Saxena Manish, Laffin Luke, Borghi Claudio, Fernandez Fernandez Beatriz, Ghali Jalal K, Kopjar Branko, Polu Krishna, Roger Simon D, Slingsby B T, Strutz Frank, Vogt Liffert, Weir Matthew R, Rodman David
Barts Health NHS Trust and Queen Mary University, London, England.
Cleveland Clinic Foundation, Cleveland, Ohio.
JAMA. 2025 Jun 30. doi: 10.1001/jama.2025.9413.
Uncontrolled hypertension remains a global health concern and dysregulated aldosterone production is a central mechanism. Lorundrostat, a novel aldosterone synthase inhibitor that reduces aldosterone production, demonstrated efficacy in participants with uncontrolled hypertension, including those with treatment-resistant hypertension.
To evaluate the efficacy and safety of lorundrostat for lowering blood pressure (BP) when added to a prescribed regimen of 2 to 5 antihypertensive medications in adults with uncontrolled hypertension and treatment-resistant hypertension.
DESIGN, SETTING, AND PARTICIPANTS: In this phase 3, randomized clinical trial, adults with uncontrolled hypertension, including those with treatment-resistant hypertension, were enrolled between November 2023 and September 2024 at 159 clinic sites across 13 countries. The last date of follow-up was January 24, 2025.
Randomization ratio of 1:2:1 to 50 mg/d of lorundrostat for 6 weeks followed by 100 mg/d of lorundrostat for 6 weeks (n = 270) if they met prespecified criteria, 50 mg/d of lorundrostat for 12 weeks (n = 541), or daily placebo for 12 weeks (n = 272). The prespecified criteria included systolic BP of 130 mm Hg or greater, potassium level of 4.8 mmol/L or less, sodium level of 135 mmol/L or greater, an estimated glomerular filtration rate (eGFR) of greater than 45 mL/min/1.73 m2, and less than a 25% reduction in eGFR.
The primary outcome was change in automated office systolic BP at week 6 for participants randomized to 50 mg of lorundrostat vs placebo. Adverse events of special interest included dose reduction, interruption, or discontinuation due to events such as hyperkalemia, hyponatremia, and reduction in kidney function.
Of the 1083 participants, the mean age was 61.6 years (SD, 10.3 years), 508 (46.9%) were female, 311 (28.7%) were Black or African American, 733 (67.7%) were White, and 685 (63.3%) had a body mass index of 30 or greater (obesity). At randomization, 432 participants (39.9%) were taking 2 prescribed antihypertensive medications and 651 (60.1%) were taking 3 or more. For the pooled 50 mg of lorundrostat group (n = 808), the least-squares mean change in automated office systolic BP at week 6 was -16.9 mm Hg (95% CI, -19.0 to -14.9 mm Hg) vs -7.9 mm Hg (95% CI, -11.5 to -4.2 mm Hg) for the placebo group (least-squares mean difference, -9.1 mm Hg [95% CI, -13.3 to -4.9 mm Hg]; P < .001). Hyponatremia, hyperkalemia, and reduction in kidney function were reported more often with lorundrostat vs placebo. In the 50 mg of lorundrostat group with possible escalation to 100 mg, treatment discontinuation occurred in 1 participant (0.37%) due to hyperkalemia, in 1 (0.37%) due to hyponatremia, and in 0 due to reduction in kidney function. In the 50 mg of lorundrostat group, treatment discontinuation occurred in 2 participants (0.37%) due to hyperkalemia, in 2 (0.37%) due to hyponatremia, and in 3 (0.56%) due to reduction in kidney function. Treatment-emergent adverse events occurred in 49.9% of participants (538/1078) and were mostly mild or moderate in severity.
The efficacy and safety of lorundrostat, an aldosterone synthase inhibitor, was demonstrated for lowering BP in adults with uncontrolled hypertension, including those with treatment-resistant hypertension.
ClinicalTrials.gov Identifier: NCT06153693.
未控制的高血压仍然是一个全球健康问题，醛固酮生成失调是其核心机制。洛伦德司他是一种新型醛固酮合酶抑制剂，可减少醛固酮生成，在未控制的高血压患者（包括难治性高血压患者）中显示出疗效。
评估在未控制的高血压和难治性高血压成人患者中，洛伦德司他添加到2至5种抗高血压药物的规定治疗方案中时降低血压（BP）的疗效和安全性。
设计、设置和参与者：在这项3期随机临床试验中，2023年11月至2024年9月期间，在13个国家的159个临床地点招募了未控制的高血压成人患者，包括难治性高血压患者。最后一次随访日期为2025年1月24日。
随机分组比例为1:2:1，若符合预先设定的标准，50mg/d的洛伦德司他服用6周，随后100mg/d的洛伦德司他服用6周（n = 270）；50mg/d的洛伦德司他服用12周（n = 541）；或每日服用安慰剂12周（n = 272）。预先设定的标准包括收缩压130mmHg或更高、钾水平4.8mmol/L或更低、钠水平135mmol/L或更高、估计肾小球滤过率（eGFR）大于45mL/min/1.73m²，以及eGFR降低小于25%。
主要结局是随机分配至50mg洛伦德司他组与安慰剂组的参与者在第6周时自动诊室收缩压的变化。特别关注的不良事件包括因高钾血症、低钠血症和肾功能减退等事件导致的剂量减少、中断或停药。
1083名参与者中，平均年龄为61.6岁（标准差，10.3岁），508名（46.9%）为女性，311名（28.7%）为黑人或非裔美国人，733名（67.7%）为白人，685名（63.3%）体重指数为30或更高（肥胖）。随机分组时，432名参与者（39.9%）正在服用2种规定的抗高血压药物，651名（60.1%）正在服用3种或更多。对于合并的50mg洛伦德司他组（n = 808），第6周时自动诊室收缩压的最小二乘均值变化为-16.9mmHg（95%置信区间，-19.0至-14.9mmHg），而安慰剂组为-7.9mmHg（95%置信区间，-11.5至-4.2mmHg）（最小二乘均值差异，-9.1mmHg [95%置信区间，-13.3至-4.9mmHg]；P <.001）。与安慰剂相比，洛伦德司他组报告低钠血症、高钾血症和肾功能减退的情况更多。在可能升级至100mg的50mg洛伦德司他组中，1名参与者（0.37%）因高钾血症停药，1名（0.37%）因低钠血症停药，无因肾功能减退停药。在50mg洛伦德司他组中，2名参与者（0.37%）因高钾血症停药，2名（0.37%）因低钠血症停药，3名（0.56%）因肾功能减退停药。49.9%的参与者（538/1078）发生了治疗中出现的不良事件，严重程度大多为轻度或中度。
醛固酮合酶抑制剂洛伦德司他在未控制的高血压成人患者（包括难治性高血压患者）中降低血压的疗效和安全性得到了证实。
ClinicalTrials.gov标识符：NCT06153693。
