Background and Introduction

Uncontrolled hypertension is defined as a seated systolic blood pressure (SBP) of 140 to less than 170 mm Hg despite treatment with 2 or more antihypertensive agents, whereas resistant hypertension persists despite 3 or more agents, including a diuretic.^1,2 Patients with resistant hypertension are at an increased risk of cardiovascular (CV) events and target-organ damage, including more than a 50% higher risk of myocardial infarction (MI), stroke, end-stage kidney disease, and CV death compared with adults with treatment-responsive hypertension.¹ Aldosterone dysregulation contributes by promoting sodium retention, vascular remodeling, and mineralocorticoid receptor–mediated injury. Mineralocorticoid receptor antagonists (MRAs) can address these mechanisms, but their use is limited by dose-dependent adverse effects, including hyperkalemia and sex hormone–related side effects.¹

In patients with resistant hypertension, the 2025 American Heart Association/American College of Cardiology guidelines recommend initial triple therapy with a calcium channel blocker, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), and a thiazide-like diuretic (level of evidence: B-R).¹ Around 20% of adults may use medications such as NSAIDs or decongestants that raise blood pressure, which should be reviewed when evaluating resistant hypertension.¹ If blood pressure remains uncontrolled, the diuretic can be optimized, followed by the addition of an MRA such as spironolactone or eplerenone, which has proven efficacy in randomized trials for participants with an estimated glomerular filtration rate (eGFR) of 45 mL/min/1.73 m² or greater (level of evidence: B-R).¹ Additional options include β-blockers or α₂-agonists, hydralazine, and, as a last resort, minoxidil, though tolerability may be poor.¹ Secondary hypertension is more common in resistant hypertension, and patients should be screened particularly for primary aldosteronism, obstructive sleep apnea, renal parenchymal disease, and renovascular disease.¹

A new investigational drug, baxdrostat (an oral aldosterone synthase inhibitor [ASI]), offers a novel strategy by lowering aldosterone production at its source rather than blocking its receptor.² Unlike conventional renin-angiotensin-aldosterone system drugs, ASIs may overcome “aldosterone escape,” a common cause of treatment failure.³ Baxdrostat is highly selective for CYP11B2 (aldosterone synthase) with greater than 100-fold selectivity over CYP11B1, the enzyme responsible for cortisol synthesis. This minimizes effects on cortisol and addresses the safety concerns observed with earlier ASIs.^2,3 Its half-life of around 30 hours allows once-daily dosing. In the phase 2 BrigHTN trial, baxdrostat produced significant, dose-dependent SBP reductions in resistant hypertension, and smaller studies in primary aldosteronism showed a similar benefit.^2,4 The HALO phase 2 trial evaluating baxdrostat in participants with uncontrolled hypertension did not meet its primary end point, although post hoc analyses suggested benefit in adherent patients.² Early evidence also suggests antifibrotic and anti-inflammatory effects, supporting ongoing phase 3 trials in resistant hypertension, chronic kidney disease (CKD), and primary aldosteronism.^2,3

Phase 3 Trial Review

The BaxHTN is a phase 3, multinational, randomized, parallel, double-blind, placebo-controlled trial that evaluated adults with uncontrolled or resistant hypertension.² Uncontrolled hypertension was defined as an SBP of 140 to 170 mm Hg despite 2 or more antihypertensive drugs and resistant hypertension as an SBP of 140 to 170 mm Hg despite 3 or more drugs including a diuretic.² Key exclusion criteria were very high blood pressure (SBP 170 mm Hg or more or diastolic blood pressure [DBP] 110 mm Hg or more), secondary causes of hypertension, New York Heart Association class IV heart failure (HF), recent CV events, use of combined ACE inhibitor and ARB therapy, electrolyte abnormalities, or advanced renal or hepatic impairment.²

