Mechanism-defined secondary hypertension enables precision diagnosis and treatment: an evidence review

Background Secondary hypertension is under-recognised despite the availability of mechanism-based diagnostic tests and, for several aetiologies, potentially curative or highly targeted therapy. The clinically important question is not only which causes exist, but how reliably mechanisms translate into diagnosis and cause-directed treatment. Objectives To systematically synthesise evidence across the principal causes of secondary hypertension using a mechanism → diagnosis → therapy framework; to compare diagnostic performance and cause-directed treatment effects; and to examine concordance between contemporary society guidelines and real-world implementation. Methods This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, with diagnostic accuracy reporting informed by PRISMA-DTA. MEDLINE (PubMed), Embase, CENTRAL, Web of Science Core Collection, Scopus, ClinicalTrials.gov, and the WHO ICTRP were searched from inception to 30 June 2025, supplemented by citation searching. The formal search identified 580 records; after removal of 168 duplicates, 412 records were screened, 106 full-text reports were assessed, and 58 included evidence records were represented across 63 publications. The review was not prospectively registered in PROSPERO. Screening, extraction and structured appraisal were performed by a single reviewer (the first author); therefore, no dual-reviewer agreement statistic was applicable. Risk of bias was appraised with RoB 2, ROBINS-I, QUADAS-2, and AMSTAR 2 as appropriate, and certainty was summarised using GRADE. A targeted post-search surveillance update through 31 July 2026 was used only to contextualise major newly available guidelines and Phase 3 trial reports and did not alter the original PRISMA counts. Results Primary aldosteronism (PA) is best understood as a continuum of renin-independent aldosterone excess: in Brown et al. [The unrecognized prevalence of primary aldosteronism: a cross-sectional study. Ann Intern Med . (2020) 173 :10–20], biochemically overt autonomous aldosterone production was present in 11.3%, 15.7%, 21.6%, and 22.0% across normotensive, stage 1, stage 2, and resistant-hypertension strata, respectively. In unilateral PA, the PASO cohort distinguished complete biochemical success after adrenalectomy (94%; 656/699) from complete clinical success (37%; 259/705), with partial clinical improvement in a further 47%. PATHWAY-2 established spironolactone as the most effective fourth-line drug in resistant hypertension; CORAL, ASTRAL, STAR, and DRASTIC did not support routine revascularisation for stable atherosclerotic renal-artery stenosis; plasma-free metanephrines remained highly sensitive for phaeochromocytoma/paraganglioma; and PA testing in eligible patients with resistant hypertension remained only 1.6%–2.1%. Post-search Phase 3 trials of selective aldosterone synthase inhibition showed approximately 9 mm Hg placebo-corrected office systolic blood pressure reductions, but cardiovascular-outcome benefit has not been established, and electrolyte/renal monitoring remains necessary. Conclusions Across secondary hypertension, a limited set of pathophysiological effector pathways maps to specific diagnostic tests and cause-directed treatments. The strongest opportunities for clinical gain are earlier recognition of high-yield phenotypes, accurate aetiological subtyping, and implementation of established testing pathways; emerging aldosterone synthase inhibitors expand blood-pressure-lowering options but should not yet be interpreted as proven cardiovascular-outcome therapies.