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给我写一篇baxdrostat的综述，包括机制、疗效、安全性、指南推荐以及目前的临床应用
Baxdrostat综述：机制、疗效、安全性、指南推荐及目前的临床应用
高血压是一种全球性的流行病，影响着约30.4%的人口，是导致死亡的首要可预防风险因素。尽管有多种降压药物，但仍有不到20%的患者血压得到有效控制，其中，难治性高血压（Resistant Hypertension, RH）对治疗提出了严峻挑战。难治性高血压的特点是尽管使用了三种或更多种降压药物（包括利尿剂），血压仍持续升高。醛固酮（aldosterone）过量生成是难治性高血压的关键病理生理驱动因素，并与心肾不良结局相关。在这种背景下，醛固酮合酶抑制剂（Aldosterone Synthase Inhibitors, ASIs）作为一类新型药物应运而生，通过抑制醛固酮的合成来降低血压，为难治性高血压患者带来了新的治疗希望。
Baxdrostat（CIN-107, RO6836191）是一种口服的、高选择性醛固酮合酶抑制剂，目前已进入三期临床试验阶段，有望为难治性高血压的治疗带来范式转变。
1. 作用机制
Baxdrostat 的核心作用机制在于选择性抑制醛固酮合酶（CYP11B2酶）。醛固酮合酶负责催化醛固酮的合成，而Baxdrostat能够有效地降低醛固酮水平，从而减轻其在血压升高和心肾疾病进展中的作用。
醛固酮在肾素-血管紧张素-醛固酮系统（RAAS）中扮演着关键角色，其过量生成会导致炎症、全身性高血压和器官纤维化，从而促成不良心血管事件。传统的RAAS抑制剂（如ACEI和ARB）虽然有效，但其作用可能因“醛固酮逃逸”（aldosterone escape）现象而被部分削弱，即长期使用RAAS抑制剂后，肾上腺醛固酮仍因替代酶途径的激活而持续升高。矿物皮质激素受体拮抗剂（MRAs）被推荐作为难治性高血压的一线治疗，但其临床应用受到依从性差和高停药率的限制，这主要是由于高钾血症和性激素相关副作用（如男性乳腺发育、阳痿和月经不调）。
与MRAs不同，Baxdrostat直接靶向醛固酮合成过程，通过抑制CYP11B2酶来减少醛固酮的产生，而不是拮抗其在受体上的作用。值得注意的是，Baxdrostat在临床前和一期研究中显示出对醛固酮合酶的100:1选择性抑制能力，能够在降低血浆醛固酮水平的同时不影响皮质醇水平。皮质醇的合成由另一种与醛固酮合酶具有93%序列相似性的酶催化，因此选择性抑制醛固酮合酶而不影响皮质醇合成至关重要，以避免肾上腺皮质功能不全等副作用。这种“皮质醇保留”（cortisol-sparing）的机制是Baxdrostat的一大优势，使其在副作用方面具有更优的安全性。
2. 疗效
Baxdrostat在多项临床试验中展现出显著的降压疗效，尤其是在难治性高血压患者中。
2.1. 难治性高血压（Resistant Hypertension, RH）
- BrigHTN II期试验：这项多中心、安慰剂对照试验将难治性高血压患者（血压≥130/80 mmHg，并接受至少三种降压药治疗，包括利尿剂）随机分配到Baxdrostat（0.5 mg、1 mg或2 mg）或安慰剂组，每日一次，持续12周。结果显示，Baxdrostat组的收缩压（SBP）呈剂量依赖性下降：2 mg组下降20.3 mmHg，1 mg组下降17.5 mmHg，0.5 mg组下降12.1 mmHg，而安慰剂组下降9.4 mmHg。与安慰剂组相比，2 mg组的收缩压变化差异为-11.0 mmHg（95% CI，-16.4至-5.5；P<0.001），1 mg组为-8.1 mmHg（95% CI，-13.5至-2.8；P=0.003）。这表明Baxdrostat能使难治性高血压患者的血压呈剂量相关性降低。
- 系统综述与Meta分析：一项对随机对照试验的系统综述和Meta分析（包括BrigHTN试验、BaxHTN试验和HALO试验）纳入了1318名患者，结果显示Baxdrostat与安慰剂相比显著降低了收缩压（平均差（MD）：-7.93 mmHg；95% CI：-12.64至-3.21；I² = 84%；高确定性证据）。舒张压（DBP）也显著降低（MD：-3.49 mmHg；95% CI：-5.18至-1.81；I² = 68%；高确定性）。该分析也观察到剂量依赖性效应，2 mg剂量下的降压效果更显著。另一项贝叶斯网络Meta分析也指出，Baxdrostat 2 mg每日一次显著降低收缩压（MD -11.0 mmHg；95% CrI -21.0至-0.30）。
- BaxHTN III期试验：这项III期、多国、双盲、随机、安慰剂对照试验纳入了796名患有非控制性或难治性高血压的患者。在接受背景治疗的基础上，患者随机分配到Baxdrostat 1 mg、2 mg或安慰剂组，每日一次，持续12周。结果显示，与安慰剂组相比，Baxdrostat 1 mg组的坐位收缩压变化差异为-8.7 mmHg（95% CI，-11.5至-5.8），2 mg组为-9.8 mmHg（95% CI，-12.6至-7.0），两组均达到统计学显著性（P<0.001）。
2.2. 非控制性高血压（Uncontrolled Hypertension, uHTN）
- BaxHTN III期试验也包括了非控制性高血压患者（接受两种降压药治疗后坐位收缩压仍在140 mmHg至<170 mmHg之间）。该试验结果同样支持Baxdrostat在非控制性高血压患者中的降压效果。
- 然而，值得注意的是，一项名为HALO的试验（评估Baxdrostat在非控制性高血压患者中的疗效和安全性）并未显示出与安慰剂相比的降压益处。这可能是由于安慰剂组对现有降压治疗的依从性改善所致，导致安慰剂效应较高。尽管如此，总体来看，多项研究（包括Meta分析）仍支持Baxdrostat在非控制性高血压中的疗效。
2.3. 慢性肾病（Chronic Kidney Disease, CKD）
- Baxdrostat在慢性肾病合并非控制性高血压患者中的疗效也得到了评估。一项II期、随机、双盲、安慰剂对照多中心试验（NCT05432167）将接受ACEI或ARB治疗且平均坐位收缩压≥140 mmHg（无糖尿病）或≥130 mmHg（有2型糖尿病），以及尿白蛋白-肌酐比值≥100 mg/g的CKD患者随机分组。结果显示，与安慰剂相比，Baxdrostat合并治疗组（低剂量0.5 mg滴定至1 mg，高剂量2 mg滴定至4 mg）的平均坐位收缩压从基线到26周的安慰剂校正变化为-8.1 mmHg（95% CI，-13.4至-2.8；P=0.003）。低剂量组为-9.0 mmHg，高剂量组为-7.2 mmHg。这表明Baxdrostat能够降低CKD合并非控制性高血压患者的收缩压。
