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Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25–75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. AbbVie.

Patients with angina and no obstructive coronary artery disease frequently have vasomotor dysfunction as the underlying mechanism for symptoms. Patients with vasomotor dysfunction have a high angina burden and their treatment frequently fails to reduce complaints sufficiently. Targeted therapies are currently unavailable due to heterogeneity in the patient population and incomplete understanding of the underlying pathophysiological mechanisms. One of the vasomotor dysfunction endotypes, epicardial spasm, is hypothesized to be a possible target for endothelin receptor antagonism treatment. The EDIT-CAS trial is a registry based, double blind, randomised, placebo-controlled clinical trial and aims to compare the efficacy of 10 weeks of add-on bosentan treatment versus placebo to prevent epicardial spasm at repeat spasm provocation test. Secondary and explorative outcomes are the effect on anginal complaints, safety of bosentan treatment, changes in coronary reactivity and the relationship between baseline endothelin levels and treatment success. We will include 100 patients with previously diagnosed epicardial vasospasm on a maximal triggering dose of 100 micrograms of acetylcholine and continuing angina(-like) symptoms at least weekly despite optimal medical treatment. The is registered in Clinical Trials Information System (2023-507782-25-00) and ClinicalTrials.gov (NCT06432452).

Aims/hypothesis In the Study Of diabetic Nephropathy with AtRasentan (SONAR), the endothelin receptor antagonist (ERA) atrasentan slowed progression of chronic kidney disease (CKD) in individuals with type 2 diabetes. Pre-clinical research suggests sex-based differences in the endothelin system might influence the efficacy and safety of atrasentan. We therefore assessed the effects of atrasentan in men and women participating in SONAR. Methods SONAR was a double-blind, placebo-controlled trial that compared atrasentan 0.75 mg/day with placebo in individuals with type 2 diabetes and CKD (eGFR 25–75 ml/min per 1.73 m 2 , urine albumin/creatinine ratio [UACR] 300–5000 mg/g). The primary endpoint was defined as the time from randomisation to the first occurrence of a doubling in serum creatinine or kidney failure (eGFR <15 ml/min per 1.73 m 2 , chronic dialysis, kidney transplantation or death from kidney failure). Hospitalisation for heart failure was the secondary endpoint. We performed Cox proportional hazards regression analyses to compare the treatment effect of atrasentan between male and female participants on the risk of the composite kidney outcome as well as hospitalisation for heart failure. Additionally, differences between male and female participants in atrasentan plasma exposure and eGFR change were assessed using, respectively, a t test and linear mixed effect model. Results Among 3668 randomised participants, 946 (25.8%) were female. Atrasentan significantly reduced the risk of the composite kidney outcome in female participants (HR 0.46 [95% CI 0.28, 0.76]) but not in male participants (HR 0.83 [95% CI 0.65, 1.05]; p value for interaction 0.032). Atrasentan compared with placebo reduced eGFR decline to a greater extent in female than in male participants (treatment effect difference between male vs female participants −0.99 ml/min per 1.73 m 2 , p value for interaction=0.020). The RR for hospitalisation for heart failure with atrasentan vs placebo was 1.14 (95% CI 0.74, 1.76) in male participants and 1.88 (95% CI 0.98, 3.63) in female participants ( p value for interaction=0.217). Female participants also had significantly higher atrasentan plasma exposure than male participants (geometric mean AUC 54.5 vs 42.6 ng/ml×h; p <0.001). Conclusions/interpretation Atrasentan showed greater kidney protection in female than in male participants but also induced more heart failure events in the female participants. These data suggest that sex-specific dosing regimens may be considered to optimise ERA treatment. Trial registration ClinicalTrials.gov NCT01858532 Graphical Abstract

