The hypertension specialist's perspective: aldosterone synthase inhibitors to fill the gap in difficult-to-control and resistant hypertension.

Abstract

Aldosterone dysregulation is a key driver of difficult-to-control and resistant hypertension. Mineralocorticoid receptor antagonists (MRAs) target the aldosterone pathway but their use can be limited by side effects, particularly hyperkalemia and antiandrogenic hormonal effects. Selective aldosterone synthase inhibitors (ASIs) have shown clinically meaningful blood pressure reductions in patients with difficult-to-control and resistant hypertension in recent phase 2b and 3 trials. In this narrative review, we summarize pivotal evidence from phase 2b and phase 3 trials of the second-generation ASIs lorundrostat, baxdrostat, and dexfadrostat, reporting efficacy and core safety signals (hyperkalemia, hyponatremia, and an early functional reduction in estimated glomerular filtration rate (eGFR]). We further discuss the implications of these findings, economic and access considerations, remaining evidence gaps, future research directions, and potential practical treatment algorithms. ASIs offer clinically significant blood pressure lowering with moderate side effects when added on top of current therapies in short-term trials, though long-term outcome data are lacking. In May 2026, the US Food and Drug Administration (FDA) approved the first ASI, baxdrostat, for hypertension treatment in combination with other antihypertensive drugs in inadequately controlled adults. However, gaps remain, most notably the absence of comparative effectiveness trials versus MRAs, the standard fourth-line agent. ASIs target upstream aldosterone production and may offer a distinct, complementary role for patients with intolerance or contraindications for MRA or insufficient response. ASIs may be best reserved for the treatment of uncontrolled or resistant hypertension in combination with other antihypertensives and where MRAs are contraindicated, poorly tolerated, or insufficient.