A New Approach to Treating Resistant Hypertension: Aldosterone Synthase Inhibitors

Table of Contents

• Introduction: Understanding Resistant Hypertension
• Current Treatment Challenges
• The New Approach: Aldosterone Synthase Inhibition
• The BaxHTN Trial Design
• Key Findings from the BaxHTN Trial
• Safety Profile and Side Effects
• Clinical Implications for Patients
• Comparison with Existing Treatments
• Study Limitations
• Future Directions and Recommendations
• Source Information

Introduction: Understanding Resistant Hypertension

Resistant hypertension is a serious medical condition where blood pressure remains high despite taking multiple medications. Specifically, doctors define it as blood pressure staying at 140/90 mm Hg or higher when a patient is taking three or more antihypertensive drugs at maximum recommended doses, including a diuretic (water pill). This condition affects approximately 1 in 10 people with high blood pressure and significantly increases their risk of heart attacks, strokes, and other cardiovascular problems.

The global burden of resistant hypertension is substantial because these patients face disproportionately higher risks of serious health complications. After excluding pseudo-resistance (incorrect blood pressure measurements) and secondary causes (other medical conditions causing high blood pressure), true resistant hypertension often represents what doctors call a salt-retaining, low-renin state. This means the body holds onto too much sodium due to inappropriate production of a hormone called aldosterone.

Current Treatment Challenges

Currently, patients with resistant hypertension often receive mineralocorticoid-receptor antagonists (MRAs) such as spironolactone or eplerenone. These medications work by blocking the effects of aldosterone. However, several limitations constrain their use:

• Hyperkalemia: MRAs can cause dangerously high potassium levels in the blood
• Reduced safety in kidney disease: They become less safe and effective in patients with advanced kidney problems
• Sex hormone-related side effects: Particularly with spironolactone, patients may experience hormonal side effects
• Compensatory increase: MRAs actually trigger the body to produce more aldosterone, which can lead to downstream consequences

These limitations highlight the need for better treatment options that can effectively control blood pressure without these significant drawbacks.

The New Approach: Aldosterone Synthase Inhibition

Aldosterone synthase inhibitors represent a fundamentally different approach to treating resistant hypertension. Instead of blocking aldosterone receptors like MRAs do, these new medications directly inhibit the enzyme that produces aldosterone in the first place. This direct approach offers several potential advantages:

Early attempts to develop aldosterone synthase inhibitors faced challenges because the target enzyme (aldosterone synthase or CYP11B2) closely resembles another enzyme called 11β-hydroxylase (CYP11B1), which is essential for cortisol production. This similarity created the risk of accidentally suppressing cortisol, a critical stress hormone. However, advanced structural research revealed differences in the active sites of these enzymes, enabling scientists to design drugs that specifically target aldosterone production without affecting cortisol.

Through careful chemical optimization, researchers developed selective aldosterone synthase inhibitors including baxdrostat and lorundrostat. These medications directly suppress aldosterone production, which:

• Reduces sodium and water retention
• Decreases mineralocorticoid receptor activity
• Limits sodium reabsorption in the kidneys
• Promotes natriuresis (sodium loss in urine)
• Mitigates aldosterone-driven fibrosis, vascular injury, and kidney damage
• Avoids cortisol-related effects

The BaxHTN Trial Design

The BaxHTN trial was a comprehensive study designed to evaluate whether selective aldosterone synthase inhibition with baxdrostat could safely deliver sustained blood pressure reduction in adults with uncontrolled or resistant hypertension. The trial included patients who were already taking at least two additional antihypertensive agents, including a diuretic.

Notably, approximately 90% of participants were taking either an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin-receptor blocker, nearly all were taking a diuretic, and many were taking a calcium-channel blocker. This means the study evaluated baxdrostat as an add-on therapy to standard treatment regimens.

The trial consisted of four distinct parts over an extended period:

1. Part 1: A 12-week randomized, placebo-controlled trial comparing 1 mg of baxdrostat, 2 mg of baxdrostat, or placebo
2. Part 2: A 12-week open-label phase designed to collect additional safety data and serve as a run-in to part 3
3. Part 3: An 8-week randomized-withdrawal phase (weeks 32 to 52) to assess what happens when treatment is stopped
4. Part 4: An ongoing 20-week open-label phase to collect additional safety data specifically for the 2-mg baxdrostat dose

The primary endpoint measured was the change in seated systolic blood pressure from baseline to week 12, providing a clear measure of the drug's effectiveness.

Key Findings from the BaxHTN Trial

The BaxHTN trial produced significant and clinically important results for patients with resistant hypertension. At the end of the 12-week randomized, double-blind period, patients receiving baxdrostat showed substantial blood pressure reductions compared to those receiving placebo.

The placebo-corrected change in systolic blood pressure was -8.7 mm Hg in the 1-mg group and -9.8 mm Hg in the 2-mg group. This reduction occurred from a mean baseline blood pressure of 149/87 mm Hg across all treatment groups. These improvements were evident by week 4 and sustained through week 12, demonstrating both rapid onset and maintained effectiveness.

Perhaps more importantly from a patient perspective, the percentage of patients who achieved controlled blood pressure (defined as seated systolic blood pressure <130 mm Hg) at week 12 was:

• 39.4% with 1-mg baxdrostat
• 40.0% with 2-mg baxdrostat
• Only 18.7% with placebo

This means more than twice as many patients achieved blood pressure control with baxdrostat compared to placebo. In the randomized-withdrawal phase (part 3), researchers observed only a gradual offset in blood pressure reduction with a minimal rebound effect, suggesting possible physiological resetting of sodium balance or long-term vascular effects.