- 此外，有研究表明ASIs（如Baxdrostat和Lorundrostat）对肾脏结局显示出有利影响。虽然长期心血管结局和肾脏结局仍在调查中，但ASIs有望缩小心肾护理的关键差距。
2.4. 主要醛固酮增多症（Primary Aldosteronism）
- 初步研究结果表明Baxdrostat在原发性醛固酮增多症中的应用也显示出潜力，但仍需进一步的临床试验来证实。
3. 安全性
Baxdrostat的安全性数据在多项临床试验中进行了评估，总体上显示出良好的耐受性，但存在一些值得关注的副作用。
- 肾上腺皮质功能不全：由于Baxdrostat具有高度的选择性，在临床前和I期研究中，它能降低血浆醛固酮水平而不影响皮质醇水平。BrigHTN试验中没有发生死亡，研究者未将任何严重不良事件归因于Baxdrostat，也未出现肾上腺皮质功能不全的情况。
- 高钾血症：高钾血症是Baxdrostat最常见的治疗相关不良事件。
- 在BrigHTN试验中，有2名患者的血钾水平升高至≥6.0 mmol/L，但在停药并重新开始用药后，这些升高未再复发。
- 一项系统综述和Meta分析显示，Baxdrostat增加了高钾血症（血清钾≥5.5 mmol/L）的风险（风险比（RR）：2.87；95% CI：1.61-5.11；中等确定性），但大多数病例为轻度且可控。
- BaxHTN III期试验中，1 mg Baxdrostat组有6名患者（2.3%），2 mg Baxdrostat组有8名患者（3.0%）报告血钾水平超过6.0 mmol/L，而安慰剂组仅有1名患者（0.4%）。
- 在CKD合并非控制性高血压的II期试验中，Baxdrostat pooled组有41%（53/128）的参与者报告高钾血症，而安慰剂组为5%（3/64）。这提示在CKD患者中，高钾血症的发生率相对较高，需要密切监测。
- 总体贝叶斯Meta分析显示，第二代ASIs（包括Baxdrostat）增加了高钾血症的几率（OR：7.1；CrI：3.56，15.2；τ 0.23）。
- 低血压：贝叶斯Meta分析显示ASIs增加了低血压的几率（OR：3.28；CrI：1.43，8.16；τ 0.1），因此需要谨慎监测血压，尤其是在治疗初期。
- 低钠血症：贝叶斯Meta分析也指出ASIs增加了低钠血症的风险（OR：2.6；CrI：1.25，5.98；τ 0.1）。
- 其他不良事件：总体不良事件和严重不良事件的发生率在Baxdrostat组与安慰剂组之间无显著差异。大多数不良事件是轻微的，严重事件不常见，且未报告药物相关死亡。Baxdrostat被认为可以安全地与其他药物（包括二甲双胍）联合使用，并且对肾功能无显著影响。
4. 指南推荐及目前的临床应用
4.1. 指南推荐
目前，Baxdrostat 尚未被纳入主流高血压治疗指南的正式推荐，因为它仍处于临床试验阶段，特别是III期试验正在进行中。
然而，现有指南通常推荐螺内酯（spironolactone）作为难治性高血压的附加治疗，但其应用受限于高钾血症和性激素相关副作用的风险，尤其是在中度至重度CKD患者中。鉴于Baxdrostat具有类似MRAs的作用机制（通过抑制醛固酮），但副作用谱可能更优（特别是无性激素相关副作用，且对皮质醇无影响），未来的指南可能会考虑将其作为难治性高血压患者，特别是那些不耐受或禁忌使用MRAs患者的一种替代或联合治疗方案。
一些评论和综述文章已经指出，Baxdrostat作为一种新型、高选择性醛固酮合酶抑制剂，为解决难治性高血压提供了一个有前景的治疗选择，尤其对于靶向醛固酮失调的患者。
4.2. 目前的临床应用
尽管Baxdrostat在III期临床试验中表现出显著的降压效果，例如BaxHTN试验显示其能显著降低非控制性或难治性高血压患者的坐位收缩压，但由于其尚未完成所有的III期试验和监管批准，目前尚未广泛应用于临床实践。
然而，正在进行的Baxdrostat高血压III期项目，包括BaxHTN（NCT06034743）、BaxAsia（NCT06344104）和Bax24（NCT06168409），正在评估Baxdrostat 1 mg和/或2 mg与安慰剂相比的疗效和安全性。这些试验旨在评估Baxdrostat在非控制性高血压和难治性高血压患者中的长期持续效应和安全性，以及在不同地理区域人群中的应用。BaxHTN和BaxAsia试验将评估从基线到第12周的平均坐位办公室收缩压变化，而Bax24试验将评估24小时动态收缩压变化作为主要终点。
此外，Baxdrostat在慢性肾病和原发性醛固酮增多症患者中的应用也在探索中，初步研究结果显示其具有潜力。特别是针对CKD患者，Baxdrostat已在一项II期试验中显示出降低收缩压的疗效，这对于合并肾功能不全的高血压患者具有重要意义，因为他们在治疗上往往更为复杂。
5. 总结
Baxdrostat作为一种新型、高选择性的醛固酮合酶抑制剂，在治疗难治性高血压和非控制性高血压方面展现出显著的降压疗效，并具有“皮质醇保留”的独特优势。其通过直接抑制醛固酮合成的机制，有望克服传统RAAS抑制剂的“醛固酮逃逸”现象，并避免MRAs的一些性激素相关副作用。尽管高钾血症是其主要副作用，但多数病例为轻度且可控，且在CKD患者中发生率较高，需密切监测。
目前，Baxdrostat正处于关键的III期临床试验阶段，以进一步评估其长期疗效和安全性，特别是对高血压靶器官损害和主要心血管事件的影响。一旦这些试验结果积极并获得监管批准，Baxdrostat有望成为难治性高血压治疗的重要新选择，尤其适用于对标准治疗无反应或不耐受MRAs的患者。未来的研究将进一步阐明Baxdrostat在更广泛患者群体中的应用价值，并指导其在临床实践中的精准定位。
References
1Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.PubMed
Mason W Freeman, Yuan-Di Halvorsen, William Marshall, et al.
