Greenwich) 2012;14:580-7. DOI: https://doi.org/10.1111/j.1751-7176.2012.00667.x
60. Pivonello R, Fleseriu M, Newell-Price J, et al. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol 2020;8:748-61. DOI: https://doi.org/10.1016/S2213-8587(20)30240-0
61. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab 2022;107:e2882-e95. DOI: https://doi.org/10.1210/clinem/dgac178
62. Fleseriu M, Pivonello R, Newell-Price J, et al. Osilodrostat improves blood pressure and glycemic control in patients with Cushing's disease: a pooled analysis of LINC 3 and LINC 4 studies. Pituitary 2025;28:22. DOI: https://doi.org/10.1007/s11102-025-01525-0
63. Dougherty JA, Desai DS, Herrera JB. Osilodrostat: a novel steroidogenesis inhibitor to treat Cushing's disease. Ann Pharmacother 2021;55:1050-60. DOI: https://doi.org/10.1177/1060028020968808
64. Freeman MW, Halvorsen YD, Marshall W, et al. Phase 2 trial of baxdrostat for treatment-resistant hypertension. N Engl J Med 2023;388:395-405. DOI: https://doi.org/10.1056/NEJMoa2213169
65. AstraZeneca. Open-label extension study of patients previously enrolled in study CIN-107-124. ClinicalTrials.gov; 2022 [cited 2025 Apr 8]. Available from: https://www.astrazenecaclinicaltrials.com/study/CIN-107-130/
66. Kumbhani DJ. HALO: aldosterone synthase inhibitor shows modest BP reduction, with endocrine effects. Washington, American College of Cardiology; 2023. Available from: https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2023/03/01/23/34/halo
67. AstraZeneca. A study to evaluate CIN-107 for the treatment of patients with uncontrolled hypertension and chronic kidney disease. ClinicalTrials.gov; 2022. Available from: https://frfr.www.astrazenecaclinicaltrials.com/study/CIN-107-123/
68. Usman MS, Hamid A, Qazi SU, et al. The effect of SGLT2 inhibitors on health status in patients with heart failure: a systematic review and meta-analysis. Global Cardiology 2024;2:35. DOI: https://doi.org/10.4081/cardio.2024.35
69. AstraZeneca. A Multicenter, open-label study to evaluate the safety, tolerability, and effectiveness of CIN-107 for the management of blood pressure in patients with primary aldosteronism. ClinicalTrials.gov; 2021. Available from: https://www.astrazenecaclinicaltrials.com/study/CIN-107-122/
70. Laffin LJ, Rodman D, Luther JM, et al. Aldosterone synthase inhibition with lorundrostat for uncontrolled hypertension: the target-HTN randomized clinical trial. JAMA 2023;330:1140-50. DOI: https://doi.org/10.1001/jama.2023.16029
71. Mulatero P. Damian Pharma. DP13 – a Phase II study in patients with primary aldosteronism to evaluate the efficacy, safety and tolerability of DP13 over an 8-week treatment period. ClinicalTrials.gov; 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT04007406
72. Boehringer Ingelheim. Promising phase II results in chronic kidney disease. 2023. Available from: https://www.boehringer-ingelheim.com/promising-phase-ii-results-chronic-kidney-disease
73. Siddiqi TJ, Butler J, Coats AJS, et al. SGLT2 inhibitors and risk reduction for mortality in high-risk patients: a meta-analysis of randomized controlled trials. Global Cardiology 2023;1:2. DOI: https://doi.org/10.4081/cardio.2023.2
74. Alshahrani S. Renin-angiotensin-aldosterone pathway modulators in chronic kidney disease: A comparative review. Front Pharmacol 2023;14:1101068. DOI: https://doi.org/10.3389/fphar.2023.1101068
75. Pham TD, Verlander JW, Wang Y, et al. Aldosterone regulates pendrin and epithelial sodium channel activity through intercalated cell mineralocorticoid receptor-dependent and -independent mechanisms over a wide range in serum potassium. J Am Soc Nephrol 2020;31:483-99. DOI: https://doi.org/10.1681/ASN.2019050551
76. Johnson TA, Fettweis G, Wagh K, et al. The glucocorticoid receptor is required for efficient aldosterone-induced transcription by the mineralocorticoid receptor. bioRxiv [Preprint] 2023:2023.01.26.525745 DOI: https://doi.org/10.1101/2023.01.26.525745
77. Rivers CA, Rogers MF, Stubbs FE, et al. Glucocorticoid receptor–tethered mineralocorticoid receptors increase glucocorticoid-induced transcriptional responses. Endocrinology 2019;160:1044-56. DOI: https://doi.org/10.1210/en.2018-00819
