From low renin to the primary aldosteronism spectrum: aldosterone synthase inhibitors and the endocrine management of hypertension

Background Hypertension remains a major contributor to global cardiovascular morbidity despite decades of available therapy. Aim This review advances an endocrinological framework in which chronic hypertension, including resistant hypertension, is understood as a consequence of dysregulated hormonal control of renal sodium handling, mediated by excess renin-angiotensin II activity, inappropriate aldosterone excess, or both. Results Within this framework, the traditional binary distinction between “essential” and “secondary” hypertension gives way to a mechanistic continuum characterized by biochemical phenotyping using renin and aldosterone. Primary aldosteronism (PA) is now recognized as existing across a spectrum of severity that is broader than classical diagnostic thresholds suggest, and aldosterone dysregulation, even at subclinical levels, confers adverse cardiorenal outcomes exceeding those of renin-dependent hypertension. Mineralocorticoid receptor antagonists (MRAs) are effective when aldosterone excess is the dominant mechanism but do not correct the underlying endocrinopathy and may be limited by tolerability at the doses required to achieve full biochemical targets. Highly selective second-generation aldosterone synthase inhibitors (ASIs), including baxdrostat and lorundrostat, directly suppress aldosterone production, mirror the biochemical response seen after surgical adrenalectomy, and may confer disease-modifying effects beyond blood pressure reduction. Conclusion Integrated into a mechanism-first clinical algorithm driven by renin and aldosterone profiling, ASIs and MRAs offer the potential to transform management of low-renin and PA-spectrum hypertension, moving clinicians from empirical, add-on drug strategies toward individualized, pathophysiology-guided care.