A New Dawn for Aldosterone as a Therapeutic Target in Hypertension | Hypertension | JAMA

In 1953, aldosterone, then termed electrocortin, was first isolated and characterized by James and Sylvia Tait in London.1 A year later, Jerome Conn described the first case of primary aldosteronism, the clinical symptoms of which were resolved by resection of an aldosterone-producing adrenal adenoma.² The first effective mineralocorticoid receptor antagonist (MRA), spironolactone, soon followed in 1957.³ However, dose- and time-dependent antiandrogenic and progestogenic adverse effects of spironolactone, resulting in painful gynecomastia in men and menstrual dysfunction in women, soon became apparent and limited its use. A search for more selective MRAs resulted in the launch early this century of eplerenone, which is a more selective but less potent aldosterone receptor antagonist.

Starting in the 1990s, clinical trials with spironolactone and eplerenone began to reveal the importance of aldosterone in the pathogenesis of heart failure and the superiority of spironolactone as a treatment for resistant hypertension.4^–6 Nevertheless, the emergence of just 2 aldosterone receptor antagonists in more than 50 years was surprising and in stark contrast to drug development targeting the renin-angiotensin system cascade, ranging from direct renin inhibition to much more commonly used angiotensin-converting enzyme inhibition and selective angiotensin II receptor blockers.

For drug development, therapies targeting aldosterone have undoubtedly been the Cinderella of the renin-angiotensin-aldosterone system, but this is set to change due to the coincidence of several factors. A new class of nonsteroidal MRAs has emerged, exemplified by the most advanced molecule in this class, finerenone, which has been shown to improve cardiovascular and kidney outcomes in patients with diabetes.7 Furthermore, there has been a renaissance of interest in primary aldosteronism, the most common but lamentably underdiagnosed cause of secondary hypertension. Progress in identifying and understanding the various somatic variants that lead to autonomous aldosterone-producing adrenal adenomas has shown that many of these are micronodular, or little more than cell clusters, and below the limit of detection by conventional computed tomography or magnetic resonance imaging.⁸ The emergence of new positron emission tomography imaging tracers, selective for aldosterone synthase⁹ and thus capable of detecting these microadenomas, will soon disrupt this field and is likely to reveal many more patients in whom their hypertension is driven by aldosterone-producing adrenal microadenomas, often bilateral, requiring better-targeted and better-tolerated medical therapy, rather than the surgical approach that is most suited to the less common macronodular unilateral disease described by Conn.²

Another significant development is the emergence of a new class of drugs specifically targeting aldosterone synthesis upstream of the MRAs, the selective aldosterone synthase inhibitors (ASIs). Developing the ASIs has been a formidable drug development challenge because of the substantial homology (>93%) between CYP11β1 (cortisol synthase) and CYP11β2 (aldosterone synthase) and the obvious need to avoid suppressing cortisol synthesis when attempting to suppress aldosterone synthesis. Two selective ASIs are in advanced clinical development, lorundrostat10 and baxdrostat.¹¹ A third, dexfadrostat, is in earlier clinical development.¹²

In this issue of JAMA, Laffin and colleagues10 report the results of an early-phase dose-ranging study evaluating the safety and efficacy of lorundrostat for treatment of 200 patients with uncontrolled hypertension, ie, blood pressure uncontrolled despite treatment with 2 or more antihypertensive medications (≥3 medications in 42%). The mean age of the study population was 66 years; 60% were women, 36% were Black or African American, and 48% were Hispanic or Latino. In 48%, body mass index was 30 or more. The study population was divided into 2 cohorts, with the majority (n = 163) in the main study cohort with a requirement for suppressed plasma renin activity (PRA) at baseline. The primary outcome showed that 8 weeks after adding lorundrostat or placebo to background therapy, lorundrostat, 50 mg once daily or 100 mg once daily, lowered seated automated office systolic blood pressure significantly more than placebo (−9.6 mm Hg and −7.8 mm Hg, respectively). In prespecified analyses, the reduction in 24-hour ambulatory systolic blood pressure appeared to show a dose response from 12.5 mg once daily to 100 mg once daily, which was numerically greater than the placebo response, but the numbers are too small to be certain. Lorundrostat treatment, as expected, suppressed serum aldosterone levels and increased PRA. There was a surprising absence of any effect of baseline PRA on blood pressure response; however, as in many exploratory analyses, the sample sizes are too small to draw conclusions.

While one must exercise extreme caution in overinterpreting the prespecified exploratory analyses, 2 aspects are likely to be real phenomena and of clinical importance. First, the placebo-corrected systolic blood pressure response to lorundrostat in patients receiving background thiazide diuretic therapy (55%-60%) appeared to be more than twice that seen in those not receiving diuretic therapy. This supports the concept that uncontrolled hypertension is often a sodium-retaining state, requiring dual diuretic therapy to optimize the blood pressure response in such patients.13 Second, almost half of the patients (48%) in this study would be classified as obese (body mass index >30), and the systolic blood pressure response in these patients appeared to be more than twice that in those who had a body mass index of 30 or lower. This is consistent with evidence suggesting that obesity is associated with relative aldosterone excess and sodium retention.¹⁴ It is unclear whether those with obesity seemingly responded better to lorundrostat because they were also receiving a thiazide diuretic.

Corresponding Author: Bryan Williams, MD, University College London, Maple House, 149 Tottenham Court Rd, First Floor, Suite A, London W1T 7DN, England (bryan.williams@ucl.ac.uk).

Published Online: September 10, 2023. doi:10.1001/jama.2023.17087

Conflict of Interest Disclosures: Dr Williams reported being the unremunerated chair of the steering committee designing a phase 3 trial of the aldosterone synthase inhibitor baxdrostat for AstraZeneca.