Background Endothelial damage induces myofibrillar breakdown and muscle degradation in COVID‐19 infection. There is a relationship between increased endothelin‐1 synthesis and sarcopenia. We evaluated the preventive effect of early bosentan therapy as an endothelin receptor blocker in sarcopenia in high‐risk outpatients with COVID‐19 infection. Methods From 15 December 2021 to 15 August 2023, patients within 3 days of the onset of signs and symptoms were randomly assigned to receive bosentan, 62.5 mg, or placebo, twice daily from enrollment for 30 days. The primary outcome was disease progression (death or hospitalization within 15 days after randomization), and the data for this outcome have been previously published. Sarcopenia as a secondary outcome was assessed prospectively at 3, 6, 9 and 12 months after randomization using the criteria of the Asian Working Group for Sarcopenia (AWGS) 2019 (IRCT.ir, IRCT20211203053263N1). Results A total of 313 patients (156 bosentan group, 157 controls) were included in the analyses, which were performed under the intent‐to‐treat principle. Overall, the incidence of sarcopenia was 8.6% (n = 27). Nineteen (73%) had severe sarcopenia. At the 3‐month follow‐up, the incidence of sarcopenia was 8.3% in the total population, with the significant risk difference (RD) of −10.17% in the bosentan group versus the control group. The incidence in the total population and RD in the bosentan group versus the control group at months 6, 9 and 12 were 8.6% (RD: −10.81%, p < 0.001), 8.3% (RD: −10.17%, p = 0.001) and 5.4% (RD: −6.99%, p = 0.003), respectively. During the study, 29 people developed severe COVID‐19 and were hospitalized. At follow‐up, sarcopenia occurred in four inpatients and 23 outpatients (p = 0.23). Mortality occurred in 5.1% (n = 16) of the total population, including 4 (1.3%) of the patients in the bosentan group and 12 (3.8%) of the patients in the placebo group (p = 0.069). None of the patients who died had sarcopenia. Bosentan did not cause any severe adverse events and was well tolerated. Conclusion Early administration of bosentan may prevent sarcopenia in high‐risk outpatients with COVID‐19.

Udenafil is an oral phosphodiesterase-5 inhibitor approved for the treatment of erectile dysfunction. In a multicenter, placebo-controlled, randomized Phase IIa study, the reduction of pulmonary vascular resistance index was greater with a 50-mg baseline dose of udenafil than with the 100-mg dose, the cardiac index did not decrease at most points, and the safety was excellent, suggesting that 50-mg udenafil could be used in a Phase IIb trial. In this 16-week, double-blind, placebo-controlled study, 63 patients with pulmonary arterial hypertension were randomized to receive 50-mg udenafil or a placebo BID. The primary efficacy end point was the 6-min walking distance. The secondary efficacy end points were the Borg dyspnea score and time to clinical worsening. Patients who completed the 16-week study could participate in a long-term extension study. : In terms of the difference between the baseline and 16-week 6-min walking distance in both groups, the mean placebo-corrected treatment effect was 25 (58) m (P = 0.0873). Among the patients with a history of endothelin receptor antagonist therapy, the treatment effect at week 16 between the udenafil and placebo groups was 34 (60) m (P = 0.0460). However, there were no significant differences in the Borg dyspnea score and time to clinical worsening between groups. The safety profile and adverse effects of udenafil were similar to those of typical phosphodiesterase-5 inhibitors seen in previous studies. Udenafil has a favorable safety profile and improves exercise capacity in patients with pulmonary arterial hypertension. ClinicalTrials.gov identifier: NCT01553721.

Background The data on bosentan were lacking for the treatment of exercise-induced elevation of pulmonary artery pressure (eePAP) or less severe PH in COPD. This study was conducted to investigate long-term efficacy and safety of bosentan for the treatment of eePAP or less severe PH in COPD. Methods COPD patients diagnosed at this hospital as having COPD (WHO functional class II, III or IV) with eePAP or less severe PH whose respiratory symptoms were stable but remained and gradually progressed even after COPD therapy were randomly assigned in a 1:1 ratio to receive either bosentan or no PH treatment for two years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right heart catheterization (RHC), and other parameters. Results A total of 29 patients who underwent RHC for detail examination were enrolled in the current study between August 2010 and October 2018.No death occurred in drug-treated group ( n  = 14) for 2 years; 5 patients died in untreated group ( n  = 15). Significant differences were noted between the 2 group in hospital-free survival (686.00 ± 55.87 days vs. 499.94 ± 53.27 days; hazard ratio [HR], 0.18; P  = 0.026) and overall survival (727 days vs. 516.36 ± 55.38 days; HR, 0.095; P  = 0.030) in all causes of death analysis, but not in overall survival in analysis of respiratory-related death. Bosentan was not associated with increased adverse events including requiring O 2 inhalation. Conclusions This study suggested that the prognosis for COPD patients with eePAP or less severe PH presenting with respiratory symptoms was very poor and that bosentan tended to improve their prognosis and suppress ADL deterioration without worsening respiratory failure. Trial registration This study was registered with UMIN-CTR Clinical Trial as UMIN000004749 . First trial registration at 18/12/2010.

