Baxdrostat significantly reduces 24-hr ASBP.The results of the phase III Bax24 trial underpin the efficacy of baxdrostat, a selective aldosterone synthase inhibitor (ASI), for the treatment of uncontrolled or resistant hypertension (HTN).
“The addition of baxdrostat 2 mg daily to background anti-HTN therapy in patients with true resistant HTN confirmed by ambulatory blood pressure monitoring (ABPM) resulted in substantial reductions in 24-hr and night-time ambulatory systolic BP (ASBP) at 12 weeks compared with placebo,” the investigators said.
At week 12, the least-squares mean (LSM) change from baseline in 24-hr ASBP without imputation was significantly greater with baxdrostat than with placebo (−16.6 vs −2.6 mm Hg; p<0.0001).
To put this further into context, all but four baxdrostat recipients had a reduction in 24-hr ASBP. Moreover, the week-12 change in 24-hr ASBP was consistent across all prespecified subgroups. [Lancet 2026;407:988-999]
Baxdrostat outperformed placebo at week 12 for LSM changes from baseline in night-time ASBP (−16 vs −2.1 mm Hg), daytime ASBP (−16.8 vs −2.7 mm Hg), and seated SBP (−14.9 vs −4.7 mm Hg; p<0.0001 for all), and in the percentage of participants achieving a 24-hr ASBP <130 mm Hg (71 percent vs 17 percent).
“The unexpectedly large nocturnal SBP reduction with baxdrostat, with comparable magnitude to daytime SBP reduction, contributed to an overall amplification of the 24-hr SBP reduction across the circadian cycle,” the researchers said.
Week 12 also saw greater median changes from baseline in serum aldosterone concentration (−5.1 vs −0.4 ng/dL), plasma renin activity (1.9 vs 0.3 ng/mL/hr), and aldosterone-to-plasma renin activity ratio (–3.5 vs –0.8 ng/dL per ng/mL/hr) with baxdrostat vs placebo. These, according to the researchers, are consistent with aldosterone synthase inhibition and enhanced renal sodium excretion.
More baxdrostat vs placebo recipients reported any adverse event (AE; 52 percent vs 37 percent). One patient in each group reported any serious AE. The most common AEs with baxdrostat were hyperkalaemia, headache, and hypotension (6, 1, and 1 percent, respectively).
Two weeks after treatment discontinuation (week 14), the mean seated SBP was lower with baxdrostat than with placebo (137.7 vs 142.6 mm Hg). There were no deaths or reports of adrenal insufficiency.
“ASIs might raise serum potassium concentrations and be associated with a functional decrease in estimated glomerular filtration rate (eGFR) due to improved BP control,” the researchers noted.
Indeed, the baxdrostat group had a higher rate of hyperkalaemia requiring clinical intervention (6 percent vs 1 percent) but a lower rate of hypokalaemia (2 percent vs 11 percent) than the placebo group. One patient from each group had hyponatraemia requiring clinical intervention. Four baxdrostat and two placebo recipients had hyponatraemia <130 mmol/L.
Five percent of baxdrostat recipients and none of those on placebo had a serum potassium concentration >6 mmol/L throughout the trial.
The changes in potassium and sodium concentrations with baxdrostat predominantly occurred during the first 2 weeks, and these returned to baseline levels at week 14.
The mean change in eGFR from baseline to week 12 was greater with baxdrostat than with placebo (−8.7 vs −0.4 mL/min/1.73 m²); this returned to baseline level at week 14. Approximately a quarter of baxdrostat recipients achieved an eGFR reduction ≥30 percent from baseline at any time during the trial; only 5 percent in the placebo group did so.
Aldosterone dysregulation is considered an important contributor to hard-to-control and resistant HTN and its associated cardiovascular (CV) and renal complications. [Hypertension 2014;63:1205-1211; Ann Intern Med 2020;173:10-20; Lancet Diabetes Endocrinol 2018;6:41-50] However, there is insufficient evidence on the effects of aldosterone synthase inhibition on 24-hr and night-time BP, which is often disproportionately elevated in individuals with resistant HTN, the researchers noted.
Bax24 is a dedicated trial evaluating the effect of baxdrostat on 24-hr and night-time ABP in patients with true resistant HTN confirmed by ABPM. A total of 217 individuals (median age 60 years, 65 percent men) with 24-hr ASBP ≥130 mm Hg were randomized 1:1 to oral baxdrostat 2 mg or placebo QD for 12 weeks on top of background therapy.
Resistant HTN was defined as a mean seated office SBP ≥140 and <170 mm Hg at screening despite treatment with maximally tolerated doses of ≥3 anti-HTN agents of different classes, including a diuretic, for at least 4 weeks prior to screening.
“We focused on 24-hr ABP … because it is more strongly associated with all-cause and CV mortality than conventional office BP, with night-time BP most strongly associated with mortality,” the researchers said. ABPM also enables detection of white-coat HTN, is less prone to observer bias, is less affected by placebo response, and provides a full 24-hr circadian BP profile, including nocturnal BP. [J Hypertens 2023;41:1874-2071]
According to the investigators, the ASBP reductions are “the largest ever reported in a randomized controlled trial of any therapeutic intervention to date in patients with true resistant HTN”. Add-on baxdrostat was also associated with substantial reductions in night-time SBP, which might provide additional benefits in reducing CV events.
The results augment those from BaxHTN, which reported significant reductions in placebo-adjusted seated office SBP with baxdrostat after 12 weeks of treatment in individuals with uncontrolled or resistant HTN. [N Engl J Med 2025;393:1363-1374]
“Our study adds to the growing body of evidence that aldosterone dysregulation is a key factor in the pathogenesis of hard-to-control and resistant HTN … [S]elective ASIs such as baxdrostat represent a promising new treatment strategy for patients with hard-to-control HTN,” they concluded.
The BaxHTN and BaxAsia trials, as well as other long-term renoprotection and cardioprotection trials, are underway to evaluate the long-term safety and efficacy of baxdrostat. [N Engl J Med 2025;393:1363-1374; Hypertens Res 2025;48:2911-2923] Studies with dedicated outcomes are warranted to determine whether the BP reductions translate to improved long-term cardiorenal outcomes.