BACKGROUND: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group. RESULTS: A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug. CONCLUSIONS: Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).
2Efficacy and Safety of Baxdrostat in Resistant Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.PubMed
Ashish Wadhwani, Sameer U Khasbage, Sumedha R Zade, et al.
Resistant hypertension (RH) is characterized by persistently elevated blood pressure despite treatment with three or more antihypertensive agents, including a diuretic. Excess production of aldosterone is a key contributor to this condition. Baxdrostat is a novel, highly selective aldosterone synthase inhibitor that reduces aldosterone synthesis without affecting cortisol production. This systematic review and meta-analysis evaluated the efficacy and safety of baxdrostat in patients with RH. Following a preregistered PROSPERO protocol (CRD420251038564) and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus through December 2025 for randomized controlled trials (RCTs) comparing baxdrostat with placebo in adults with RH. Primary efficacy outcomes were changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Primary safety outcomes included adverse events and hyperkalemia. Data were pooled using random-effects models. Risk of bias was assessed using Cochrane RoB 2, and evidence certainty was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Three RCTs (the BrigHTN trial, the BaxHTN trial, and the HALO trial) involving 1,318 patients were included. Pooled analysis demonstrated that baxdrostat significantly reduced SBP compared with placebo (mean difference (MD): -7.93 mmHg; 95% CI: -12.64 to -3.21; I² = 84%; high-certainty evidence). DBP was also significantly reduced (MD: -3.49 mmHg; 95% CI: -5.18 to -1.81; I² = 68%; high certainty). Dose-dependent effects were observed, with greater reductions at 2 mg. There was no significant difference in overall adverse events (risk ratio (RR): 1.05; 95% CI: 0.95-1.16) or serious adverse events (RR: 1.10; 95% CI: 0.70-1.73). However, baxdrostat increased hyperkalemia risk (serum potassium ≥5.5 mmol/L) (RR: 2.87; 95% CI: 1.61-5.11; moderate certainty), although most cases were mild and manageable. Baxdrostat provides clinically meaningful blood pressure reductions in RH with a favorable safety profile. Its highly selective, cortisol-sparing mechanism offers a promising therapeutic option that directly targets aldosterone dysregulation in RH.
3Baxdrostat for uncontrolled and resistant hypertension: rationale and design of the Phase 3 clinical trials BaxHTN, BaxAsia, and Bax24.PubMed
John M Flack, Michel Azizi, Jenifer M Brown, et al.
Inappropriately elevated aldosterone is a common feature of uncontrolled hypertension (uHTN) and resistant hypertension (rHTN), and is a major pathophysiological driver of adverse cardiorenal outcomes beyond elevated blood pressure (BP). Baxdrostat is a selective aldosterone synthase inhibitor that has demonstrated dose-dependent seated office systolic BP (SBP) lowering in a Phase 2 trial of patients with rHTN. Here, we report the design of the baxdrostat hypertension Phase 3 program. BaxHTN (NCT06034743), BaxAsia (NCT06344104), and Bax24 (NCT06168409) are randomized, multi-national, double-blind, placebo-controlled Phase 3 trials evaluating the efficacy and safety of baxdrostat 1 and/or 2 mg versus placebo. BaxHTN includes patients with uHTN or rHTN, BaxAsia includes patients with uHTN or rHTN primarily from Asia, and Bax24 includes patients with rHTN. Eligibility criteria include age ≥18 years, mean seated office SBP of ≥140 mmHg to <170 mmHg at screening, and ≥2 antihypertensive treatments of different classes for ≥4 weeks before screening. BaxHTN and BaxAsia have four sequential periods following placebo run-in: 12-week double-blind; 12-week open-label; 8-week randomized withdrawal; 20-week open-label. Bax24 has a placebo run-in and 12-week double-blind period. Primary endpoints are changes from baseline to Week 12 in mean seated office SBP (BaxHTN and BaxAsia) and ambulatory 24-h average SBP (Bax24). Safety and tolerability are also assessed. The Baxdrostat hypertension Phase 3 program will assess efficacy, long-term sustained effect, and safety profile in patients with hypertension across multiple geographies. The trials will evaluate the BP lowering efficacy of aldosterone synthase inhibition as a novel treatment for uHTN and rHTN.