Exploratory analyses confirmed that these blood pressure improvements correlated with reduced aldosterone levels and increased plasma renin activity, supporting the proposed mechanism of action. The reductions in ambulatory systolic blood pressure (measured over 24 hours) aligned with the office measurements, indicating consistent blood pressure control throughout the day.

Safety Profile and Side Effects

The safety profile of baxdrostat is crucial for clinical adoption. In the BaxHTN trial, most electrolyte abnormalities occurred within the first 2 weeks of treatment, allowing for early detection and management. The most significant safety findings included:

Confirmed potassium levels exceeding 6.0 mmol per liter (hyperkalemia) occurred in 1.1% of patients in both the 1-mg and 2-mg baxdrostat groups, compared to 0% in the placebo group. Importantly, discontinuations due to hyperkalemia were rare, suggesting that this side effect can typically be managed without stopping treatment.

Hyponatremia (low sodium levels, defined as <135 mmol per liter) occurred in 19-23% of patients receiving baxdrostat but rarely required intervention. An early decrease in estimated glomerular filtration rate (eGFR, a measure of kidney function) of approximately 7 ml per minute per 1.73 m² of body surface area was observed but reversed when treatment was withdrawn.

These electrolyte changes followed expected patterns based on the drug's mechanism of action within the renin-angiotensin-aldosterone system and stabilized after initial shifts. The predictable nature of these adverse effects suggests a favorable risk-benefit balance, particularly for the 1-mg dose, with appropriate monitoring.

Clinical Implications for Patients

The BaxHTN trial delivers three clear messages that matter to patients with resistant hypertension. First, regarding efficacy, baxdrostat significantly lowered systolic blood pressure by approximately 9-10 mm Hg compared to placebo. This effect was similar to that of spironolactone and other aldosterone synthase inhibitors but occurred on top of existing RAAS blockade and near-universal diuretic use.

Second, regarding safety, the adverse biochemical changes (shifts in potassium, sodium, and eGFR) emerged within 2 weeks and were manageable with laboratory monitoring at baseline, at 1-2 weeks, and after 4 weeks. The rare discontinuations for hyperkalemia suggest that most patients can continue treatment with appropriate monitoring.

Third, regarding durability, the modest blood pressure increase during the withdrawal phase despite drug clearance suggests a potential physiological reset of sodium balance or vascular tone. If confirmed in longer studies, this could support steadier blood-pressure control and reduced need for rescue therapy over time.

Comparison with Existing Treatments

Currently, mineralocorticoid-receptor antagonists (MRAs), especially spironolactone, remain guideline-recommended for resistant hypertension. The PATHWAY-2 trial demonstrated spironolactone's superiority over bisoprolol and doxazosin. However, aldosterone synthase inhibitors like baxdrostat and lorundrostat offer distinct advantages.

Unlike MRAs, which raise levels of renin and aldosterone and miss the nonreceptor aldosterone actions, aldosterone synthase inhibitors directly suppress aldosterone production. This mechanism complements existing RAAS blockade strategies. With sodium sensitivity common in older patients and those with obesity or chronic kidney disease, the natriuretic (sodium-removing) effect has central clinical relevance.

By reducing aldosterone-driven sodium reabsorption, aldosterone synthase inhibitors augment proven natriuretic strategies in patients with cardiovascular disease, including thiazide diuretics, MRAs, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and neprilysin inhibitors. Collectively, they provide a mechanistically distinct, clinically validated, and synergistic option for patients with hard-to-control hypertension.

Study Limitations

While the BaxHTN trial results are promising, several limitations should be considered. The descriptive findings regarding electrolyte changes and eGFR remain hypothesis-generating rather than conclusive. The trial duration, while substantial, may not capture long-term effects that would only emerge with extended use.

The study population specifically focused on patients with resistant hypertension already on multiple medications, so the results may not directly apply to patients with less severe hypertension or those on different medication regimens. Additionally, the comparison with existing MRAs was indirect rather than head-to-head, making direct efficacy comparisons challenging.

Finally, while the safety profile appears manageable, the potential for electrolyte abnormalities requires careful monitoring, which may present practical challenges in real-world clinical practice outside of a controlled trial setting.

Future Directions and Recommendations

The next steps for aldosterone synthase inhibitors will include defining which patients are most likely to respond for precision therapy approaches. Researchers need to clarify how these drugs compare directly with MRAs in head-to-head trials and standardize monitoring protocols for early detection of electrolyte changes.

Long-term data on durability and actual cardiovascular event reduction (rather than just blood pressure lowering) will be essential for establishing these medications as mainstays of treatment. Success in these areas could shift aldosterone synthase inhibition from a promising adjunct therapy to a central pillar of treatment for difficult-to-control hypertension.

For patients currently struggling with resistant hypertension, these developments represent hope for better control with fewer side effects. As always, patients should discuss these new treatment options with their healthcare providers to determine the most appropriate approach for their individual situation.

Source Information

Original Article Title: Aldosterone Synthase Inhibition for Hypertension
Authors: Tomasz J. Guzik, M.D., Ph.D. and Maciej Tomaszewski, M.D.
Publication: The New England Journal of Medicine Editorial
Publication Date: August 30, 2025

This patient-friendly article is based on peer-reviewed research and aims to provide comprehensive information about new developments in hypertension treatment. Always consult with your healthcare provider before making any changes to your treatment regimen.