Background Axonal degeneration is related to long-term disability in patients with multiple sclerosis (MS). The underlying mechanism remains ill understood but appears to involve axonal energetic dysfunction. A globally impaired cerebral blood flow (CBF) has been observed in the normal-appearing white matter (NAWM) of patients with MS, which is probably related to astrocytic overexpression of endothelin-1 (ET-1). Cerebral hypoperfusion has been associated with reduced mitochondrial activity and disabling symptoms (e.g. fatigue and cognitive decline) of MS. Countering this process could therefore be beneficial in the disease course. Short-term CBF restoration with a single 62.5-mg dose of the ET-1 receptor antagonist bosentan has already been demonstrated in patients with MS. Methods The ROCHIMS study is a proof-of-concept double-blind randomized clinical trial in which patients with relapsing-remitting MS will receive either 62.5 mg bosentan or matching placebo twice daily during 28 ± 2 days. Clinical evaluation and brain magnetic resonance imaging (MRI) will be performed at baseline and treatment termination. Based on previous work, we expect a global increase of CBF in the individuals treated with bosentan. The primary outcome measure is the change of N-acetyl aspartate in centrum semiovale NAWM, which is a marker of regional axonal mitochondrial activity. Other parameters of interest include changes in fatigue, cognition, motor function, depression, and brain volume. Discussion We hypothesize that restoring cerebral hypoperfusion in MS patients improves axonal metabolism. Early positive effects on fatigue and cognitive dysfunction related to MS might additionally be detected. There is a medical need for drugs that can slow down the progressive axonal degeneration in MS, making this an important topic of interest. Trial registration Clinical Trials Register, EudraCT 2017-001253-13 . Registered on 15 February 2018.

Macitentan (Opsumit ® ) is an orally active, potent, dual endothelin (ET) receptor antagonist that is indicated for the treatment of pulmonary arterial hypertension (PAH). In the pivotal SERAPHIN trial in patients aged ≥12 years with PAH, the risk of first PAH-related event or all-cause death (primary composite endpoint) was significantly reduced by 45 % with oral macitentan 10 mg once daily versus placebo. Macitentan significantly reduced the risk of the primary composite endpoint across various patient subgroups. The risk of all-cause hospitalization and PAH-related hospitalization was also significantly reduced by macitentan, according to post hoc analysis. Macitentan was generally well tolerated in SERAPHIN. In conclusion, macitentan is an important option for the treatment of PAH.

We hypothesized that chronic specific endothelin-A (ET-A) receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs, and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed tomography. All pigs with renovascular disease were divided such that seven were untreated, seven were treated with ET-A blockers, and five were treated with ET-B blockers. Four weeks later, all pigs were restudied in vivo, and then killed and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. Renal blood flow, glomerular filtration rate, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation, and fibrosis in the stenotic kidney. These effects were functionally consequential as ET-A blockade improved single kidney microvascular endothelial function, renal blood flow, and glomerular filtration rate, and decreased albuminuria.

The incidence and prevalence of chronic kidney disease (CKD), with diabetes and hypertension accounting for the majority of cases, is on the rise, with up to 160 million individuals worldwide predicted to be affected by 2020. Given that current treatment options, primarily targeted at the renin-angiotensin system, only modestly slow down progression to end-stage renal disease, the urgent need for additional effective therapeutics is evident. Endothelin-1 (ET-1), largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation, and fibrosis leading to CKD. Endothelin receptor antagonists (ERAs) have been demonstrated to ameliorate or even reverse renal injury and/or fibrosis in experimental models of CKD, whereas clinical trials indicate a substantial antiproteinuric effect of ERAs in diabetic and nondiabetic CKD patients even on top of maximal renin-angiotensin system blockade. This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.