4Baxdrostat: A Novel Aldosterone Synthase Inhibitor for Treatment Resistant Hypertension.PubMed
Sonia Dogra, Swara Shah, Lucas Gitzel, et al.
Hypertension is a global epidemic, affecting around 30.4% of the population and being the leading preventable risk factor for death. Despite the availability of numerous antihypertensive agents, less than 20% of individuals have their blood pressure controlled. Resistant hypertension poses a challenge, but a new class of medication, aldosterone synthase inhibitors (ASI), shows promise. ASI reduces aldosterone production by inhibiting aldosterone synthase. This review article focuses on Baxdrostat, a highly potent ASI currently in phase 3 trials. It discusses the drug's biochemical pathway, efficacy trials in animals and humans, and its potential in uncontrolled hypertension, chronic kidney disease, and primary aldosteronism.
5Baxdrostat: An Aldosterone Synthase Inhibitor for the Treatment of Systemic Hypertension.PubMed
Subo Dey, William H Frishman, Wilbert S Aronow
Systemic hypertension remains one of the leading cause of morbidity and mortality in the United States and throughout the world. Baxdrostat (CIN-107), a new drug developed by Roche is a selective aldosterone synthase inhibitor that is being evaluated as one of the potential treatments for hypertension, especially in patients with drug treatment-resistant hypertension. An increased level of aldosterone is associated with inflammation, systemic hypertension, and organ fibrosis, contributing to adverse cardiovascular events. A phase 2 trial, BrigHTN, showed promising results in demonstrating the efficacy of baxdrostat, where The HALO (efficacy and safety of baxdrostat in patients with uncontrolled hypertension) trial did not demonstrate any blood pressure-lowering benefit of baxdrostat when compared with the placebo. Several additional studies are now underway to evaluate the effectiveness of baxdrostat as an anti-hypertensive agent.
6Aldosterone synthase inhibitors in hypertension and chronic kidney disease: double the benefit?PubMed
Alessio Mazzieri, Sara Battistoni, Gianpaolo Reboldi
PURPOSE OF REVIEW: Aldosterone synthase inhibitors (ASIs) are novel drugs for cardiorenal protection. These compounds block aldosterone production and lower blood levels by targeting its biosynthesis pathway. ASIs induce a complete suppression of both genomic and nongenomic aldosterone effects, while reducing the risks of hyperkalaemia and aldosterone escape. In the present review, we will summarize the clinical potential of current ASIs in hypertension and chronic kidney disease (CKD). RECENT FINDINGS: Selective ASIs have been extensively evaluated in patients with both primary and resistant hypertension, and are promising therapeutic agents in CKD. Baxdrostat and lorundrostat effectively lowered blood pressure in patients with resistant or uncontrolled hypertension and showed favourable effects on renal outcomes. In CKD patients, vicadrostat determined a dose-dependent reduction of albuminuria and additive beneficial effects when used on top of empagliflozin. SUMMARY: In randomized controlled trials, patients assigned to second generation ASIs had beneficial effects on blood pressure and albuminuria, with enhanced safety profiles. Although long-term clinical outcomes are still under investigation, ASIs have the potential to narrow critical gaps in cardiorenal care.
7Aldosterone synthase inhibitors in uncontrolled and resistant hypertension: A phenotype-stratified systematic review and network meta-analysis of randomized trials.PubMed
Ismaila Ajayi Yusuf, Olurotimi J Badero, Alozie Ihesiulo, et al.
BACKGROUND: Aldosterone synthase inhibitors (ASIs) have emerged as a mechanistically targeted strategy for resistant and uncontrolled hypertension; however, no head-to-head trials exist, and comparative efficacy and safety remain uncertain. We compared their efficacy and safety using network and pairwise meta-analysis of randomized trials. METHODS: This systematic review and meta-analysis adhered to the PRISMA guidelines. PubMed/MEDLINE, Scopus, Embase, ClinicalTrials.gov, and Cochrane Library were searched from inception to January 14, 2026, for randomized trials evaluating ASIs versus placebo or standard care. A frequentist random-effects network meta-analysis assessed systolic (SBP) and diastolic blood pressure (DBP). Dichotomous safety outcomes were pooled using Hartung-Knapp random-effects models. Network consistency was evaluated using design-by-treatment interaction modeling. Prespecified subgroup analyses stratified outcomes by hypertension phenotype (resistant vs uncontrolled). RESULTS: Across 7 RCTs (n = 2,828), all ASIs significantly reduced SBP versus placebo: baxdrostat -8.63 mmHg (95% CI -10.84 to -6.42), lorundrostat -7.47 mmHg (95% CI -9.54 to -5.40), and LCI699/osilodrostat -5.63 mmHg (95% CI -9.15 to -2.12), with no significant indirect differences between agents. In resistant hypertension, lorundrostat (-9.00 mmHg; 95% CI -13.19 to -4.81) and baxdrostat (-8.77 mmHg; 95% CI -10.50 to -7.05) demonstrated pronounced reductions. In uncontrolled hypertension, LCI699/osilodrostat showed the largest point estimate (-10.55 mmHg; 95% CI -16.49 to -4.61), though this derives from a single early-phase trial and requires cautious interpretation. DBP reductions were significant for baxdrostat (-3.23 mmHg; 95% CI -4.73 to -1.73) and lorundrostat (-3.60 mmHg; 95% CI -5.43 to -1.77). Hypotension (RR 2.67), hyperkalemia (RR 7.94), and hyponatremia (RR 2.07) were significantly increased; serious adverse events, discontinuation, and network inconsistency were not detected. CONCLUSIONS: ASIs provide clinically meaningful BP reduction across both hypertension phenotypes; however, short-term use is associated with hypotension and electrolyte disturbances, necessitating careful monitoring. Phenotype-specific efficacy and long-term safety require validation in outcome-driven trials. Systematic Review Registration: PROSPERO CRD420251266257.
