From ABCD to E for endothelin in resistant hypertension

Abraham, George; Davenport, Anthony P.

doi:10.1016/j.cell.2022.12.014

Cited by 6 publications

(3 citation statements)

References 9 publications

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“…The observed blood pressure lowering effect of zibotentan supports further evaluation through clinical trials for resistant hypertension. 27 Our results indicate that myocardial blood flow quantified using cardiovascular MRI may represent a novel biomarker for clinical trials in microvascular angina. In the future, myocardial blood flow quantified by MRI could be used as an eligibility criterion and as surrogate outcome measure of treatment effect.…”

Section: Discussionmentioning

confidence: 68%

Precision Pharmacotherapy With Zibotentan in Microvascular Angina: a randomized, placebo-controlled, cross-over trial.

Berry,

Morrow,

Abraham

et al. 2023

Preprint

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Microvascular angina, linked to endothelin system dysregulation, was the focus of this double-blind, placebo-controlled, randomized, sequential crossover trial (NCT04097314). The trial compared zibotentan, an oral endothelin A receptor selective antagonist, with placebo in 118 patients with microvascular angina. Over 12 weeks, participants received either 10 mg daily zibotentan or placebo, with the primary outcome treadmill exercise duration. The study found no significant difference in exercise duration with zibotentan (-4.26 seconds; 95% CI: -19.60 to 11.06; P=0.5871). However, zibotentan increased plasma big endothelin-1, endothelin-1, and global myocardial blood flow, while reducing hemoglobin, diastolic, and systolic blood pressure (all p<0.001). Adverse events were more common during the zibotentan period (60.2%) compared to placebo (14.4%, p<0.001). In conclusion, daily administration of 10 mg zibotentan for 12 weeks did not enhance exercise duration and was commonly associated with adverse effects related to fluid retention. Further trials exploring lower zibotentan doses in combination with agents to mitigate fluid retention, and longer treatment durations, are warranted.

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Section: Discussionmentioning

confidence: 68%

Precision Pharmacotherapy With Zibotentan in Microvascular Angina: a randomized, placebo-controlled, cross-over trial.

Berry,

Morrow,

Abraham

et al. 2023

Preprint

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“…Overexpression of both tissue ET-1 and ET receptors is shown in various pathologies including essential hypertension, pulmonary arterial hypertension, chronic kidney disease, and diabetes mellitus, which has led to the development of multiple selective ET A R and mixed ET A R and ET B R antagonists over the years [ 5 , 10 , 11 •]. Although there is significant evidence supporting the involvement of ET-1 in the pathophysiology of hypertension [ 13 ], clinical trials have not yet convincingly demonstrated the efficacy of ET receptor antagonists as a treatment for systemic or resistant hypertension.…”

Section: Role Of the Endothelin Pathway In Hypertensionmentioning

confidence: 99%

“…With up to 15% of hypertensive patients above recommended BP targets despite the use of three guideline-recommended antihypertensive drugs [ 5 ], the necessity of exploring novel therapeutic approaches is obvious. Failure to control BP may indicate that pathways relevant to resistant hypertension are not or not sufficiently opposed by current established approaches.…”

Section: Introductionmentioning

confidence: 99%

Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension

2023

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Purpose of Review Resistant hypertension (RH) defined as uncontrolled blood pressure despite the use of a combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic at maximally tolerated doses is associated with a substantially increased risk of cardiovascular and renal events. Despite targeting relevant pathophysiological pathways contributing to elevated blood pressure, approximately 10–15% of hypertensive patients remain above recommended blood pressure targets. Further optimization of blood pressure control is particularly challenging in patient populations who frequently present with RH such as elderly and patients with chronic kidney disease, due to the unfavorable safety profile of the recommended fourth-line therapy with mineralocorticoid receptor antagonists. This review explores the potential role of endothelin antagonists as an alternative fourth-line therapy. Recent Findings Despite the well-described role of the endothelin pathway in the pathogenesis of hypertension, it is currently not targeted therapeutically. Recently however, main outcome data from the PRECISION study, a randomized placebo-controlled phase 3 trial, in patients with RH on guideline-recommended standardized single-pill background therapy convincingly demonstrated the safety and blood pressure-lowering efficacy of the dual endothelin antagonist Aprocitentan. Summary Findings from the phase 3 PRECISION study could signify a turning point in the utilization of endothelin receptor antagonists as a standard treatment for patients with RH.

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Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential

Xu,

Jiang,

2023

Drug Discovery Today

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From ABCD to E for endothelin in resistant hypertension

Cited by 6 publications

References 9 publications

Precision Pharmacotherapy With Zibotentan in Microvascular Angina: a randomized, placebo-controlled, cross-over trial.

Precision Pharmacotherapy With Zibotentan in Microvascular Angina: a randomized, placebo-controlled, cross-over trial.

Dual Endothelin Antagonism with Aprocitentan as a Novel Therapeutic Approach for Resistant Hypertension

Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential

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