N Engl J Med. 2025 Aug 30:10.1056/NEJMoa2507109. doi: 10.1056/NEJMoa2507109. Online ahead of print.
Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension
John M Flack, Michel Azizi, Jenifer M Brown, Jamie P Dwyer, Jakub Fronczek, Erika S W Jones, Daniel S Olsson, Shira Perl, Hirotaka Shibata, Ji-Guang Wang, Ulrica Wilderäng, Janet Wittes, Bryan Williams; BaxHTN Investigators
PMID: 40888730
PMCID: PMC7618089
Why was this study done?
So, in case you haven’t noticed, hypertension has been a hot topic at NephJC. More and more data has accumulated that normalization of blood pressure, regardless of comorbidities, improves patient composite cardiovascular outcomes (i.e. SPRINT, BPROAD, ESPRIT). Attaining normalization of systolic blood pressure (SBP) is obviously easier said than done, and may result in the physician's blood pressure rising as well. In the 1950s, chlorothiazide and hydralazine were the first medications released in the modern era of hypertension treatment. Unfortunately, innovation has slowed and there have not been many new and effective treatments released in the last two decades.
Enter the aldosterone synthase inhibitors (ASIs). These agents were spot-lighted in “meet the ‘-stats’” in 2023, and again in 2025 with a discussion of lorundrostat. The hope has been that the ASIs might just be the treatment we’ve been missing in resistant hypertension. These emerging oral therapies, unlike MRAs which imprecisely block aldosterone receptors, directly inhibit aldosterone synthesis. This means no gynecomastia, potentially less hyperkalemia, and no direct effects on cortisol. This last one took some time, as aldosterone synthase has a close homology to the 11beta-hydroxylase enzyme which is involved in cortisol synthesis. The ASIs in phase 3 trials are quite specific for aldosterone synthase, but testing for adrenal axis involvement is an intrinsic safety outcome in all ASI trials.
Figure 1. Inhibition of ASIs, from Ando H, Hypertens Res, 2023
ASIs have been circling for the last decade, with growing evidence for their use in resistant hypertension, but have yet to meet FDA approval for clinical use. Aldosterone dysregulation plays an important pathogenic role in hard-to-control hypertension, and it is anticipated that this group of medications may be approved soon, as more and more data becomes available. A large, multinational, double-blind, randomized, placebo-controlled phase 3 trial has now been completed with the ASI baxdrostat.
How was the study done and what did it show?
A total of 796 patients underwent randomization and 794 received 1-mg baxdrostat (264 patients), 2-mg baxdrostat (266 patients), or placebo (264 patients) in addition to background therapy. The trial enrolled patients who were at least 18 years of age and were diagnosed with hard-to-control hypertension (mean seated office SBP of 140-170 mm Hg, despite treatment with maximally tolerated doses of either two or three antihypertensive medications), not just true resistant hypertension which usually requires at least 3 drugs including a thiazide at optimal doses. After a 2-week single-blind run-in period in which patients received placebo in addition to their stable background medications, those who had a seated SBP ≥ 135 mm Hg and had good adherence to background antihypertensive therapy were randomized.
Table 1 Baseline Characteristics. Flack JM et al, NEJM 2025.
The trial had 4 sequential parts. Part 1 was a 12-week, double-blind, randomized, placebo-controlled period and formed the basis of the primary end point. Randomization was stratified according to the hypertension status (uncontrolled or resistant hypertension) and seated systolic blood pressure (<145 mm Hg or ≥145 mm Hg) at baseline. Part 2 (weeks 12 to 24) was an open label phase that was designed to collect safety data. Part 3 (weeks 24 to 32) was a double blind, randomized-withdrawal phase. Part 4 (weeks 32 to 52) is an ongoing 20-week, open-label phase to collect additional safety data regarding 2-mg baxdrostat.
Figure S1 Study design. Flack JM et al, NEJM 2025.