8Evaluating phase II results of Baxdrostat, an aldosterone synthase inhibitor for hypertension.PubMed
Ayoola Awosika, Yoonje Cho, Ujjal Bose, et al.
INTRODUCTION: Hypertension, a global health concern, poses a significant risk for other cardiovascular diseases. While lifestyle modifications and interventions like the Dietary Approaches to Stop Hypertension (DASH) diet offer some respite, their maintenance can be challenging. Recently, the spotlight has turned toward the renin-angiotensin-aldosterone system, a crucial player in the pathophysiology of hypertension. Contrary to other drugs, Baxdrostat, an innovative aldosterone synthase inhibitor (ASI), targets aldosterone synthesis, mitigating negative systemic effects. AREAS COVERED: Baxdrostat showcases rapid absorption, high oral bioavailability, and significant selectivity for aldosterone synthase which presents a proactive approach to hypertension management by reducing aldosterone levels. Early trials have demonstrated its potential in lowering blood pressure in resistant hypertension cases. Current clinical trials are also exploring its application in primary aldosteronism and chronic kidney disease, with preliminary findings indicating its promise as a novel antihypertensive agent. This article encapsulates the current state of knowledge regarding Baxdrostat, encompassing its uses, ongoing clinical trials, and potential future clinical applications. EXPERT OPINION: Future research endeavors will play a pivotal role in unveiling the effectiveness and safety profile of this novel medication. Thus, positioning the baxdrostat as a valuable addition to the armamentarium of antihypertensive agents, especially for patients with complex, multifactorial hypertensive conditions.
9Blood Pressure-Lowering Effects of Aldosterone Synthase Inhibitors-A Systematic Review.PubMed
Anders Almskou Rasmussen, Ketil Lehm Nordestgaard, Ulf Simonsen, et al.
Excess aldosterone production contributes to the development of hypertension and results in fibrosis with dysfunction of the heart, vasculature and kidneys. Consequently, new agents have been developed to reduce endogenous aldosterone synthesis. The primary objective of this systematic review is to describe the BP-lowering effects of aldosterone synthase inhibitors (ASIs) in hypertensive patients and, secondly, to describe their potential renal protective effects and possible influence on cortisol production and plasma potassium. We searched PubMed, Embase and ClinicalTrials.gov and included randomized controlled and clinical trials according to PICO using the review tool Covidence. Thirteen studies were included and all demonstrated BP reduction through ASI treatment. Among patients with apparent resistant hypertension, the placebo-corrected reductions in seated systolic BP were 11.0 mmHg for baxdrostat and 9.6 mmHg for lorundrostat. A significant suppression of cortisol production was found for LCI699 (osilodrostat) but not for baxdrostat, lorundrostat, BI 690517 (vicadrostat) or dexfadrostat. Studies on BI 690517 showed a reduction in urine-albumin-creatinine ratio, indicating renal protection. ASIs may increase potassium levels. We conclude that ASIs have promising BP-lowering effects with very limited effects on cortisol production and offer reno-protective effects in chronic kidney disease. Studies on hypertensive target organ damage and cardiovascular outcomes are, however, lacking.
10New trials in resistant hypertension: mixed blessing stories.PubMed
Carmine Zoccali, Francesca Mallamaci, Luca De Nicola, et al.
Resistant hypertension (RH) is linked to an increased risk of cardiovascular and renal complications. Treatment options include non-pharmacological interventions, such as lifestyle modifications, and the use of specific antihypertensive drug combinations, including diuretics. Renal denervation is another option for treatment-resistant hypertension. New compounds targeting different pathways involved in RH-including inhibitors of aminopeptidase A, endothelin antagonists and selective aldosterone synthase inhibitors-have been tested in clinical trials in this condition. The centrally acting drug firibastat, targeting the brain renin-angiotensin system, failed to demonstrate significant effectiveness in reducing blood pressure (BP) in patients with difficult-to-treat and RH in the Firibistat in Resistant Hypertension (FRESH) trial. Aprocitentan, a dual endothelin A and B receptor antagonist, showed a moderate but statistically significant decrease in BP in patients with RH in the Parallel-Group, Phase 3 Study with Aprocitentan in Subjects with Resistant Hypertension (PRECISION) trial. However, concerns remain about potential adverse events, such as fluid retention. The use of baxdrostat, a selective aldosterone synthase inhibitor, showed promising results in reducing BP in patients with treatment-resistant hypertension in the Baxdrostat in Resistant Hypertension (BrigHTN) trial. However, a subsequent trial, HALO, failed to meet its primary endpoint. The unexpected results may be influenced by factors such as patient adherence and white-coat hypertension. Despite the disappointing results from HALO, the potential benefits of inhibiting aldosterone synthesis remain to be fully understood. In conclusion, managing RH remains challenging, and new compounds like firibastat, aprocitentan and baxdrostat have shown varied effectiveness. Further research is needed to improve our understanding and treatment of this condition.