78. Mikhail N. Aldosterone synthase inhibitors for treatment of hypertension and chronic kidney disease. Arch Pharmacol Ther 2024;6:8-12. DOI: https://doi.org/10.33696/Pharmacol.6.048
79. Judge PK, Tuttle KR, Staplin N, et al. The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial. Nephrol Dial Transplant 2025;40:1175-86. DOI: https://doi.org/10.1093/ndt/gfae263
80. Perosevic M, Tritos NA. Clinical utility of osilodrostat in Cushing's disease: review of currently available literature. Drug Des Devel Ther 2023;17:1303-12. DOI: https://doi.org/10.2147/DDDT.S315359
81. Pivonello R, Simeoli C, Di Paola N, et a. Osilodrostat: a novel potent inhibitor of 11-beta-hydroxylase for the treatment of Cushing's syndrome. touchREV Endocrinol 2024;20:43-51. DOI: https://doi.org/10.17925/EE.2024.20.1.8
82. Forzano I, Mone P, Varzideh F, et al. The selective aldosterone synthase inhibitor baxdrostat significantly lowers blood pressure in patients with resistant hypertension. Front Endocrinol (Lausanne) 2022;13:1097968. DOI: https://doi.org/10.3389/fendo.2022.1097968
83. Feldman JM, Frishman WH, Aronow WS. Emerging therapies for treatment-resistant hypertension: a review of lorundrostat and related selective aldosterone synthase inhibitors. Cardiol Rev 2024:665. DOI: https://doi.org/10.1097/CRD.0000000000000665
84. Medsafe. Drug metabolism – The importance of cytochrome P450 3A4. https://www.medsafe.govt.nz/profs/puarticles/march2014drugmetabolismcytochromep4503a4.htm
85. WuXi AppTec. Drug-drug interaction: an overview of substrates and metabolizing enzymes. 2023. Available from: https://labtesting.wuxiapptec.com/2023/03/14/drug-drug-interaction-an-overview-of-substrates-and-metabolizing-enzymes/
86. Manyara AM, Davies P, Stewart D, et al. Reporting of surrogate endpoints in randomised controlled trial protocols (SPIRIT-Surrogate): extension checklist with explanation and elaboration. BMJ 2024;386:e078525. DOI: https://doi.org/10.1136/bmj-2023-078525
87. Georgianos PI, Agarwal R. The nonsteroidal mineralocorticoid-receptor-antagonist finerenone in cardiorenal medicine: a state-of-the-art review of the literature. Am J Hypertens 2023;36:135-43. DOI: https://doi.org/10.1093/ajh/hpac124
88. Lenzini L, Zanotti G, Bonchio M, Rossi GP. Aldosterone synthase inhibitors for cardiovascular diseases: A comprehensive review of preclinical, clinical and in silico data. Pharmacol Res 2021;163:105332. DOI: https://doi.org/10.1016/j.phrs.2020.105332
89. Marzano L, Merlo M, Martinelli N, et al. Efficacy and safety of aldosterone synthase inhibitors for hypertension: a meta-analysis of randomized controlled trials and systematic review. Hypertension 2025;82:e47-e56. DOI: https://doi.org/10.1161/HYPERTENSIONAHA.124.23962
90. Triebel H, Castrop H. The renin angiotensin aldosterone system. Pflugers Arch 2024;476:705-13. DOI: https://doi.org/10.1007/s00424-024-02908-1
91. Colombijn JMT, Idema DL, van Beem S, et al. The persistent underrepresentation of patients with chronic kidney disease in cardiovascular trials: a systematic review and evidence map of exclusion and outcomes. medRxiv 2023:2023.07.18.23292848. DOI: https://doi.org/10.1101/2023.07.18.23292848
92. Pinho-Gomes AC, Carcel C, Woodward M, Hockham C. Women's representation in clinical trials of patients with chronic kidney disease. Clin Kidney J 2023;16:1457-64. DOI: https://doi.org/10.1093/ckj/sfad018
93. Nieckarz A, Graff B, Burnier M, et al. Aldosterone in the brain and cognition: knowns and unknowns. Front Endocrinol (Lausanne) 2024;15:1456211. DOI: https://doi.org/10.3389/fendo.2024.1456211
94. Wu VC, Wang SM, Chang CH, et al. Long term outcome of aldosteronism after target treatments. Sci Rep 2016;6:32103. DOI: https://doi.org/10.1038/srep32103
95. Nanba K, Vaidya A, Williams GH, et al. Age-related autonomous aldosteronism. Circulation 2017;136:347-55. DOI: https://doi.org/10.1161/CIRCULATIONAHA.117.028201
96. Jansen PM, van den Meiracker AH, Jan Danser AH. Aldosterone synthase inhibitors: pharmacological and clinical aspects. Curr Opin Investig Drugs 2009;10:319-26.