This 52-week study enrolled 794 adults with uncontrolled or resistant hypertension who were receiving stable background antihypertensive therapy, including at least 2 agents for uncontrolled disease or at least 3 agents (with a diuretic) for resistant disease. Baseline characteristics were balanced across groups: mean age 61.2 years, 62.2% male, 63% White, 26.3% Asian, 7.4% Black, and 13.1% Hispanic or Latino. The mean clinical baseline characteristics were as follows: baseline blood pressure 149/87 mm Hg, 27.1% uncontrolled hypertension, 72.9% resistant hypertension, 86.7% diabetes, serum sodium 139.8 mEq/L, serum potassium 4.2 mEq/L, and eGFR 85 mL/min/1.73 m². Participants were randomized 1:1:1 to receive baxdrostat 1 mg, baxdrostat 2 mg, or placebo orally once daily for 12 weeks while continuing background antihypertensive therapy.²

The primary end point was change in seated SBP from baseline to week 12.² The trial was conducted in 4 phases. The first 450 randomized participants (cohort 1) took part in all 4 phases, whereas the remaining participants (cohort 2) were only included in the first 2 phases.² Part 1 evaluated the primary outcome over 12 weeks, followed by parts 2 (weeks 12-24), 3 (weeks 24-32), and 4 (weeks 32-52); parts 2 and 4 were open-label extensions designed to assess safety.

Table 1 highlights a summary of the primary and secondary end points and adverse events. Both 1 mg and 2 mg of baxdrostat resulted in reductions in seated SBP that were more than double those in placebo.² Results for the estimated difference from placebo showed statistically significant reductions in SBP (around 9 mm Hg), a consistent effect across both doses for the primary outcome. Results for the resistant hypertension and DBP subgroups also showed lowering effects, with placebo-corrected reductions averaging 9.45 and 3.6 mm Hg, respectively.² During the randomized-withdrawal phase, participants who changed from treatment to placebo experienced increases in SBP, whereas those continuing baxdrostat maintained reductions, supporting the sustainability of the drug’s effect.² A key secondary end point included the proportion of participants achieving SBP control to less than 130 mm Hg at week 12, which was reached in 39.4% receiving 1 mg of baxdrostat and 40.0% receiving 2 mg, compared with 18.7% in the placebo group.²

Table 1. Summary of End Points and Adverse Events for the BaxHTN trial²

Safety and Tolerability

Adverse events included hyperkalemia, hyponatremia, and hypotension. Overall, adverse events occurred in 47.3% (1 mg), 44.7% (2 mg), and 41.3% (placebo) of participants, with only 1 death reported in the placebo group.² Discontinuations because of adverse events were 3.5% (1 mg), 6% (2 mg), and 1.9% (placebo).² Hyperkalemia was one of the more notable adverse events, with possible dose-dependent effects being demonstrated. These changes in potassium were mainly observed within the first 2 weeks of treatment.² Hyponatremia and hypotension were also reported, but less often. Decline in renal function was also shown to be more common in the baxdrostat groups than in the placebo group in a dose-dependent manner during the 12-week treatment.² These findings suggest that monitoring for adverse drug reactions (hyperkalemia, hyponatremia) and safety (eGFR decline) should be done within the early weeks of treatment and at higher doses of baxdrostat.

Discussion

Key strengths of this trial were its design and the inclusion of a large, global population. However, of note, only around 27% of participants were enrolled from the Americas, which encompassed Canada, Argentina, and the United States.² This highlights the relatively small representation of the US population. Other limitations include the underrepresentation of women and Black participants, which may reduce generalizability to populations disproportionately affected by hypertension and known to experience higher rates of treatment resistance and CV complications. In addition, adherence was assessed through pill counts and plasma drug concentrations, which may not reflect real-world patterns of medication use where nonadherence is a top driver of uncontrolled blood pressure.^1,2