11Hypertension in chronic kidney disease-treatment standard 2023.PubMed
Panagiotis I Georgianos, Rajiv Agarwal
Hypertension is very common and remains often poorly controlled in patients with chronic kidney disease (CKD). Accurate blood pressure (BP) measurement is the essential first step in the diagnosis and management of hypertension. Dietary sodium restriction is often overlooked, but can improve BP control, especially among patients treated with an agent to block the renin-angiotensin system. In the presence of very high albuminuria, international guidelines consistently and strongly recommend the use of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as the antihypertensive agent of first choice. Long-acting dihydropyridine calcium channel blockers and diuretics are reasonable second- and third-line therapeutic options. For patients with treatment-resistant hypertension, guidelines recommend the addition of spironolactone to the baseline antihypertensive regimen. However, the associated risk of hyperkalemia restricts the broad utilization of spironolactone in patients with moderate-to-advanced CKD. Evidence from the CLICK (Chlorthalidone in Chronic Kidney Disease) trial indicates that the thiazide-like diuretic chlorthalidone is effective and serves as an alternative therapeutic opportunity for patients with stage 4 CKD and uncontrolled hypertension, including those with treatment-resistant hypertension. Chlorthalidone can also mitigate the risk of hyperkalemia to enable the concomitant use of spironolactone, but this combination requires careful monitoring of BP and kidney function for the prevention of adverse events. Emerging agents, such as the non-steroidal mineralocorticoid receptor antagonist ocedurenone, dual endothelin receptor antagonist aprocitentan and the aldosterone synthase inhibitor baxdrostat offer novel targets and strategies to control BP better. Larger and longer term clinical trials are needed to demonstrate the safety and efficacy of these novel therapies in the future. In this article, we review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of hypertension in patients with CKD.
12Aldosterone synthesis inhibitors in resistant hypertension: the BaxHTN trial.PubMed
Giovanna Gallo, Maurizio Volterrani, Giuliano Tocci, et al.
Inhibitors of the renin-angiotensin-aldosterone system remain foundational therapies for arterial hypertension across major international guidelines. Their effectiveness, however, may be partially attenuated by the phenomenon of aldosterone escape, characterized by chronic elevation of adrenal aldosterone due to activation of alternative enzymatic pathways. Mineralocorticoid receptor antagonists are recommended as first-line therapy for resistant hypertension, yet their clinical utility is limited by poor adherence and high discontinuation rates, driven largely by hyperkalaemia and sex hormone-related adverse effects such as gynaecomastia, impotence, and menstrual irregularities. Recent pharmacologic research has focused on alternative strategies for suppressing aldosterone activity, particularly through the development of selective aldosterone synthase inhibitors (ASIs). This approach has led to the emergence of highly selective agents such as baxdrostat and lorundrostat. Clinical studies have demonstrated meaningful reductions in blood pressure among patients with resistant or uncontrolled hypertension, with favourable tolerability and without clinically significant adverse events. Further studies are required to determine the impact of ASIs on hypertensive-mediated organ damage, major cardiovascular events, nephrovascular outcomes, and long-term safety.
13Comparative efficacy and safety of aldosterone synthase inhibitors in hypertension: a Bayesian network meta-analysis of randomised controlled rials.PubMed
Ivana Purnama Dewi, Andreas Mercyan Anggitama, Evaristus Brama Jati, et al.
INTRODUCTION: Resistant hypertension remains a clinical challenge, often linked to elevated aldosterone levels not fully controlled by mineralocorticoid receptor antagonists. Aldosterone synthase inhibitors (ASIs) directly suppress aldosterone production. We evaluated the efficacy and safety of ASIs for blood pressure (BP) control. METHOD: We performed a Bayesian network meta-analysis of randomised controlled trials (RCTs) assessing systolic (SBP) and diastolic BP (DBP) in adults with hypertension. Major databases were searched to 2025. Treatment effects were summarised as mean differences (MDs) with 95% credible intervals (CrIs), and treatment rankings were determined using the surface under the cumulative ranking curve (SUCRA). Risk of bias was assessed using the Cochrane RoB V.2.0 tool. RESULTS: Six RCTs including 2149 patients were analysed. Risk of bias assessment using RoB2 showed that four studies were at low risk of bias, and two studies had some concerns. Compared with placebo, Baxdrostat 2 mg once a day significantly reduced SBP (MD -11.0 mm Hg; 95% CrI -21.0 to -0.30), while Osilodrostat 1 mg once a day significantly reduced both SBP (MD -7.6 mm Hg; 95% CrI -14.0 to -0.73) and DBP (MD -5.4 mm Hg; 95% CrI -10.0 to -0.69). Lorundrostat 50 mg once a day also reduced SBP significantly (MD -9.1 mm Hg; 95% CrI -17.0 to -1.7). SUCRA rankings confirmed these findings, with Baxdrostat 2 mg once a day ranking highest for SBP reduction (77%) and Osilodrostat 1 mg two times per day ranking highest for DBP reduction (84%). Most adverse events were mild, serious events were infrequent and no drug-related deaths were reported. CONCLUSION: ASIs significantly reduce BP with generally favourable tolerability. Osilodrostat and Baxdrostat demonstrated the most consistent efficacy across outcomes, while Lorundrostat also showed potential benefit. This analysis supports the use of ASIs as effective alternatives for BP reduction. Further large-scale and long-term RCTs are needed to validate these findings and guide clinical decision-making. PROSPERO REGISTRATION NUMBER: PROSPERO CRD420251024035.
14Baxdrostat: A Next-Generation Aldosterone Synthase Inhibitor Offering New Hope in Resistant Hypertension.PubMed
Ewelina Młynarska, Witold Czarnik, Natasza Dzieża, et al.
Hypertension is a leading global cause of cardiovascular disease and mortality, with resistant hypertension (RH) posing treatment challenges. Aldosterone synthase inhibitors (ASIs) are a novel drug class that reduce blood pressure by lowering aldosterone levels. Baxdrostat is a selective ASI that inhibits the CYP11B2 enzyme, responsible for aldosterone synthesis, without affecting cortisol production. This selectivity minimizes hormonal side effects. Clinical trials have shown that baxdrostat reduces plasma aldosterone in a dose-dependent manner while preserving cortisol levels. In the Phase 2 BrigHTN trial, baxdrostat significantly lowered systolic and diastolic blood pressure in patients with RH, with the 2 mg dose showing the most consistent efficacy. However, in the HALO trial, similar blood pressure reductions were observed in the placebo group, possibly due to improved adherence to background antihypertensive therapy. Baxdrostat has demonstrated a favorable safety profile, with mostly mild adverse effects and no significant impact on kidney function. It is considered safe for use with other medications, including metformin. Ongoing trials are investigating its potential in patients with chronic kidney disease (CKD) and primary hyperaldosteronism (PA). Baxdrostat represents a promising therapeutic option for aldosterone-driven hypertension, especially in patients unresponsive to standard treatments.
