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期刊来源：JAMA

文献发表时间：2023-09-10

原文链接：https://jamanetwork.com/journals/jama/article-abstract/2809625

关键点内容如下：

问题

在未控制的高血压患者中，醛固酮合酶抑制剂lorundrostat是否能安全地降低血压？

调查结果

在这项包括200名参与者的随机临床试验中，每天一次服用50毫克和100毫克的lorundrostat比安慰剂更能显著降低血压，包括高钾血症在内的不良事件并不常见。

意义

尽管进行了背景抗高血压治疗，但高血压患者的血压仍未得到充分控制，因此，用lorundrostat抑制醛固酮合酶显示出降低高血压患者血压的潜力。

摘要内容如下：

重要性

在典型的醛固酮增多症和肥胖相关的高血压中，醛固酮生成过多都会导致高血压。减少醛固酮合成的治疗可以降低血压。

目的

比较Lorundrostat（一种醛固酮合酶抑制剂）与安慰剂的安全性和有效性，并描述剂量依赖性安全性和有效性，以便为未来试验的剂量选择提供信息。

研究设计和参与者

在服用2种或2种以上抗高血压药物的未控制高血压成人中进行的随机、安慰剂对照、剂量范围试验最初的队列包括163名血浆肾素抑制（血浆肾素活性[PRA]≤1.0 ng/mL/H）和血浆醛固酮升高（≥1.0 ng/DL）的参与者，随后纳入了37名PRA大于1.0ng/mL/H的参与者。

干预

在最初的队列中，参与者随机接受安慰剂或5种剂量的lorundrostat中的一种（12.5 mg、50 mg或100 mg，每日一次或12.5 mg或25 mg，每日两次）。在第二个队列中，参与者以1:6的比例随机分配至安慰剂组或氯仑司他组，每日一次，每次100 mg。

主要结果和措施

主要终点是从基线到研究第8周自动诊室收缩压的变化。

次要结果

在2021年7月至2022年6月期间，200名参与者被随机分组，并于2022年9月进行最终随访。在PRA受抑制的参与者接受8周治疗后，每天一次服用100 mg、50 mg和12.5 mg的lorundrostat和安慰剂，分别观察到办公室收缩压的变化为−14.1、−13.2、−6.9和−4.1 mm Hg。在接受每日两次25 mg和12.5 mg剂量的lorundrostat的个体中，观察到的收缩压降低分别为-10.1和-13.8 mm Hg。安慰剂和治疗组之间收缩压的最小二乘均数差异为-9.6 mm Hg，（90%CI为-15.8至-3.4 mm Hg；P=0.01）对于50-mg每日一次剂量和-7.8 mm Hg（90%CI，-14.1至-1.5 mm Hg；每日100毫克，P=0.04）。在没有受抑制PRA的参与者中，每天一次服用100 mg lorundrostat使收缩压降低11.4 mm Hg（SD，2.5 mm Hg），这与接受相同剂量的受抑制PRA的参与者的血压降低相似。6名参与者的血清钾升高超过6.0 mmol/L，通过减少剂量或停药进行纠正。没有发生皮质醇不足的情况。

结论和相关性

在未控制的高血压患者中，与安慰剂相比，使用Lorundrostat可有效降低血压，这需要进一步的验证性研究。

英文原文如下：

Key Points

Question  Among patients with uncontrolled hypertension, does the aldosterone synthase inhibitor lorundrostat safely lower blood pressure?

Findings  In this randomized clinical trial that included 200 participants, lorundrostat decreased blood pressure significantly more than placebo with 50-mg and 100-mg once-daily doses, and adverse events, including hyperkalemia, were uncommon.

Meaning  Aldosterone synthase inhibition with lorundrostat showed potential for blood pressure lowering in patients with hypertension that was inadequately controlled despite background antihypertensive treatment.

Abstract 

Importance  Excess aldosterone production contributes to hypertension in both classical hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis may lower blood pressure.

Objective  To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and characterize dose-dependent safety and efficacy to inform dose selection in future trials.

Design, Setting, and Participants  Randomized, placebo-controlled, dose-ranging trial among adults with uncontrolled hypertension taking 2 or more antihypertensive medications. An initial cohort of 163 participants with suppressed plasma renin (plasma renin activity [PRA] ≤1.0 ng/mL/h) and elevated plasma aldosterone (≥1.0 ng/dL) were enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0 ng/mL/h.

Interventions  Participants were randomized to placebo or 1 of 5 dosages of lorundrostat in the initial cohort (12.5 mg, 50 mg, or 100 mg once daily or 12.5 mg or 25 mg twice daily). In the second cohort, participants were randomized in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.

Main Outcomes and Measures  The primary end point was change in automated office systolic blood pressure from baseline to study week 8.

Results  Between July 2021 and June 2022, 200 participants were randomized, with final follow-up in September 2022. Following 8 weeks of treatment in participants with suppressed PRA, changes in office systolic blood pressure of −14.1, −13.2, −6.9, and −4.1 mm Hg were observed with 100 mg, 50 mg, and 12.5 mg once daily of lorundrostat and placebo, respectively. Observed reductions in systolic blood pressure in individuals receiving twice-daily doses of 25 mg and 12.5 mg of lorundrostat were −10.1 and −13.8 mm Hg, respectively. The least-squares mean difference between placebo and treatment in systolic blood pressure was −9.6 mm Hg (90% CI, −15.8 to −3.4 mm Hg; P = .01) for the 50-mg once-daily dose and −7.8 mm Hg (90% CI, −14.1 to −1.5 mm Hg; P = .04) for 100 mg daily. Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 mm Hg (SD, 2.5 mm Hg), which was similar to blood pressure reduction among participants with suppressed PRA receiving the same dose. Six participants had increases in serum potassium above 6.0 mmol/L that corrected with dose reduction or drug discontinuation. No instances of cortisol insufficiency occurred.

Conclusions and Relevance  Among individuals with uncontrolled hypertension, use of lorundrostat was effective at lowering blood pressure compared with placebo, which will require further confirmatory studies.

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