Another group of antihypertensives?!

Despite numerous drugs for the treatment of hypertension, many patients still fail to sufficiently lower their blood pressure. When a patient (adherently!) simultaneously uses three or more antihypertensive drugs from different groups in the highest tolerated doses and still fails to achieve blood pressure values ​​below the target, he has resistant hypertension (RH). This public health problem maintains the need for innovation and development of blood pressure-lowering drugs. Thus, a new group of antihypertensive drugs has recently appeared on the market.

What is RAAS?

The renin-angiotensin-aldosterone system (RAAS) is a hormonal system that plays an important role in the regulation of arterial blood pressure and electrolyte balance. When blood pressure drops, the kidneys produce renin, which stimulates the production of the vasoconstrictor angiotensin II. In addition to increasing blood pressure, this also stimulates the secretion of aldosterone, which causes sodium and water retention, further increasing blood pressure.

Although this mechanism of blood pressure elevation sounds malicious, the RAAS is of exceptional importance in controlling blood pressure in healthy people. In hypertension, the RAAS is “overactive,” and it has proven to be an excellent target for antihypertensive drugs. Drugs that reduce RAAS activity include: ACE inhibitors (ACEIs), angiotensin II AT1 receptor antagonists (ARBs), direct renin inhibitors (DRIs), mineralocorticoid receptor antagonists (MRAs), and the youngest member of the family, baxdrostat, which belongs to the aldosterone synthase inhibitors (ASIs).

What does aldosterone do?

Aldosterone, in addition to its role in water and electrolyte regulation, contributes to maladaptive cardiovascular remodeling (harmful changes in the structure and function of the heart and blood vessels). Excess aldosterone, in addition to resistant hypertension, is also associated with heart failure, chronic kidney disease, and primary aldosteronism.

Therefore, inhibition of its synthesis is a logical mechanism of action for drugs for hypertension and reducing the risk of cardiovascular disease. MRAs, which act as aldosterone receptor antagonists, work in a similar way.

Why is the development of baxdrostat significant?

Aldosterone synthase or CYP11B2 is responsible for aldosterone biosynthesis reactions from cholesterol. The development of inhibitors of this enzyme has been going on for many years, and the biggest obstacle in the success of finding such antihypertensives was insufficient selectivity. CYP11B2 is structurally very similar to the CYP11B1 enzyme that catalyzes the biosynthesis reactions of cortisol, a steroid similar to aldosterone. Numerous molecules in drug development did not prove to be good candidates precisely because of “off-target” action that leads to unwanted effects. Nevertheless, some of these “unsuccessful” molecules have shown potential, for example, in the therapy of Cushing’s disease.

After painstaking research, with a better understanding of the differences in the structure of the enzyme and the application of high-throughput screening, the scientists finally came to the discovery of the highly selective ASI baxdrostat.

The most important thing – safety and efficiency

In a clinical trial, baxdrostat at a dose of 1 mg showed a reduction in systolic blood pressure of an average of 14.5 mmHg, and at a dose of 2 mg by 15.7 mmHg. Taking into account the placebo-adjusted reduction, baxdrostat reduced blood pressure by 8.7 mmHg (1 mg) and 9.8 mmHg (2 mg).

Comparatively, standard doses of the five most commonly used antihypertensive groups (ACEIs, ARBs, calcium channel blockers, diuretics, and beta-blockers) in monotherapy show a similar reduction in systolic pressure by an average of 9.1 mmHg.

Analogous to the drug mechanism, the most common side effect of baxdrostat is hyperkalemia, so blood potassium levels need to be monitored. In addition, hyponatremia, low blood pressure (yes…), dizziness, and muscle spasms can occur. Of course, the long-term safety of a new drug is always monitored and questioned.

The future of baxdrostat

The FDA approved baxdrostat in May 2026 for the treatment of hypertension that is not controlled by other medications. It is not yet available in Europe, and its price and availability could be a problem in the future. However, patients resistant to many antihypertensive drugs could finally have an effective addition to their treatment regimen.

Translated by: Mirta Maršić