15Efficacy and Safety of Baxdrostat in Participants with CKD and Uncontrolled Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial.PubMed
Jamie P Dwyer, Noha Maklad, Ola Vedin, et al.
KEY POINTS: This phase 2 trial assessed baxdrostat, an aldosterone synthase inhibitor, in participants with CKD and uncontrolled hypertension. Baxdrostat showed placebo-corrected reduction in systolic BP of –8.1 (95% confidence interval, –13.4 to –2.8) mm Hg, = 0.003. Baxdrostat was well tolerated; hyperkalemia was the most frequent treatment-emergent adverse event. BACKGROUND: Aldosterone increases BP and contributes to CKD progression. We evaluated the efficacy and safety of baxdrostat, an aldosterone synthase inhibitor, in participants with CKD and uncontrolled hypertension. METHODS: This was a phase 2, randomized, double-blind, placebo-controlled, multicenter trial (NCT05432167). Eligible participants were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had a mean seated office systolic BP ≥140 mm Hg (without diabetes) or ≥130 mm Hg (with type 2 diabetes) and a urine albumin-creatinine ratio of≥100 mg/g. Participants were randomized (1:1:1) to baxdrostat low-dose (0.5 mg up-titrated to 1 mg), high-dose (2 mg up-titrated to 4 mg), or placebo for 26 weeks. The primary end point was change from baseline in mean seated office systolic BP at week 26 in the baxdrostat pooled treatment group versus placebo. The secondary end point assessed this change by high-dose or low-dose baxdrostat; end points were tested sequentially in a hierarchal manner. RESULTS: Between April 29, 2022, and May 2, 2024, 195 participants were randomized. The mean (SD) age was 66 (11) years, 32% were women, 113 (58%) were White, and 80% had type 2 diabetes. The mean (SD) baseline systolic BP was 151.2 (13.1) mm Hg; the mean (SD) baseline eGFR was 44 (14) ml/min per 1.73 m, and the median (Q1, Q3) urine albumin-creatinine ratio was 714 (307, 1429) mg/g. The mean placebo-corrected change in systolic BP from baseline to week 26 for the baxdrostat pooled group was –8.1 (95% confidence interval, −13.4 to −2.8; = 0.003) mm Hg; low-dose −9.0 (−15.1 to −2.9; = 0.004) mm Hg; high-dose −7.2 (−13.2 to −1.2; = 0.02) mm Hg. Hyperkalemia was recorded as an adverse event in 41% (53/128) of participants in the baxdrostat pooled group and 5% (3/64) in the placebo group. CONCLUSIONS: Baxdrostat reduced systolic BP in participants with CKD and uncontrolled hypertension. Hyperkalemia was reported more commonly as an adverse event with baxdrostat versus placebo. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER:: NCT05432167.
16Baxdrostat: A First-in-Class Aldosterone Synthase Inhibitor for Resistant Hypertension.PubMed
Imma Capriello, Alexander Dömling
Hypertension remains the world's leading preventable cause of cardiovascular morbidity and mortality. Despite the availability of diverse antihypertensive drug classes, resistant hypertension continues to affect millions globally, leading to a disproportionate risk of stroke, heart failure, kidney disease, and premature death. Aldosterone excess is a central driver of treatment resistance, yet direct pharmacological suppression of aldosterone biosynthesis has long eluded clinical success due to the challenge of selectively targeting aldosterone synthase (CYP11B2) over its near-identical paralog 11β-hydroxylase (CYP11B1). Baxdrostat (CIN-107, RO6836191), an orally bioavailable, highly selective aldosterone synthase inhibitor (ASI), has now demonstrated robust blood pressure reduction in phase 3 clinical trials, marking a potential paradigm shift in the management of resistant hypertension. This Review summarizes the pathophysiology of aldosterone in hypertension, the molecular pharmacology of CYP11B2 inhibition, the discovery and development of Baxdrostat, and its clinical evaluation. We further discuss the broader implications of targeting steroidogenic cytochrome P450 enzymes and highlight future opportunities and challenges as Baxdrostat and related agents enter the cardiovascular pharmacopeia.
17New ways of mitigating aldosterone in cardiorenal disease.PubMed
Felix Götzinger, Michael Kunz, Lucas Lauder, et al.
Steroidal mineralocorticoid receptor antagonists (MRAs) bind to the mineralocorticoid receptor and antagonize the effects of aldosterone, which contributes to the development and progression of cardio- and renovascular diseases. Guidelines recommend steroidal MRAs in patients with heart failure with reduced or mildly reduced ejection fraction, as they reduce morbidity and mortality. In heart failure with preserved ejection fraction, MRAs have not convincingly shown to improve prognosis. Steroidal MRAs delay the progression of chronic kidney disease, reduce proteinuria and lower blood pressure in resistant hypertension but can induce hyperkalaemia. Due to their limited selectivity to the mineralocorticoid receptor, steroidal MRAs can cause significant adverse effects, i.e. libido loss, erectile dysfunction, gynaecomastia, and amenorrhoea, leading to low rates of persistance. Against this background, new avenues for developing non-steroidal, selective (ns)MRAs and aldosterone-synthase inhibitors have been taken. Finerenone has been shown to delay the progression of diabetic nephropathy and lower the incidence of heart failure hospitalizations in patients with chronic kidney disease and diabetes compared with placebo. Finerenone has therefore been recommended by the 2023 European Society of Cardiology Guidelines for the management of diabetes in patients with type 2 diabetes and chronic kidney disease. Further randomized controlled trials assessing the safety and effectiveness of finerenone in patients with heart failure are currently ongoing. Esaxerenone provides antihypertensive effects and has been approved for the treatment of hypertension in Japan. Baxdrostat and lorundostat, novel selective aldosterone-synthase inhibitors, are currently under investigation. In phase II trials, baxdrostat and lorundostat were safe and effective in lowering blood pressure in resistant hypertension. In this review, we summarize and critically discuss the evidence for new drugs mitigating aldosterone in heart failure, hypertension, and chronic kidney disease.
