Physicians' Academy for Cardiovascular Education

Selective aldosterone synthase inhibitor effective in uncontrolled hypertension

Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial

Literature - Laffin LJ, Rodman D, Luther JM, et al. - JAMA. 2023 Sep 26;330(12):1140-1150. doi: 10.1001/jama.2023.16029

Introduction and methods


Although contemporary guidance recommend MRAs as part of the treatment regimen for resistant hypertension [1], hormonal adverse effects hinder their wider use. Moreover, MRAs do not block the nongenomic effects of aldosterone, which may lead to increased sympathetic nervous system activation and stimulate vascular contractility and stiffness [2,3]. Interestingly, aldosterone production can also be reduced by inhibition of aldosterone synthase, thereby potentially avoiding these adverse effects.

Aim of the study

The authors investigated the safety and efficacy of different doses of lorundrostat, a selective inhibitor of aldosterone synthase, compared with placebo in patients with uncontrolled hypertension, with a specific focus on blood pressure (BP) reduction among participants with obesity or suppressed renin.


The Target-HTN (Trial on the Safety and Efficacy of MLS-101 (Lorundrostat) in Patients With Uncontrolled Hypertension) trial was a multicenter, prospective, double-blind, placebo-controlled, dose-ranging, phase 2 RCT conducted in the USA in which 200 adults with automated office systolic BP (SBP) ≥130 mmHg while taking ≥2 antihypertensive medications at maximally tolerated doses were enrolled. Key exclusion criteria included orthostatic hypotension, T1D, and concomitant use of an MRA or epithelial sodium channel inhibitor.

Cohort 1 comprised 163 participants with plasma renin activity (PRA) ≤1.0 ng/mL per hour and plasma aldosterone ≥1.0 ng/dL, who were randomized in a 1:1:1:1:1:1 ratio to lorundrostat (12.5 mg once daily, 50 mg once daily, 100 mg once daily, 12.5 mg twice daily, or 25 mg twice daily) or placebo for 8 weeks. In cohort 2, 37 participants with PRA >1.0 ng/mL per hour were randomized in a 6:1 ratio to lorundrostat 100 mg once daily or placebo for 8 weeks.

At baseline and prior to the 8-week visit, 24-hour ambulatory BP monitoring was performed.


The primary endpoint was change in automated office SBP from baseline to 8 weeks. Secondary efficacy endpoints included the change in automated office diastolic BP, the change in 24-hour ambulatory BP, and the proportion of participants achieving automated office BP <130/80 mmHg at 7 or 8 weeks.

Additional safety and pharmacodynamic biomarker endpoints included changes in PRA, serum aldosterone, cortisol, and potassium, and eGFR. Prespecified adverse events of special interest were incidence of hyperkalemia with dose modification, hypotension with symptoms, and adrenocortical insufficiency.

All cohort 2 analyses were exploratory in nature.

Main results

Primary endpoint

Secondary endpoints

Pharmacodynamic biomarker endpoints

Safety endpoints


Treatment with lorundrostat 50 or 100 mg once daily reduced automated office SBP compared with placebo in patients with uncontrolled hypertension, particularly in those with concomitant obesity. The authors attribute the ineffectiveness of the lower doses of lorundrostat to its relatively short half-life. Overall, the selective aldosterone synthase inhibitor was well tolerated and did not lead to adrenocortical insufficiency.


Show references

Find this article online at JAMA.

Share this page with your colleagues and friends: