The FDA recently approved baxdrostat (Baxfendy™), the first aldosterone synthase inhibitor approved for hypertension, as an add-on therapy for adults whose blood pressure is not adequately controlled on other antihypertensive agents. Aldosterone contributes to hypertension by promoting renal sodium and water retention, which increases blood volume, and it can also drive vascular dysfunction, inflammation, and fibrosis independent of its effects on blood pressure. Baxdrostat lowers plasma aldosterone concentrations by selectively inhibiting aldosterone synthase, the terminal enzyme in the aldosterone synthesis pathway. Unlike earlier, less selective inhibitors of this pathway, baxdrostat has a high degree of selectivity for aldosterone synthase over the closely related enzyme 11β-hydroxylase (the final enzyme in cortisol synthesis), so cortisol production is preserved across a wide dose range. Baxdrostat also does not inhibit synthesis of sex hormones such as testosterone and estrone, avoiding the antiandrogenic and antiestrogenic effects seen with some other agents that interfere with steroidogenesis.

Approval was based on the BaxHTN trial, a phase 3 study of 794 adults with baseline systolic blood pressure (SBP) of 149 mmHg who were already taking at least two antihypertensive medications, including a diuretic. Patients were randomized to baxdrostat 1 mg, 2 mg, or placebo once daily for 12 weeks. At Week 12, both doses significantly reduced blood pressure compared to placebo: the 2 mg dose lowered SBP by 9.8 mmHg and diastolic blood pressure (DBP) by 3.9 mmHg more than placebo (p<0.0001 for both), with similar, slightly smaller reductions seen with the 1 mg dose. The blood pressure–lowering effect was durable through an 8-week randomized-withdrawal period. As expected with a drug that suppresses aldosterone, hyperkalemia was the most common adverse effect, occurring in 10.2% of patients on the 2 mg dose and 6.6% on the 1 mg dose, versus 2.5% with placebo. Serum potassium exceeded 5.5 mEq/L in 12.2% of patients on 2 mg, and hyperkalemia led to permanent drug discontinuation in 1.8% of patients on that dose. Risk increased further with age, reaching 21% among patients 75 years or older taking the 2 mg dose.

Baxdrostat's efficacy and safety profile closely resembles that of the aldosterone antagonists spironolactone and eplerenone, which is not surprising given that all three drugs ultimately reduce aldosterone's downstream effects, whether by blocking its synthesis or blocking its receptor. Spironolactone, in particular, has repeatedly outperformed other add-on agents for resistant hypertension in trials like PATHWAY, and like baxdrostat, its main limiting side effect is hyperkalemia. Given this overlap in benefit and risk, and the fact that spironolactone and eplerenone are both inexpensive generic drugs with decades of clinical experience behind them, they remain the more reasonable first choice for add-on therapy in resistant or difficult-to-control hypertension. Baxdrostat may still find a role in patients who cannot tolerate an aldosterone antagonist's off-target effects (e.g., spironolactone's antiandrogenic effects), but its added cost is hard to justify as a routine first-line add-on.

• Baxdrostat (Baxfendy™) review
• Aldosterone antagonists review
• Baxfendy prescribing information (DailyMed)