18Efficacy and Safety of Baxdrostat in Uncontrolled and Resistant Hypertension.PubMed
John M Flack, Michel Azizi, Jenifer M Brown, et al.
BACKGROUND: Aldosterone dysregulation plays an important pathogenic role in hard-to-control hypertension. In several studies, baxdrostat, an aldosterone synthase inhibitor, reduced the seated systolic blood pressure of patients with uncontrolled or resistant hypertension. METHODS: In this phase 3, multinational, double-blind, randomized, placebo-controlled trial, we recruited patients with a seated systolic blood pressure of between 140 mm Hg and less than 170 mm Hg despite the receipt of stable treatment with two antihypertensive medications (uncontrolled hypertension) or three or more such medications (resistant hypertension), including a diuretic. After a 2-week placebo run-in period, we randomly assigned patients with a seated systolic blood pressure of 135 mm Hg or more in a 1:1:1 ratio to receive baxdrostat at a dose of 1 mg, baxdrostat at a dose of 2 mg, or placebo once daily for 12 weeks. The primary end point was the change in seated systolic blood pressure from baseline to week 12. RESULTS: A total of 796 patients underwent randomization and 794 received 1-mg baxdrostat (264 patients), 2-mg baxdrostat (266 patients), or placebo (264 patients) in addition to background therapy. At 12 weeks, the change from baseline in the least-squares mean seated systolic blood pressure was -14.5 mm Hg (95% confidence interval [CI], -16.5 to -12.5) with 1-mg baxdrostat, -15.7 mm Hg (95% CI, -17.6 to -13.7) with 2-mg baxdrostat, and -5.8 mm Hg (95% CI, -7.9 to -3.8) with placebo. The estimated difference from placebo (placebo-corrected difference) was -8.7 mm Hg (95% CI, -11.5 to -5.8) with 1-mg baxdrostat and -9.8 mm Hg (95% CI, -12.6 to -7.0) with 2-mg baxdrostat (P<0.001 for both comparisons). A potassium level of more than 6.0 mmol per liter was reported in 6 patients (2.3%) with 1-mg baxdrostat, in 8 patients (3.0%) with 2-mg baxdrostat, and in 1 patient (0.4%) with placebo. CONCLUSIONS: Among patients with uncontrolled or resistant hypertension, the addition of baxdrostat to background therapy resulted in a significantly lower seated systolic blood pressure at 12 weeks than placebo. (Funded by AstraZeneca and others; BaxHTN ClinicalTrials.gov number, NCT06034743.).
19Second-Generation Aldosterone Synthase Inhibitors for Hypertension: A Bayesian Meta-Analysis of Randomized Trials.PubMed
Flavia Queiroga, Beatriz Araújo, André Rivera, et al.
BACKGROUND: Second-generation aldosterone-synthase inhibitors (ASIs) may offer a novel treatment for hypertension. OBJECTIVES: The objective of the study was to assess the efficacy and safety of ASIs in this clinical setting. METHODS: We searched major databases for randomized controlled trials (RCTs) assessing ASIs (baxdrostat, lorundrostat, and vicadrostat) in patients with hypertension. For efficacy outcomes, mean differences (MD) with 95% credible intervals (CrIs) were estimated using a Bayesian random-effects model. For adverse events, OR with 95% CrI were estimated using a Bayesian binomial-normal hierarchical model. The protocol was registered in Prospective Register of Systematic Reviews (CRD420251132306). RESULTS: Eight RCTs were included (n = 3,369; 2,430 [72%] randomized to ASI). ASI reduced systolic blood pressure (SBP) (MD: -6.7 mm Hg; CrI: -8.78, -4.59; τ 3.24), diastolic blood pressure (MD: -2.09 mm Hg; CrI: -3.68, -0.44; τ 1.44), and hypertensive urgency (OR: 0.36; CrI: 0.13, 0.90; τ 0.07) compared with placebo. There was no difference in all-cause mortality (OR: 0.45; CrI: 0.06, 3.20; τ 0.10) or adrenal insufficiency (OR: 0.5; CrI: 0.1, 3.1; τ 0.3) between groups. However, ASIs increased the odds of hyperkalemia (OR: 7.1; CrI: 3.56, 15.2; τ 0.23), hyponatremia (OR: 2.6; CrI: 1.25, 5.98; τ 0.1), and hypotension (OR: 3.28; CrI: 1.43, 8.16; τ 0.1). In subgroup analysis, the probability of achieving a clinically meaningful reduction in SBP (MD < -5 mm Hg) was 87.5% with baxdrostat and 94.3% with lorundrostat. CONCLUSIONS: Second-generation ASIs had a high likelihood of a clinically significant reduction in SBP compared with placebo. However, hyperkalemia, hyponatremia, and hypotension were more frequent with ASIs.
20Taming resistant hypertension: The promise of novel pharmacologic approaches and renal denervation.PubMed
Omar Azzam, Sayeh Heidari Nejad, Revathy Carnagarin, et al.
Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline-recommended therapy. While spironolactone is widely considered as the preferable fourth-line drug, its broad application is limited by its side effect profile, especially off-target steroid receptor-mediated effects and hyperkalaemia in at-risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter-based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension.