A new class of antihypertensive agent that blocks the production of aldosterone — a key hormone believed to drive increased blood pressure — has shown impressive results in one of the first pivotal phase 3 trials in patients with resistant or uncontrolled hypertension. 

Use of baxdrostat was associated with a reduction in office-measured systolic blood pressure of around 9 mm Hg at 12 weeks and reductions in 24-hour ambulatory systolic blood pressure of around 15 mm Hg in the BaxHTN trial. 

Presentation of the results prompted spontaneous applause from the audience at the 2025 annual congress of the European Society of Cardiology. The trial was also simultaneously published online in The New England Journal of Medicine.

Bryan Williams, MD, chair of medicine at University College London, United Kingdom, called the new class of drugs “a potential game changer” for patients. “They target the core mechanism contributing to resistant/uncontrolled hypertension and should therefore reduce the future risk of heart disease, stroke, kidney disease, and potentially dementia in these patients,” he said.

Williams, the senior researcher on the BaxHTN trial, called the reduction in blood pressure with baxdrostat “very large” and “remarkably consistent across every subgroup.”

The decreases were observed with 24-hour ambulatory monitoring and at night and were maintained for “several weeks after drug withdrawal,” he said. “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.” 

Baxdrostat was generally well tolerated with no unanticipated side effects, Williams said.

“A Triumph of Scientific Discovery”

Despite the availability of many treatments, high blood pressure is hard to control. “Elevated blood pressure is still the single most important preventable cause of premature death globally, with about 50% of patients who are treated globally not reaching the recommended treatment targets, and this represents hundreds of millions of people,” Williams said.

The development of baxdrostat and related drugs is “a triumph of scientific discovery,” following the finding that disturbed aldosterone production to be a key driver of hard-to-control hypertension, he said.

“Aldosterone is the master regulator of how the body handles salt and water, and when the levels are inappropriately high, as they become as we age, this can make people less able to eliminate salt, and it drives up blood pressure and contributes to the development of heart failure, heart disease, stroke, and kidney disease,” Williams said.

Better understanding of the role of aldosterone in hypertension has led to the development of agents to selectively block the enzyme that produces the hormone. The result is the first group of highly selective long-acting aldosterone synthase inhibitors designed to normalize aldosterone levels.

Several agents in this class are understood to be in late-stage development.

The trial included 794 patients with uncontrolled (27%) or resistant (73%) hypertension despite already taking a mean of three antihypertensive medications, including a diuretic. At baseline, their median office blood pressure was 149/87 mm Hg. 

Participants were randomly assigned to receive 1 mg or 2 mg of baxdrostat, or a placebo once daily for 12 weeks.

The primary endpoint was the change in seated systolic blood pressure from baseline to week 12. 

According to the researchers, 1 mg baxdrostat was associated with a reduction in blood pressure of 14.5 mm Hg. The decrease was 15.7 mm Hg with the 2-mg dose, while the placebo group experienced an average reduction of 5.8 mm Hg, giving placebo-corrected reductions of 8.7 mm Hg and 9.8 mm Hg with the 1- and 2-mg doses of baxdrostat, respectively. 

A substudy of 24-hour ambulatory blood pressure found placebo-corrected reductions in systolic blood pressure of around 15 mm Hg. The placebo-corrected reduction at night was 12 mm Hg in a pooled analysis, which Williams said confirmed the once daily long-acting effect of the drug.

Williams described the 24-hour reductions as “particularly remarkable.” 

“Normally, the reduction in 24-hour blood pressure is less than we see in clinic,” he said. “I've never seen blood pressure reductions of this magnitude with other medications.” 

The researchers are currently conducting a larger study of 24-hour blood pressure to confirm these results.

The study also involved an 8-week withdrawal phase, in which blood pressure rose by only 1.4 mm Hg despite the expected clearance of baxdrostat from the blood by 1 week, Williams reported. Levels of serum aldosterone fell as expected with baxdrostat treatment but did not fully return to baseline levels after withdrawal of the drug.

Potassium Spike 

As would be expected from a drug that blocks aldosterone, use of baxdrostat was linked to an increase in potassium of about 10%, Williams reported. 

“For many patients, that's a good thing, because hypertension is often associated with slightly lower potassium levels due to the use of other diuretics which drive potassium out the system,” he said. “But obviously, if patients have renal impairment or difficulty in handling potassium, then that rise in potassium could get to a level where we would have to take some action.”

Serum potassium levels of more than 6 mmol/L occurred in 2.3% of patients receiving 1-mg of baxdrostat and in 3% on the 2-mg dose. Serum potassium levels between 5.5 mmol/L and 6 mmol/L occurred in 6.1% of patients on the 1-mg dose and 11.1% of taking the 2-mg dose. Clinical intervention because of hyperkalemia was reported in 2.7% of patients taking the 1-mg dose and in 7.9% of those receiving the 2-mg dose. 

Should the drug win regulatory approval, patients taking it would likely have their potassium monitored for at least a few weeks after starting treatment, Williams said. 

“Almost all of these changes take place in the first 2 weeks. And doctors themselves are very familiar with this because they see it with ACE [angiotensin-converting enzyme] inhibitors or angiotensin receptor blockers on occasion, and with the older aldosterone antagonists such as spironolactone. This would be something they would have in their normal workflows,” he added.

“Changing Underlying Disease Trajectory”

Tomasz Guzik, MD, PhD, of the University of Edinburgh, Edinburgh, UK, said resistant and uncontrolled hypertension remains the greatest challenge for hypertension clinics.

“The patient is on three, four, or even five medications but remains uncontrolled and therefore at high cardiovascular risk, and aldosterone is at the center of this, driving sodium retention, vascular stiffening, and other mechanisms of cardiovascular damage,” said Guzik, who was not involved with the study. 

The new findings are particularly impressive given patients in the trial already were being intensively treated on a median of three drugs, with 99% on a diuretic and 90% on an ACE inhibitor or angiotensin receptor blocker, he said. “So, we have new medication that clinically relevantly lowers blood pressure on top of already intensive therapy,” Guzik said.

Guzik suggested that the most interesting finding of the trial was related to durability, with only a minimal rise in blood pressure when the drug was stopped. 

“This indicates that there is minimal rebound despite drug clearance. We are not dealing with drug-on/drug-off effect, but with resetting of some physiological or pathophysiological mechanisms involving sodium handling, and shows that we have a medication that not only efficiently lowers blood pressure, but actually changes underlying disease trajectory,” he commented.

The BaxHTN trial was funded by AstraZeneca. Williams reports honoraria from Servier and Medtronic; consulting to Antlia Bioscience, AstraZeneca, and Novartis; and is a clinical trial investigator for AstraZeneca and Eli Lilly. Guzik reports no relevant financial relationships.