New Hope for Resistant Hypertension: Lorundrostat’s Effectiveness in the ADVANCE-HTN Trial

ADVANCE-HTN Trial Demonstrates Benefit of Lorundrostat in Resistant Hypertension Treatment

Resistant hypertension, a condition where blood pressure remains high despite the use of multiple antihypertensive medications, has long posed a significant challenge in clinical practice. The recent findings from the ADVANCE-HTN trial, presented at the 2025 American College of Cardiology (ACC) Scientific Session, bring hope to patients suffering from this complex and persistent condition. The trial investigated the use of lorundrostat, an investigational aldosterone synthase inhibitor, as an add-on therapy in patients with uncontrolled hypertension, revealing promising results.

The ADVANCE-HTN Trial: A Landmark Study in Hypertension Treatment

The ADVANCE-HTN trial is a pivotal phase 2b study designed to evaluate the efficacy and safety of lorundrostat as an adjunctive treatment for patients with resistant hypertension. This multicenter trial enrolled 285 patients across the United States, all of whom had blood pressure that remained inadequately controlled despite being on two to five different antihypertensive medications. The aim was to assess whether adding lorundrostat could improve blood pressure control in this difficult-to-treat population.

Participants in the trial were transitioned from their current antihypertensive regimen to a standardized background treatment, which included indapamide, olmesartan, and amlodipine. They were then randomized to receive either lorundrostat 50 mg daily, lorundrostat with a dose escalation to 100 mg daily, or a placebo. The study assessed the effects of lorundrostat on 24-hour ambulatory blood pressure, which is a more accurate and reflective measure of blood pressure control compared to traditional office measurements.

Promising Results: Significant Blood Pressure Reduction

The results of the trial were encouraging. After 12 weeks, patients in the lorundrostat 50 mg group experienced a placebo-adjusted reduction of 7.9 mm Hg in their 24-hour average ambulatory blood pressure. In the dose-escalation group, the reduction was slightly lower at 6.5 mm Hg, suggesting that increasing the dose did not result in a greater improvement in blood pressure control. These findings are particularly significant because they demonstrate that lorundrostat, when added to a standard antihypertensive regimen, can help lower blood pressure in patients who have not responded adequately to multiple other medications.

Dr. Luke Laffin, a cardiologist at the Cleveland Clinic and the lead investigator of the study, emphasized that lorundrostat was generally well tolerated by patients. The side effect profile was consistent with other drugs that inhibit aldosterone synthesis, which is the mechanism of action for lorundrostat. However, some participants did experience increases in potassium levels, as well as a decrease in their estimated glomerular filtration rate (eGFR), indicating potential effects on renal function. Importantly, the dose-escalation group experienced a higher incidence of adverse effects than the 50 mg group, but this did not translate into greater efficacy in lowering blood pressure.

Lorundrostat's Mechanism: A New Approach to Blood Pressure Control

Lorundrostat works by inhibiting CYP11B2, the enzyme responsible for aldosterone production. Aldosterone is a hormone that plays a central role in regulating blood pressure by increasing sodium retention and promoting water retention in the kidneys. Elevated aldosterone levels are often seen in patients with resistant hypertension and can contribute to the persistence of high blood pressure. By reducing aldosterone synthesis, lorundrostat helps to mitigate these effects, offering a novel approach for treating patients whose hypertension is not controlled by conventional medications.

In a previous phase 3 study, Launch-HTN, patients receiving lorundrostat 50 mg daily in addition to their existing antihypertensive therapy experienced a placebo-adjusted reduction of 9.1 mm Hg in office-measured blood pressure after just six weeks. The results from the ADVANCE-HTN trial add to this evidence, showing that lorundrostat can have a significant impact on blood pressure control in patients with resistant hypertension.

An Exciting Development for Clinicians and Patients

Dr. Gina Lundberg, a cardiologist from Emory University in Atlanta, Georgia, who commented on the study, highlighted the importance of the trial's design. The use of 24-hour ambulatory blood pressure measurement in the study provides more realistic and actionable data than traditional office-based blood pressure readings. This method allows for a better understanding of how well blood pressure is controlled throughout the day and night, offering insights that are more reflective of real-world blood pressure management.

The diversity of the trial population is another key strength. With 40% of participants being women and 53% being Black, the study addressed a broad spectrum of patients who are often underrepresented in clinical trials. This inclusivity ensures that the findings are more applicable to the diverse patient populations seen in clinical practice.

While side effects such as increased potassium levels and a decrease in eGFR will require ongoing monitoring, Dr. Lundberg noted that the results are exciting. "It's great to have one more option in our toolkit to treat resistant hypertension patients," she said. For clinicians, this trial provides valuable evidence for the use of lorundrostat as an adjunctive therapy, giving them a new weapon in the fight against resistant hypertension.

Conclusion: Lorundrostat as a Potential Game-Changer in Hypertension Treatment

The ADVANCE-HTN trial has provided compelling evidence that lorundrostat, an aldosterone synthase inhibitor, can significantly lower blood pressure in patients with resistant hypertension when added to standard antihypertensive therapy. The results of the trial are promising, suggesting that lorundrostat could become an important tool in managing this challenging condition. However, as with any new treatment, careful monitoring of side effects, particularly those related to potassium and renal function, will be essential.

For clinicians managing patients with resistant hypertension, lorundrostat represents a potential game-changer. Its ability to lower blood pressure effectively, combined with a relatively well-tolerated side effect profile, offers a much-needed option for patients whose hypertension has remained difficult to control despite multiple medications. The ongoing advancements in the field of hypertension treatment, including the introduction of drugs like lorundrostat, provide hope for better management and improved outcomes for patients with this complex condition.