The results come at a time when the role of aldosterone is gaining more attention within the field.
MADRID, Spain—Baxdrostat (AstraZeneca), an investigational aldosterone synthase inhibitor, provides substantial reductions in blood pressure when added to background therapy in patients with uncontrolled or resistant hypertension, according to results from the phase III BaxHTN trial.
By 12 weeks, seated systolic BP was 8.7 mm Hg lower with the 1-mg dose of baxdrostat and 9.8 mm Hg lower with the 2-mg dose after accounting for placebo effects (P < 0.001 for both), Bryan Williams, MD (University College London, England), reported here at the European Society of Cardiology Congress 2025. Treatment effects were shown to last for at least 32 weeks.
Baxdrostat was well tolerated with no unexpected safety issues, Williams said.
The findings, published simultaneously online in the New England Journal of Medicine, fill in details around the top-line results released in July.
“This is a potential game changer for patients because at the present time . . . despite the best efforts of clinicians and the drugs they have available, at least 50% of patients, even in the most developed healthcare systems, don’t have their blood pressure controlled,” Williams said at a press conference.
The results are encouraging and show “real promise,” according to Sidney Smith Jr, MD (UNC School of Medicine, Chapel Hill, NC), who has led guideline efforts for the National Heart, Lung, and Blood Institute of the US National Institutes of Health as well as the American College of Cardiology/American Heart Association.
Smith had some questions about how resistance to treatment was determined in the trial and whether home BP readings were used, saying, too, that he’d like to see how the effects of baxdrostat hold up over longer follow-up.
“These are early results, but they looked very good,” he told TCTMD, adding that the timing of their publication is fortuitous. In the latest US hypertension guidelines released earlier this month, which Smith helped write, “we increased the focus on aldosterone. Generally, 20 to 25% of the patients with resistant hypertension have hyperaldosteronism.”
The importance of aldosterone for hypertension may go beyond this resistant group, Smith indicated, noting that there are gradual increases in aldosterone levels with age. Professional societies from the US and Europe “are suggesting outside of this group that is termed resistant that patients should be monitored long-term,” he said. “It’s getting increasing focus.”
Williams touched on a similar point, saying there’s “recognition now that this isn’t a niche issue that is affecting a tiny percentage of people. This is a core problem that accounts for quite a lot of the uncontrollable hypertension that’s out there.”
Tackling Aldosterone Dysregulation
Aldosterone dysregulation plays a key role in both difficult-to-treat hypertension and organ damage related to high BP, the BaxHTN investigators note. Though the older mineralocorticoid receptor antagonists (MRAs) like spironolactone block the effects of aldosterone, their use for this purpose has been limited by dose-dependent adverse effects, Williams said.
Novel aldosterone synthase inhibitors, including baxdrostat and lorundrostat (Mineralys Therapeutics), have been designed to treat stubborn hypertension with improved safety. In phase II trials, baxdrostat yielded mixed results, with large placebo-corrected drops in BP seen in BrigHTN, which included patients with treatment-resistant hypertension, but not in HALO, which included patients with uncontrolled hypertension.
The phase III BaxHTN trial, conducted across 214 sites in 29 countries, included both types of patients. Investigators enrolled adults who had a seated systolic BP of 140 to < 170 mm Hg despite stable treatment with two antihypertensive agents (uncontrolled) or three or more antihypertensives (resistant), with one of those medications being a diuretic. Participants also had an estimated glomerular filtration rate of at least 45 mL/min/1.73 m2 and a normal potassium level (3.5 to < 5.0 mmol/L). Those currently using an MRA or potassium-sparing diuretic were excluded.
After a 2-week placebo run-in period, 796 patients (mean age 61 years, 62% men) who had a seated systolic BP of 135 mm Hg or higher were randomized to placebo, baxdrostat 1 mg, or baxdrostat 2 mg once daily for 12 weeks. That was followed by a 12-week open-label treatment period and then an 8-week withdrawal period, in which patients who had been taking baxdrostat 2 mg were randomized to continue that treatment or take placebo.
Most patients (73%) had resistant hypertension, with the rest falling into the uncontrolled category. At baseline, mean BP was 149/87 mm Hg and potassium was 4.2 mmol/L. Participants were taking an average of three antihypertensive medications at the start of the trial.
The change in seated systolic BP from baseline to 12 weeks (primary endpoint) was -5.8 mm Hg with placebo, -14.5 mm Hg with baxdrostat 1 mg, and -15.7 mm Hg with baxdrostat 2 mg, with similar effects across various subgroups.
