Lorundrostat Lowers Blood Pressure but Raises Hyperkalemia Risk in Uncontrolled Hypertension: Study Cautions
Brazil: A new systematic review and meta-analysis has evaluated the benefits and risks of lorundrostat, a novel selective aldosterone synthase inhibitor, in patients with uncontrolled hypertension, suggesting meaningful blood pressure reductions alongside a dose-related safety concern.
The study, published in the American Journal of Hypertension, was led by Vicente Morales Ribeiro from the Department of Internal Medicine, University of Southern Santa Catarina, Palhoça, Brazil, in collaboration with researchers from Hospital Israelita Albert Einstein, Goiânia, Brazil.
Uncontrolled hypertension remains a major public health challenge despite the availability of multiple antihypertensive drug classes. Excess aldosterone activity is known to contribute to resistant and difficult-to-control blood pressure. Lorundrostat targets this pathway by selectively inhibiting aldosterone synthesis, offering a potential alternative to traditional mineralocorticoid receptor antagonists. However, its overall efficacy and safety profile in this patient group has not been fully established, prompting the current analysis.
The investigators conducted a comprehensive search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov to identify randomized controlled trials comparing lorundrostat with placebo. Trials published up to July 2025 were eligible. Pooled analyses were performed using a random-effects model with restricted maximum likelihood estimation to account for between-study variability. In addition, Trial Sequential Analysis was applied to determine whether the available evidence was sufficient to draw firm conclusions regarding safety outcomes, particularly hyperkalemia.
The following were the key findings:
- Three randomized controlled trials involving 1,060 patients with uncontrolled hypertension were included in the analysis.
- Lorundrostat significantly lowered systolic blood pressure at a 50 mg dose, with a reduction of just over 9 mmHg.
- A higher dose of 100 mg resulted in an even greater systolic blood pressure reduction, exceeding 11 mmHg.
- Diastolic blood pressure showed a meaningful reduction at the 50 mg dose, supporting the drug’s antihypertensive efficacy.
- Treatment with lorundrostat was associated with an increased risk of hyperkalemia compared with placebo.
- The risk of hyperkalemia was higher at the 100 mg dose than at 50 mg, indicating a dose-dependent safety concern.
- The number needed to harm suggested that hyperkalemia occurred more frequently with increasing lorundrostat doses.
- Trial Sequential Analysis confirmed hyperkalemia at the 100 mg dose as a conclusive adverse safety signal.
- Evidence for other safety outcomes remained inconclusive due to limited data.
The authors conclude that lorundrostat shows promise as an effective blood pressure–lowering therapy for patients with uncontrolled hypertension, particularly given its targeted mechanism of action. At the same time, the dose-dependent risk of hyperkalemia highlights the need for careful patient selection and monitoring.
They emphasize that longer-term studies assessing cardiovascular outcomes, as well as head-to-head comparisons with established mineralocorticoid receptor antagonists, are essential before lorundrostat can be widely adopted in clinical practice.
Reference:
Ribeiro, V. M., Cavalcante, D. N., Celkevicius, H. E., Camacho, G. C., Neves, H. A., De Souza, K., Machado, R. H., Lopes, L. M., Donaldy, W., Bortolotto, L. A., & Schneider, J. C. Lorundrostat for Patients with Uncontrolled Hypertension: A Systematic Review with Meta-Analysis and Trial Sequential Analysis. American Journal of Hypertension. https://doi.org/10.1093/ajh/hpaf246
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