Lorundrostat effective for lowering BP among patients with uncontrolled hypertension: JAMA

The randomized clinical trial of 200 participants showed that lorundrostat reduced BP significantly more than placebo with 50-mg and 100-mg once-daily doses. Adverse events, including hyperkalemia, were uncommon. The findings were published online in the Journal of the American Medical Association (JAMA) on September 10, 2023.

Hypertension is the leading cause of cardiovascular mortality and morbidity worldwide, and most individuals with hypertension have inadequately controlled blood pressure. An increased global hypertension prevalence has paralleled increasing obesity rates. In patients with obesity and other associated diseases, such as metabolic syndrome and obstructive sleep apnea, excess aldosterone production contributes to uncontrolled BP.

Therapies that reduce aldosterone synthesis may lower BP. Therefore, Luke J. Laffin, Cleveland Clinic Foundation, Cleveland, Ohio, and colleagues aimed to compare the safety and efficacy of an aldosterone synthase inhibitor lorundrostat with a placebo. They also characterized dose-dependent efficacy and safety to inform dose selection in future trials.

The study included adults with uncontrolled hypertension taking 2 or more antihypertensive medications. The researchers enrolled an initial cohort of 163 participants with suppressed plasma renin and elevated plasma aldosterone, and then they subsequently enrolled 37 participants with PRA greater than 1.0 ng/mL/h.

Participants were randomized to placebo or 1 of 5 lorundrostat dosages in the e 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 ratio of 1:6 to placebo or lorundrostat, 100 mg once daily.

The study's primary endpoint was determined as the change in automated office systolic BP from baseline to study week 8.

The study led to the following findings:

• 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 for the 50-mg once-daily dose and −7.8 mm Hg for 100 mg daily.
• Among participants without suppressed PRA, 100 mg once daily of lorundrostat decreased systolic blood pressure by 11.4 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 were corrected with dose reduction or drug discontinuation.
• No instances of cortisol insufficiency occurred.

"The use of lorundrostat was effective at BP lowering compared with placebo in patients with uncontrolled hypertension, which will require further confirmation," the researchers concluded.

Reference:

Laffin LJ, Rodman D, Luther JM, et al. Aldosterone Synthase Inhibition With Lorundrostat for Uncontrolled Hypertension: The Target-HTN Randomized Clinical Trial. JAMA. Published online September 10, 2023. doi:10.1001/jama.2023.16029