“This is consistent with the hypothesis that aldosterone is playing a fundamental role in the generation of difficult-to-control hypertension in all of the patients, whatever their makeup, in both uncontrolled and resistant hypertension,” Williams said.
At the beginning of randomized withdrawal phase of the trial, the mean seated systolic BP was 133 mm Hg. Over the next 8 weeks, there was a slight increase in BP (+1.4 mm Hg) in the patients taking placebo and a further decline in those on baxdrostat 2 mg (-3.7 mm Hg), for an estimated difference between groups of -5.7 mm Hg. That’s reflective, Williams said, of both the slow offset of baxdrostat’s effects and the continued BP lowering on treatment out to 32 weeks.
These are early results, but they looked very good. Sidney Smith
Additional exploratory analyses showed baxdrostat reduced serum aldosterone concentrations—by about 60% with the lower dose and 65% with the higher dose—and provided significant reductions in ambulatory BP in a subset of patients who underwent such monitoring. Placebo-corrected falls in 24-hour systolic BP from baseline to 12 weeks were 14.6 and 16.9 mm Hg with the lower and higher baxdrostat doses, respectively. In addition, nighttime average systolic BP declined by 11.7 mm Hg after placebo correction in the pooled baxdrostat group.
Treatment was well tolerated, with most adverse events being mild, and there were no cases of adrenal insufficiency, Williams reported, adding that potassium levels greater than 6.0 mmol/L—seen at rates of 0.4% with placebo, 2.3% with baxdrostat 1 mg, and 3.0% with baxdrostat 2 mg—were “reassuringly low.” The most common adverse events were hyperkalemia, hyponatremia, hypotension, muscle spasms, and dizziness, all of which were more common with baxdrostat.
There is a roughly 10% rise in potassium when baxdrostat is started, “so you do have to monitor potassium at least after the first 2 weeks of treatment. Almost all of the change takes place in the first 2 weeks,” Williams said. “Doctors themselves are very familiar with this because they see it with ACE inhibitors or angiotensin receptor blockers on occasion. And they also see it with the older drugs that we’ve used in the past, like spironolactone, to block this pathway, so this will not be something that surprises doctors or stresses them in any way.”
There are no major safety concerns at this point, Smith said, noting that the profile of baxdrostat is similar to that of other antihypertensives.
Where Might Baxdrostat Fit?
Tomasz Guzik, MD, PhD (University of Edinburgh, Scotland, and Jagiellonian University Medical College, Krakow, Poland), the discussant for the study, said that difficult-to-treat hypertension—either resistant or uncontrolled—“remains probably the greatest challenge we are facing in the hypertension clinic,” with patients having high cardiovascular risk despite taking several medications to try to lower their BP.
Aldosterone is a key player is this scenario, said Guzik, who wrote an NEJM editorial with Maciej Tomaszewski, MD (University of Manchester and Manchester University National Health Service Foundation Trust, England).
What’s important to note about the BaxHTN findings, he said, is that the reductions in BP with baxdrostat occurred in patients who were already receiving intensive treatment for hypertension and were achieved with expected changes in potassium and kidney function. Discontinuations due to hyperkalemia were rare, he added. “Of course, they warrant vigilance, and I think that monitoring of laboratory parameters will be indicated before and after initiation of treatment.”
We are dealing with medication that . . . not only lowers blood pressure, but actually changes underlying disease trajectory. Tomasz Guzik
But the most interesting finding of the trial, Guzik said, came from the randomized withdrawal period, which showed only a slight increase in BP among patients taking placebo. “That is very interesting because it indicates that there is minimal rebound despite drug clearance, that we are not dealing with a drug on-drug off effect, but [are seeing a] resetting of some physiological or pathophysiological mechanisms—sodium handling or maybe another one,” he explained.
This needs to be understood further, he continued, “because it shows that we are dealing with medication that . . . not only lowers blood pressure, but actually changes underlying disease trajectory.”
Guzik raised the question about where baxdrostat, if approved, would fit into the treatment of resistant hypertension.
Williams said it probably would be used initially as an add-on therapy in the types of patients studied in BaxHTN, but he highlighted its broader potential.
“I think our findings are really consistent with the idea that aldosterone is playing a much more important role in the evolution of hypertension in many more patients than perhaps we previously realized,” he said. “It’s long been my view that what we’ve often called essential hypertension is in fact underpinned in many cases by abnormalities in salt handling and sodium sensitivity, and the master regulator of salt sensitivity is indeed aldosterone. I think we’re going to find that this will be quite effective in a broad population of patients.”
He predicted that baxdrostat would eventually be used earlier in the course of treatment, “because I’m convinced that this mechanism is at the core of a lot of what we’ve described as essential hypertension—the so-called missing link.”