Aldosterone Synthase Inhibitors and Dietary Interventions: A Combined Novel Approach for Prevention and Treatment of Cardiovascular Disease

Abstract

Systemic hypertension (HTN) is the hallmark of cardiovascular disease and the forerunner of heart failure. These associations have been established over decades of research on essential HTN. Advancements in the treatment of patients diagnosed with HTN, consisting of alpha-or beta-adrenergic receptor blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide, or aldosterone receptor blockers known as anti-mineralocorticoids, in the presence or absence of low sodium salt diets, often fail to control blood pressure adequately to prevent morbidity and mortality. Low sodium diets have had limited success in controlling HTN because low sodium intake is associated with renin-angiotensin-aldosterone system upregulation. Therefore, upregulating aldosterone secretion, sodium, and water retention which, in turn, moves the blood pressure back toward the range of HTN dictated by the baroreceptor reset value, as a compensatory mechanism, especially in resistant HTN. These impediments to blood pressure control in HTN may have been effectively circumvented by the advent of a new class of drugs known as aldosterone synthase inhibitors, represented by baxdrostat. The mechanism of action of baxdrostat as an aldosterone synthase inhibitor demonstrates the inextricable linkage between sodium and blood pressure regulation. Theoretically, combining a low sodium diet with the activity of this aldosterone synthesis inhibitor should alleviate the adverse effect of renin-angiotensin-aldosterone system upregulation. Aldosterone synthesis inhibition should also decrease the oxidative stress and endothelial dysfunction associated with HTN, causing more endothelial nitric oxide synthesis, release, and vasorelaxation. To the best of our knowledge, this is the first systematic review to summarize evidence-based articles relevant to the use of a novel drug (aldosterone synthase inhibitor) in the treatment of HTN and cardiovascular disease. Making the current database of relevant information on baxdrostat and other aldosterone synthase inhibitors readily available will, no doubt, aid physicians and other medical practitioners in their decision-making about employing aldosterone synthase inhibitors in the treatment of patients.

Renin–Angiotensin–Aldosterone System: From History to Practice of a Secular Topic

“…At variance with MRAs which target to mitigate the effects of aldosterone, Asis act one step earlier by inhibiting the production of aldosterone itself [59]. Baxdrostat is a highly selective Asi, with no impact on cortisol secretion, that has shown promising results in the treatment of resistant hypertension [60]. In a recently published phase 2 trial (BrigHTN), baxdrostat exhibited a dose-dependent reduction in systolic blood pressure when compared with placebo (2 mg vs. placebo: −11.0 mmHg [95%CI −16.4 to −5.5; p < 0.001]; 1 mg vs. placebo: −8.1 mmHg [95%CI, −13.5 to −2.8; p = 0.003]) [43].…”

Aldosterone synthase inhibitor “Baxdrostat” for resistant hypertension: A clinical approach or futuristic idea?

“…5 Clinical research has demonstrated that aldosterone synthesis inhibitors lower circulating aldosterone levels by directly blocking the synthesis of aldosterone rather than blocking its receptor activity, subsequently lowering BP. 6 The first aldosterone synthase inhibitor to be developed was Osilodrostat (LCI699), which was intended to reduce serum aldosterone levels and manage hypertension. It was soon discovered, nevertheless, that Osilodrostat also inhibits 11-beta hydroxylase (CYP11B1), which lowers serum cortisol levels.…”

“… 8 , 10 Differences in diastolic blood pressure, the secondary objective, were achieved at the 2 mg dose. 6 Baxdrostat was shown to reach its maximal plasma level in 4 h, causing a dose‐dependent drop in serum aldosterone without changing cortisol levels as one of the exploratory endpoints. 8 , 10 The background medication utilized in the experiment was the same for all groups.…”