Aldosterone Synthase Inhibition for Resistant Hypertension

Introduction

The body has several mechanisms to regulate blood pressure (BP). One of them is the renin-angiotensin-aldosterone system (RAAS). It exerts its effects through the action of angiotensin II (the end-product of RAAS). In addition to increasing BP, angiotensin II stimulates aldosterone (a mineralocorticoid) secretion from the adrenal gland. Aldosterone causes an increase in sodium and water reabsorption leading to elevated BP. Persistent hypertension (HTN - prolonged increase in BP) can lead to left ventricular hypertrophy (increase in the size of the left ventricle of the heart), which can lead to cardiovascular disease (CVD). Treatment with angiotensin-converting enzyme inhibitors (ACE-I, a class of drugs that lower BP) initially decreases aldosterone. However, with chronic treatment, aldosterone levels increase back (aldosterone escape). Hence, aldosterone blockade adds value to HTN treatment.

What Is the Importance of Aldosterone Inhibition in Resistant Hypertension?

Resistant HTN is defined by BP targets not achieved despite using at least three different anti-hypertensive drugs. It is diagnosed in more than ten percent of hypertensive patients and represents an increased risk of CVD and death. In resistant HTN cases, Spironolactone (an aldosterone receptor antagonist) is added to the treatment regimen. Aldosterone antagonism with Spironolactone or Eplerenone is effective at lowering BP in such patients. Moreover, it has many beneficial cardiovascular effects. It is because HTN is the hallmark of CVD and heart failure (HF).

Aldosterone synthase is an enzymatic protein expressed in the adrenal gland regulated by RAAS. It produces aldosterone and plays an important role in electrolyte balance and BP regulation. The first developed aldosterone receptor antagonist was Spironolactone. However, Spironolactone use is limited due to adverse effects. Eplerenone is a more recently developed drug of the same class with a better adverse effect profile. However, it is not devoid of effects similar to Spironolactone. Hence, the aldosterone synthase inhibitors (a novel drug group) are currently under development for resistant HTN.

What Are the Advantages of Aldosterone Synthase Inhibitors in Resistant Hypertension?

Substantial research indicates an increase in aldosterone levels in patients with resistant hypertension. Furthermore, primary hyperaldosteronism (also called Conn's syndrome, a disorder in which the adrenal glands make excess aldosterone) is present in about 20 percent of these patients. Despite its side effects (reduced testosterone synthesis, hyperkalemia (increased blood potassium), gynecomastia (increased breast tissue in males), breast tenderness, menstrual irregularities, and postmenopausal bleeding), Spironolactone remains the preferred add-on therapy in patients with resistant hypertension. These occur due to interaction with other steroid hormone receptors. Hence, a different path of directly targeting the synthesis of aldosterone is used.

Osilodrostat was the first introduced aldosterone synthase inhibitor. Fadrozole (FAD 286) has inhibitory properties against aldosterone synthase. However, it has been experimentally tested but has never been investigated in patients. Baxdrostat is another novel aldosterone synthase inhibitor with a safer profile. The advantages of various aldosterone synthase inhibitors noted in clinical trials are:

• Fadrozole: In genetically engineered mice, Fadrozole reduced death and prevented heart hypertrophy and collagen deposition in the heart and kidneys. However, it was not as effective as established antihypertensives at reducing BP. In rat models of HF, Fadrozole showed beneficial hemodynamic (blood flow) effects and improved left ventricular function and remodeling.

• Baxdrostat: Baxdrostat selectively inhibits aldosterone synthase without affecting other steroid receptors. Preclinical studies in monkeys demonstrate that Baxdrostat inhibits aldosterone synthesis without affecting cortisol (a steroid hormone). These findings have also been confirmed in clinical trials (in healthy human subjects). The trials also tested the safety, pharmacokinetics (the study of how the body interacts with the drug), and pharmacodynamics (the study of how the drug interacts with the body) of multiple increasing doses of Baxdrostat. It further confirmed that Baxdrostat was safe and well tolerated. Further, it induced a reduction in blood aldosterone (but not cortisol). Another trial showed good efficacy of the drug twelve weeks after initiation. Baxdrostat (one and two milligrams) significantly lowered BP compared to placebo (an inert material or substance).

• Osilodrostat: A recent trial compared aldosterone synthase inhibition using Osilodrostat with aldosterone receptor blockade (Eplerenone) in patients with primary hyperaldosteronism. In addition to usual medications, patients were treated with Osilodrostat for 30 days, followed by a placebo for one week. Osilodrostat was associated with a 75 percent decrease in plasma aldosterone. In a trial on 12 healthy normotensives (normal BP) subjects, Osilodrostat (0.5 to 3.0 mg) once daily caused a decrease in blood and urine aldosterone levels. Furthermore, it did not affect cortisol levels and was well tolerated. However, at 3 mg, it caused increased heart rate, mild hyponatremia, and reduced body weight. These results support further evaluation of Osilodrostat. The development of Osilodrostat has allowed assessment of the benefits and safety of inhibiting aldosterone synthesis in hypertensive patients. Unfortunately, the lack of selectivity at higher doses (above 3 mg daily) gives rise to the alteration of other mechanisms limiting the dose. The development of more selective aldosterone synthase inhibitors can achieve more reductions in BP without affecting other mechanisms.

What Are the Potential Side Effects of Aldosterone Synthase Inhibitors?

The potential side effects of aldosterone synthase inhibition have been studied only in recent clinical trials.

• Osilodrostat is associated with the inhibition of cortisol synthesis. It is because of the more than 90 percent sequence similarity between the enzyme for cortisol production and aldosterone synthase.

• Aldosterone synthase inhibitors can cause hyperkalemia and hyponatremia (decreased blood sodium). Furthermore, their long-term effect on kidney function is also not known.

• In an aldosterone absence, mineralocorticoid receptors can be activated by cortisol or deoxycorticosterone (aldosterone precursor). Moreover, the combination of mineralocorticoid receptor blockade and aldosterone synthase inhibition may lead to severe hypoaldosteronism (decreased aldosterone levels).

• The possible long-term effects of cortisol inhibition with these drugs warrant further study.

However, none of the serious adverse events in trials are related to Baxdrostat. A fact of the clinical trials that need to be highlighted is that Baxdrostat was only compared to a placebo and not to other anti-hypertensive drugs. Hence, further investigations regarding this are warranted.

Conclusion

To conclude, the selective aldosterone synthase inhibitors lead to a significant reduction in BP in patients with resistant hypertension. Hence, it represents a novel tool to treat resistant hypertension. Still, the preclinical studies have shown positive results regarding end-organ damage in the kidneys, heart, and blood vessels. However, these findings need confirmation in large-scale trials in humans. Also, further studies are required to compare the cardiovascular benefit of suppressing aldosterone production compared with mineralocorticoid receptor blockade.