From bench to formulary: a pharmacological appraisal of aldosterone synthase inhibitors for uncontrolled and resistant hypertension

Background Currently available options for managing uncontrolled and resistant hypertension are limited by safety concerns and their inability to prevent the nongenomic effects of aldosterone. Aldosterone synthase inhibitors (ASI) have emerged with Phase 3 data suggesting they provide adequate blood pressure (BP) lowering with reasonable safety profiles. Methods This review synthesizes the current evidence for ASIs (baxdrostat and lorundrostat) to improve BP, including pertinent pharmacologic, pharmacokinetic, effectiveness, and safety considerations. Results Through inhibition of the enzyme cytochrome-P450 11B2 (CYP11B2), baxdrostat and lorundrostat reduce aldosterone synthase expression, lowering aldosterone concentrations. Beyond BP-lowering effects, aldosterone synthase inhibition attenuates myocardial and vascular fibrosis promotion, endothelial dysfunction, and kidney injury. Evidence from phase 2 and 3 clinical trials in patients with uncontrolled and resistant hypertension despite being on multiple antihypertensive drugs suggests that the ASIs typically produce 5-15 mm Hg reductions in systolic BP. While generally well tolerated, the main safety concerns include hyperkalemia, hyponatremia, hypotension, and reductions in kidney function. As mineralocorticoid receptor antagonists (MRAs) are currently recommended as the treatment of choice for resistant hypertension, comparative trials of ASIs with the MRAs are needed to better identify their place in practice. Conclusions The ASIs represent a promising class of antihypertensive drug classes with proven efficacy in reducing both office and ambulatory blood pressure, although studies on their comparative efficacy and safety with MRAs such as spironolactone are needed, along with evidence of cost-effectiveness.