97. Sun Y, Zhang J, Lu L, et al. Aldosterone-induced inflammation in the rat heart : role of oxidative stress. Am J Pathol 2002;161:1773-81. DOI: https://doi.org/10.1016/S0002-9440(10)64454-9
98. Treihaft AM, Parikh MA, Jackson KA, et al. Aldosterone synthase inhibitor BI 690517: specificity for mineralocorticoid receptor. Cardiol Rev 2025;838. DOI: https://doi.org/10.1097/CRD.0000000000000838
99. Hegyi B, Mira Hernandez J, Ko CY, et al. Diabetes and excess aldosterone promote heart failure with preserved ejection fraction. J Am Heart Assoc 2022;11:e027164. DOI: https://doi.org/10.1161/JAHA.122.027164
100. Deswal A, Richardson P, Bozkurt B, Mann DL. Results of the randomized aldosterone antagonism in heart failure with preserved ejection fraction trial (RAAM-PEF). J Card Fail 2011;17:634-42. DOI: https://doi.org/10.1016/j.cardfail.2011.04.007
101. Tuttle KR, Hauske SJ, Canziani ME, et al. Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial. Lancet 2024;403:379-90. DOI: https://doi.org/10.1016/S0140-6736(23)02408-X
102. Yoshida Y, Shibata H. Evolution of mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, and alternative treatments for managing primary aldosteronism. Hypertens Res 2025;48:854-61. DOI: https://doi.org/10.1038/s41440-024-01970-7
103. Nejatizadeh A, Kumar R, Stobdan T, et al. CYP11B2 gene haplotypes independently and in concurrence with aldosterone and aldosterone to renin ratio increase the risk of hypertension. Clin Biochem 2010;43:136-41. DOI: https://doi.org/10.1016/j.clinbiochem.2009.09.015
104. Mendez KM, Reinke SN, Kelly RS, et al. A roadmap to precision medicine through post-genomic electronic medical records. Nat Commun 2025;16:1700. DOI: https://doi.org/10.1038/s41467-025-56442-4
105. Johnson KB, Wei WQ, Weeraratne D, et al. Precision medicine, AI, and the future of personalized health care. Clin Transl Sci 2021;14:86-93. DOI: https://doi.org/10.1111/cts.12884
106. Burton J, Wheeler D, Tangri N, Pollock C. An expert approach to cardio-renal protection in CKD [Internet]. Radcliffe Medical Education; 2024. Available from: https://www.radcliffemedicaleducation.org/course/expert-approach-cardio-renal-protection-ckd
107. Berbari BA. Treatment options in cardiorenal syndrome. Kidney News 2010;2:19-21. DOI: https://doi.org/10.1007/978-88-470-1463-3
108. Filidou E, Kandilogiannakis L, Tarapatzi G, et al. Anti-inflammatory and anti-fibrotic effect of immortalized mesenchymal-stem-cell-derived conditioned medium on human lung myofibroblasts and epithelial cells. Int J Mol Sci 2022;23:4570. DOI: https://doi.org/10.3390/ijms23094570
109. Antar SA, Ashour NA, Marawan ME, Al-Karmalawy AA. Fibrosis: types, effects, markers, mechanisms for disease progression, and its relation with oxidative stress, immunity, and inflammation. Int J Mol Sci 2023;24:4004. DOI: https://doi.org/10.3390/ijms24044004
110. Collins BF, Raghu G. Antifibrotic therapy for fibrotic lung disease beyond idiopathic pulmonary fibrosis. Eur Respir Rev 2019;28:190022. DOI: https://doi.org/10.1183/16000617.0022-2019
111. Guo C, Zhang G, Wu C, et al. Emerging trends in small molecule inhibitors targeting aldosterone synthase: A new paradigm in cardiovascular disease treatment. Eur J Med Chem 2024;274:116521. DOI: https://doi.org/10.1016/j.ejmech.2024.116521
How to Cite
1.
Dawood MH, Khan MS, Rashid AM, Haverkamp W. Aldosterone synthase inhibitors in cardio-renal diseases: a state-of-the-art review. Global Cardiol [Internet]. 2025 Dec. 31 [cited 2026 Jan. 18];3(4). Available from: https://www.globalcardiology.info/site/article/view/91
Copyright (c) 2026 the Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