Baxdrostat represents a promising new therapeutic option for patients with resistant or uncontrolled hypertension. By directly inhibiting aldosterone production, it provides a different pathway for blood pressure control and could serve as either an add-on or an alternative to standard therapy.^2,3 Study results were not only statistically significant, but also clinically meaningful: baxdrostat lowered SBP by 8.7 to 9.8 mm Hg compared with placebo, which exceeds the 5-mm Hg reduction in SBP threshold that has been associated with about a 10% reduction in major CV events.⁵ In prior randomized controlled trials, the addition of spironolactone reduced SBP by 6.6 to 8.7 mm Hg compared with placebo.¹ This shows that baxdrostat’s SBP lowering effect is at least similar to, and in some cases greater than, established add-on therapy. If approved, it would be the first drug in the new class of ASIs specifically designed to overcome many of the safety limitations seen with MRAs. Early-phase and phase 3 trials show consistent reductions in SBP with manageable safety, where the most clinically relevant concern is mild, early increases in serum potassium.^2,3 Looking ahead, AstraZeneca has announced plans to advance regulatory filings in the coming months and is pursuing additional studies to better define baxdrostat’s role in difficult-to-control hypertension.⁶

Future/Ongoing Trials

Currently, 2 active trials are listed on ClinicalTrials.gov that evaluate baxdrostat in hypertension and CKD (Table 2). The Bax24 trial is assessing the effect of baxdrostat on 24-hour ambulatory SBP in participants with resistant hypertension, with results expected in late 2025.⁷ AstraZeneca has also initiated a large trial combining baxdrostat with dapagliflozin to investigate its effect on CKD progression and CV outcomes in participants with CKD and high blood pressure, projected to be completed in 2028.⁸ Collectively, these studies build on the BaxHTN trial and may help support baxdrostat’s potential approval and clinical impact in hypertension and aldosterone-driven cardiorenal disease.

Table 2. Key Elements of Ongoing Trials Evaluating Baxdrostat in Patients^7,8

AI Disclaimer: AI assistance (ChatGPT) was used for grammatical and language refinement. Analysis and interpretations were conducted by the authors.

References

1. Writing Committee Members; Jones DW, Ferdinand KC, Taler SJ, et al. 2025 AHA/ACC/AANP/AAPA/ABC/ACCP/ACPM/AGS/AMA/ASPC/NMA/PCNA/SGIM guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Hypertension. 2025;82(10):e212-e316. https://doi.org/10.1161/HYP.0000000000000249

2. Flack JM, Azizi M, Brown JM, et al; BaxHTN Investigators. Efficacy and safety of baxdrostat in uncontrolled and resistant hypertension. N Engl J Med. 2025;393(14):1363-1374. Published online August 30, 2025. https://doi.org/10.1056/NEJMoa2507109

3. Patel SK, Teoh H, Saunthar A, Yau TM, Verma S. The emerging role of aldosterone synthase inhibitors in overcoming renin-angiotensin-aldosterone system therapy limitations: a narrative review. Card Fail Rev. 2025;11:e20. https://doi.org/10.15420/cfr.2025.09

4. Freeman MW, Halvorsen YD, Marshall W, et al. Phase 2 trial of baxdrostat for treatment-resistant hypertension. N Engl J Med. 2023;388(5):395-405. https://doi.org/10.1056/NEJMoa2213169

5. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957-967. https://doi.org/10.1016/S0140-6736(15)01225-8

6. AstraZeneca. Baxdrostat demonstrated statistically significant and clinically meaningful reduction in systolic blood pressure in patients with hard-to-control hypertension in the BaxHTN phase III trial. Published August 30, 2025. Accessed September 25, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/baxdrostat-demonstrated-statistically-significant-clinically-meaningful-reduction-sbp-patients-hard-control-hypertension-baxhtn-phase-iii-trial.html

7. Clinicaltrials.gov. A randomized, double-blind, placebo-controlled, parallel group study to assess the effect of baxdrostat on ambulatory blood pressure in participants with resistant hypertension (NCT06168409). Accessed September 16, 2025. https://www.clinicaltrials.gov/study/NCT06168409

8. Clinicaltrials.gov. A phase III study to investigate the efficacy and safety of baxdrostat in combination with dapagliflozin on CKD progression in participants with CKD and high blood pressure (NCT06268873). Accessed September 16, 2025. https://www.clinicaltrials.gov/study/NCT06268873