The primary efficacy endpoint was the change in the seated SBP from baseline to week 12, as assessed for each baxdrostat group as compared with placebo. The secondary endpoints were the change in the seated SBP from week 24 to 32 (after the randomized withdrawal of baxdrostat among patients who received open-label 2-mg baxdrostat daily for 12 weeks during part 2 and then were randomly assigned to receive 2-mg baxdrostat or placebo for 8 weeks).
At week 12 , treatment with baxdrostat at doses of 1 mg and 2 mg resulted in a change from baseline in the least-squares mean seated SBP of –14.5 mm Hg and –15.7 mm Hg, respectively. Patients in the placebo group only saw a change of –5.8 mm Hg (p= 0.001 for both doses of baxdrostat).
At the start of the 8-week randomized withdrawal period, the mean seated SBP among patients who had been randomly assigned to receive 2-mg baxdrostat or placebo was 133 mm Hg. The change in the least-squares mean seated SBP during the randomized withdrawal period was –3.7 mm Hg with 2-mg baxdrostat and +1.4 mm Hg with placebo (estimated difference, –5.1 mm Hg; 95% CI, –8.3 to –1.9; P = 0.002).
Figure 1 Change in blood pressure. Flack JM et al, NEJM 2025.
The most common adverse events were hyperkalemia, hyponatremia, hypotension, muscle spasms, and dizziness. No adrenal insufficiency was reported. The mean change in the estimated glomerular filtration rate (eGFR) from baseline to week 12 was –7.0±12.8 ml per minute per 1.73 m2 of body-surface area with 1-mg baxdrostat, –6.9±12.4 ml per minute per 1.73 m2 with 2-mg baxdrostat, and –0.1±8.6 ml per minute per 1.73 m2 with placebo. A change of 30% or more in the eGFR occurred during treatment in 12.6% of the patients with 1-mg baxdrostat, in 15.6% with 2-mg baxdrostat, and in 1.5% with placebo. During the randomized-withdrawal period, the eGFR remained stable in the patients receiving 2-mg baxdrostat and returned toward baseline levels in the placebo group.
Table 3 Adverse events. Flack JM et al, NEJM 2025.
S9 eGFR baseline to week 12 and withdrawal. Flack JM et al, NEJM 2025.
What are the implications?
Treatment of uncontrolled and resistant hypertension is complex. Factors such as medication non-adherence due to cost or side-effects, diet and obesity, unrecognized sleep apnea, and/or the use of interfering substances (alcohol, NSAIDs, oral contraception, herbal supplements) can contribute to the failure to control blood pressure in many patients. Having a new medication to address the RAAS, with potentially fewer side-effects than existing MRAs, would be a welcome addition. Although ASIs do not represent an entirely new physiologic approach to hypertension (nephrologists have arm wrestled with the RAAS for over forty years) we are always trying to build a better mousetrap. The nephrology community, and the FDA, have taken a slow and methodical approach to introducing ASIs after suffering the introduction and subsequent waning use of direct renin inhibitors (DRIs). DRIs never found a footing in nephrology due to poor bioavailability and a lack of efficacy with an associated unfavorable side-effect profile when used with proven medications (ACEi/ARB). It remains to be seen, however, that after a decade of testing whether ASIs will find their niche in hypertension management. This does represent dual RAASi which has failed with DRI + ACEi/ARB and ACEi + ARB (with more AKI, hyperkalemia and no clinical outcome benefit). However, with finerenone we have tasted success of MRA + ACEi/ARB even for clinical outcomes in diabetic kidney disease and HFpEF. For hypertension, we already have data to support spironolactone use in resistant hypertension (PATHWAY Williams et al, Lancet 2015 | NephJC summary). Will there be a compelling reason to use an (likely quite) expensive shiny new ASI over the old tried and tested spironolactone? Time will tell.
Conclusion
In patients with uncontrolled or resistant hypertension, on 2 or 3 baseline hypertension medications, the addition of baxdrostat resulted in a reduction in the seated systolic blood pressure at 12 weeks as compared with placebo.
Brian Rifkin MD, FASN, FASDIN
Hattiesburg Clinic
Hattiesburg, MS
Reviewed by Swapnil Hiremath