{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:51:48Z","timestamp":1787496708971,"version":"build-2736575974"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Aldosterone synthase inhibitors (ASIs) have emerged as a mechanistically targeted strategy for resistant and uncontrolled hypertension; however, no head-to-head trials exist, and comparative efficacy and safety remain uncertain. We compared their efficacy and safety using network and pairwise meta-analysis of randomized trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This systematic review and meta-analysis adhered to the PRISMA guidelines. PubMed\/MEDLINE, Scopus, Embase, ClinicalTrials.gov, and Cochrane Library were searched from inception to January 14, 2026, for randomized trials evaluating ASIs versus placebo or standard care. A frequentist random-effects network meta-analysis assessed systolic (SBP) and diastolic blood pressure (DBP). Dichotomous safety outcomes were pooled using Hartung\u2013Knapp random-effects models. Network consistency was evaluated using design-by-treatment interaction modeling. Prespecified subgroup analyses stratified outcomes by hypertension phenotype (resistant vs uncontrolled).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Across 7 RCTs (n\u2009=\u20092,828), all ASIs significantly reduced SBP versus placebo: baxdrostat \u22128.63 mmHg (95% CI \u221210.84 to \u22126.42), lorundrostat \u22127.47 mmHg (95% CI \u22129.54 to \u22125.40), and LCI699\/osilodrostat \u22125.63 mmHg (95% CI \u22129.15 to \u22122.12), with no significant indirect differences between agents. In resistant hypertension, lorundrostat (\u22129.00 mmHg; 95% CI \u221213.19 to \u22124.81) and baxdrostat (\u22128.77 mmHg; 95% CI \u221210.50 to \u22127.05) demonstrated pronounced reductions. In uncontrolled hypertension, LCI699\/osilodrostat showed the largest point estimate (\u221210.55 mmHg; 95% CI \u221216.49 to \u22124.61), though this derives from a single early-phase trial and requires cautious interpretation. DBP reductions were significant for baxdrostat (\u22123.23 mmHg; 95% CI \u22124.73 to \u22121.73) and lorundrostat (\u22123.60 mmHg; 95% CI \u22125.43 to \u22121.77). Hypotension (RR 2.67), hyperkalemia (RR 7.94), and hyponatremia (RR 2.07) were significantly increased; serious adverse events, discontinuation, and network inconsistency were not detected.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ASIs provide clinically meaningful BP reduction across both hypertension phenotypes; however, short-term use is associated with hypotension and electrolyte disturbances, necessitating careful monitoring. Phenotype-specific efficacy and long-term safety require validation in outcome-driven trials. Systematic Review Registration: PROSPERO CRD420251266257<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0349932","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:45:30Z","timestamp":1780508730000},"page":"e0349932","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aldosterone synthase inhibitors in uncontrolled and resistant hypertension: A phenotype-stratified systematic review and network meta-analysis of randomized trials"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2319-3899","authenticated-orcid":true,"given":"Ismaila Ajayi","family":"Yusuf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2401-6117","authenticated-orcid":true,"given":"Olurotimi J.","family":"Badero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8313-6350","authenticated-orcid":true,"given":"Alozie","family":"Ihesiulo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6023-1756","authenticated-orcid":true,"given":"Micah Nnabuko","family":"Okwah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abieyuwa","family":"Oshodin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7790-6259","authenticated-orcid":true,"given":"Emmanuella","family":"Asikong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"issue":"12","key":"pone.0349932.ref001","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1001\/jama.2020.14545","article-title":"Trends in blood pressure control among US adults with hypertension, 1999\u20132000 to 2017\u20132018","volume":"324","author":"P Muntner","year":"2020","journal-title":"JAMA"},{"issue":"5","key":"pone.0349932.ref002","doi-asserted-by":"crossref","DOI":"10.1161\/HYP.0000000000000084","article-title":"Resistant hypertension: Detection, evaluation, and management","volume":"72","author":"RM Carey","year":"2018","journal-title":"Hypertension"},{"issue":"2","key":"pone.0349932.ref003","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1136\/heartjnl-2018-313599","article-title":"Global prevalence of resistant hypertension: A meta-analysis of data from 3.2 million patients","volume":"105","author":"JJ Noubiap","year":"2019","journal-title":"Heart"},{"issue":"5","key":"pone.0349932.ref004","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.3390\/jcm11051455","article-title":"Rethinking resistant hypertension","volume":"11","author":"G Bourque","year":"2022","journal-title":"J Clin Med"},{"issue":"7","key":"pone.0349932.ref005","first-page":"1951","article-title":"Hypertension and resistant hypertension prevalence","volume":"18","author":"S Romano","year":"2023","journal-title":"Intern Emerg Med"},{"key":"pone.0349932.ref006","doi-asserted-by":"crossref","DOI":"10.1136\/bmj-2023-079108","article-title":"Diagnosis and management of resistant hypertension","volume":"385","author":"EL Schiffrin","year":"2024","journal-title":"BMJ"},{"issue":"7","key":"pone.0349932.ref007","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1038\/s41440-021-00643-z","article-title":"Novel therapeutics for the treatment of hypertension and its associated complications","volume":"44","author":"T Ghatage","year":"2021","journal-title":"Hypertens Res"},{"key":"pone.0349932.ref008","volume-title":"Physiology, renin angiotensin system","author":"JH Fountain","year":"2025"},{"issue":"5","key":"pone.0349932.ref009","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","volume":"334","author":"M Saxena","year":"2025","journal-title":"JAMA"},{"issue":"11","key":"pone.0349932.ref010","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1007\/s40265-025-02229-2","article-title":"Aldosterone synthase inhibitors for resistant hypertension: Pharmacological Insights - 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