Key points Among patients with uncontrolled hypertension, does the aldosterone synthase inhibitor lorundrostat safely reduce blood pressure? Findings In this randomized clinical trial that included 200 participants , lorundrostat lowered blood pressure significantly more than placebo at doses of 50 mg and 100 mg once daily, and adverse events, including hyperkalemia, were rare. Meaning that inhibition of aldosterone synthase with lorundrostat showed potential to reduce blood pressure in patients with hypertension that was not adequately controlled despite background antihypertensive treatment. |
High blood pressure is the leading contributor to cardiovascular morbidity and mortality worldwide, and the majority of people in the United States with hypertension do not adequately control their blood pressure (BP). A higher global prevalence of hypertension has been paralleled by increasing rates of obesity . Excess aldosterone production contributes to uncontrolled BP in patients with obesity and other associated diseases, such as obstructive sleep apnea and metabolic syndrome.
Contemporary guidelines for the treatment of resistant hypertension recommend the use of mineralocorticoid receptor antagonists (MRAs) after treatment with a three-drug regimen: a thiazide-type diuretic, a dihydropyridine-type calcium channel blocker, and an inhibitor. of angiotensin-converting enzyme or an angiotensin receptor blocker.
However, adverse effects related to antiandrogenic and progestogenic effects are common barriers to broader use of MRAs, particularly the use of spironolactone. Furthermore, MRAs do not block the non-genomic effects of aldosterone, which can lead to increased sympathetic activation, negatively affect glucose homeostasis, and stimulate vascular contractility and stiffness.
Decreasing aldosterone production by inhibiting aldosterone synthase , rather than blocking the mineralocorticoid receptor, may prevent these adverse effects. Lorundrostat is a selective aldosterone synthase inhibitor that is currently under investigation. The MLS-101 (Lorundrostat) Safety and Efficacy in Patients with Uncontrolled Hypertension (Target-HTN) trial was designed to examine the safety and effectiveness of lorundrostat at 5 different doses in participants with uncontrolled hypertension, with a specific objective of blood pressure reduction among participants with obesity or suppressed renin.
Importance
Excessive aldosterone production contributes to hypertension in both classic hyperaldosteronism and obesity-associated hypertension. Therapies that reduce aldosterone synthesis can lower blood pressure.
Aim
To compare the safety and efficacy of lorundrostat, an aldosterone synthase inhibitor, with placebo, and to characterize dose-dependent safety and efficacy to inform dose selection in future trials.
Design, environment 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) was enrolled, with subsequent enrollment of 37 participants with PRA greater than 1.0. ng/mL/h.
Interventions
Participants were randomly assigned to placebo or 1 of 5 doses 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 randomly assigned in a 1:6 ratio to placebo or lorundrostat, 100 mg once daily.
Main results and measures
The primary endpoint was the change in automated office systolic blood pressure from baseline to week 8 of the study.
Results
Between July 2021 and June 2022, 200 participants were randomized and final follow-up was performed in September 2022. After 8 weeks of treatment in participants with suppressed plasma renin activity [PRA], changes in systolic blood pressure were observed in office −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.
The 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 = 0.01) for dose of 50 mg once daily and −7.8 mm Hg (90% CI, −14.1 to −1.5 mm Hg; P = 0.04) for 100 mg daily.
Among participants without suppressed plasma renin activity [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 the reduction in blood pressure among participants with suppressed plasma renin activity [PRA] who received the same dose.
Six participants had increases in serum potassium above 6.0 mmol/L that were corrected with dose reduction or drug discontinuation. There were no cases of cortisol insufficiency.
Figure : CDD indicates cumulative daily dose. A, Middle data show blood pressure changes for individual participants. Box plots demonstrate the median (thick horizontal line), mean (circle), IQR (top and bottom of box), and maximum and minimum changes in blood pressure (whiskers). The tan graph shows low pooled CDD changes (≤25 mg/d total). Blue graph shows elevated combined CDD changes (≥50 mg/d total). The orange graph shows changes in the placebo group. The graph on the far right shows the change in blood pressure during the trial for each group. B, Middle data show blood pressure changes for individual participants. Box plots demonstrate the median (thick horizontal line), mean (circle), IQR (top and bottom of box), and maximum and minimum changes in blood pressure (whiskers). The blue graph shows changes in the lorundrostat, 100 mg once daily group; the orange graph shows changes in the placebo group. The graph on the far right shows the change in blood pressure during the trial for each group.
Conclusions and relevance Lorundrostat at doses of 50 mg and 100 mg once daily decreased AOBP significantly more than placebo. Blood pressure reduction was particularly evident among participants with comorbid hypertension and obesity. Lorundrostat was well tolerated and the expected small increases in serum potassium and decreases in eGFR suggest a favorable safety profile, particularly with a dose of 50 mg once daily. The trial results support further study of lorundrostat as a treatment for uncontrolled hypertension. |
Comments
Findings from a clinical trial led by a Cleveland Clinic cardiologist showed that lorundrostat, a new type of blood pressure medication, safely lowered blood pressure in patients with uncontrolled hypertension.
The findings were presented at the American Heart Association’s annual Hypertension Scientific Sessions in Boston and simultaneously published in the Journal of the American Medical Association .
Lorundrostat was developed to address abnormally elevated aldosterone, a hormone released by the adrenal glands that regulates blood pressure by controlling sodium and potassium levels in the blood. Aldosterone synthase inhibitors are a new class of blood pressure-lowering medications that decrease the production of aldosterone. Medications currently available to patients block the aldosterone receptor , but aldosterone may still be circulating and having a negative impact on patients. Up to 25 percent of all people with hypertension have abnormal levels of aldosterone.
In the Target-HTN randomized phase 2 clinical trial, 200 patients received a placebo or one of five different doses of lorundrostat, ranging from 12.5 mg to 100 mg per day. The researchers found that patients who had taken the drug had lower blood pressure, particularly at higher doses. Those taking a daily dose of 50 mg of lorundrostat experienced a 10-point decrease in blood pressure compared to placebo. The amount of blood pressure reduction was even greater among people with obesity .
"We know that only one-third of people with high blood pressure in the United States have it under control, and we know that obesity is a major factor that increases blood pressure," said the study’s lead author, Luke Laffin, MD, co-director. from the center. for blood pressure disorders at the Heart Vascular & Thoracic Institute at the Cleveland Clinic . “New strategies and new safe and effective medications are needed to help this patient population. While more studies are needed on this drug, these results are encouraging, particularly among patients with obesity-related hypertension.”
"These findings are important because new classes of medications to lower blood pressure have not been introduced for many years," said the study’s senior author, Steven E. Nissen, MD, academic director of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic. "Blood pressure is difficult to control in some patients, especially those with obesity and diabetes, so new options will be valuable."
Additional trials are planned to further study this medication along with standard treatments.
Final message : Among people with uncontrolled hypertension, the use of lorundrostat was effective in reducing blood pressure compared to placebo, which will require further confirmatory studies.
The Target-HTN Randomized Clinical Trial. The study was funded by Mineralys Therapeutics, developer of lorundrostat. Trial Registration ClinicalTrials.gov Identifier: NCT05001945
