Comparative Efficacy of Aldosterone-Related Sodium-Retention Pathway Therapies for Resistant Hypertension: A Drug-Level Network Meta-Analysis of Randomized Controlled Trials.

Mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), and epithelial sodium channel (ENaC) blockade target different levels of the aldosterone-related sodium-retention pathway in resistant hypertension (RH), but the comparative efficacy of individual agents remains uncertain. We conducted a focused drug-level network meta-analysis of randomized controlled trials (RCTs) comparing pathway-directed therapies in adults with RH. PubMed, Scopus, Embase, Cochrane CENTRAL, Cochrane Reviews, and ClinicalTrials.gov were searched from inception to July 20, 2026. The primary outcome was change in office systolic blood pressure (BP). Secondary outcomes included office diastolic BP and 24-hour ambulatory systolic and diastolic BP. Ten RCTs including 2865 participants were analyzed. In the primary drug-level analysis, amiloride, spironolactone, baxdrostat, eplerenone, and lorundrostat significantly reduced office systolic BP compared with placebo, with mean differences (MDs) of -14.08, -10.78, -9.09, -8.14, and -6.80 mmHg, respectively. Osilodrostat showed a statistically uncertain effect, with an MD of -2.61 mmHg. At the class level, both MRAs and ASIs showed clinically meaningful reductions in office systolic BP. Secondary outcomes were generally consistent with the primary analysis, although fewer trials contributed to these networks. Sensitivity analyses did not materially change the primary findings. These results support the aldosterone-related sodium-retention pathway as an important therapeutic target in RH. MRAs remain the established reference add-on therapy, whereas newer ASIs and amiloride may represent pathway-based alternatives for selected patients. Trial Registration: INPLASY202670099.