Highlight
– Lorundrostat, an aldosterone synthase inhibitor, produced greater reductions in 24‑hour average systolic blood pressure than placebo in people with uncontrolled, treatment‑resistant hypertension (placebo‑adjusted −7.9 mm Hg and −6.5 mm Hg at 12 weeks for two dosing strategies).
– Early BP lowering was measurable by week 4 (placebo‑adjusted −5.3 mm Hg for combined lorundrostat groups).
– Clinically significant hyperkalemia (serum K+ >6.0 mmol/L) occurred in 5–7% of lorundrostat‑treated participants and in none of the placebo group, highlighting a safety signal requiring monitoring.
Background and clinical need
Resistant and uncontrolled hypertension remains a major contributor to cardiovascular morbidity and mortality despite the availability of multiple effective drug classes. Aldosterone excess or inappropriate aldosterone activation contributes to sodium retention, volume expansion, and target‑organ damage, and is implicated in a subset of patients with difficult‑to‑control blood pressure. Mineralocorticoid receptor antagonists (MRAs) such as spironolactone are effective in many patients with resistant hypertension, but their use can be limited by adverse effects and hyperkalemia. Aldosterone synthase inhibitors (ASIs) act upstream by reducing aldosterone synthesis and therefore represent an alternative strategy to suppress aldosterone activity. However, rigorous randomized data on ASIs in patients with treatment‑resistant hypertension have been limited until recently.
Study design
The Advance‑HTN trial (NCT05769608) is a multicenter, double‑blind, randomized, placebo‑controlled study evaluating lorundrostat in adults with uncontrolled hypertension despite two to five antihypertensive drugs. After a 3‑week period on a standardized antihypertensive regimen, participants whose mean 24‑hour ambulatory systolic blood pressure (ABP) was ≥130 mm Hg were randomized 1:1:1 to receive placebo, lorundrostat 50 mg daily (stable‑dose group), or lorundrostat starting at 50 mg daily with an increase to 100 mg daily at week 4 if clinic systolic BP remained ≥130 mm Hg (dose‑adjustment group).
The primary outcome was change from baseline to week 12 in 24‑hour average systolic ABP, expressed as least‑squares mean difference versus placebo. A key secondary outcome was the change in 24‑hour average systolic ABP from baseline to week 4 in the combined lorundrostat arms. Safety evaluation included laboratory monitoring (notably serum potassium) and adverse event reporting.
Population
Among 285 randomized participants, 94 received lorundrostat 50 mg (stable), 96 were in the dose‑adjustment arm, and 95 received placebo. Mean age was 60 years and 53% of participants were Black, reflecting appropriate inclusion of a group often disproportionately affected by resistant hypertension. All participants had persistent hypertension on multiple antihypertensive agents at baseline.
Key results
Primary endpoint (change in 24‑hour systolic ABP at 12 weeks):
- Stable‑dose lorundrostat (50 mg): mean change −15.4 mm Hg; placebo‑adjusted difference −7.9 mm Hg (97.5% CI, −13.3 to −2.6).
- Dose‑adjustment group (50 → 100 mg as indicated): mean change −13.9 mm Hg; placebo‑adjusted difference −6.5 mm Hg (97.5% CI, −11.8 to −1.2).
- Placebo: mean change −7.4 mm Hg.
Key secondary endpoint (combined lorundrostat groups at 4 weeks):
- Placebo‑adjusted change in 24‑hour systolic ABP −5.3 mm Hg (95% CI, −8.4 to −2.3).
Interpretation of magnitude
A placebo‑adjusted reduction of approximately 6–8 mm Hg in 24‑hour systolic ABP is clinically meaningful. Epidemiological and trial data indicate that even modest reductions in systolic blood pressure translate into reductions in stroke and myocardial infarction risk over time. Compared with effects reported for spironolactone in prior resistant‑hypertension trials (which often produce larger average reductions in office BP), lorundrostat’s ambulatory BP changes are promising, particularly as ambulatory BP is a stronger predictor of outcomes and less affected by white‑coat effects.
Safety and tolerability
The most notable safety signal was hyperkalemia. Potassium concentrations >6.0 mmol/L occurred in 5 participants (5%) in the stable‑dose group and 7 participants (7%) in the dose‑adjustment group; no such events occurred in the placebo group. The report did not indicate fatal events attributable to hyperkalemia in the primary summary, but the frequency of marked hyperkalemia is clinically important and would necessitate careful monitoring in practice. Other adverse events were not detailed in the summary provided, but standard concerns for aldosterone suppression — e.g., effects on renal function or adrenal steroid profiles — merit attention in full data tables.
Dose strategy observations
Interestingly, the stable 50 mg dose produced numerically greater placebo‑adjusted BP reductions at 12 weeks than the strategy of escalating to 100 mg when indicated. Possible explanations include the timing of dose escalation (only after 4 weeks), individual variability, or small sample differences; further analysis of dose–response and exposure–effect relationships is needed.
Strengths of the trial
- Randomized, double‑blind, placebo‑controlled design minimizes bias.
- Use of 24‑hour ambulatory blood pressure as the primary endpoint provides a robust and clinically relevant measure less susceptible to office measurement variability.
- Inclusion of a substantial proportion of Black participants improves generalizability to a higher‑risk population often underrepresented in trials.
Limitations
- Duration was relatively short (12 weeks) and does not inform long‑term efficacy, durability, or cardiovascular event reduction.
- Hyperkalemia events were concentrated in active treatment arms; longer follow‑up is required to understand the frequency, severity, reversibility, and clinical consequences of hyperkalemia and any renal function changes.
- Background antihypertensive regimens were standardized prior to randomization, but heterogeneity in prior drug exposure and adherence could influence real‑world responses.
- The trial primarily assessed surrogate physiologic endpoints (ambulatory BP) rather than clinical outcomes; outcome trials will be needed to establish net clinical benefit.
Clinical implications
Lorundrostat appears to be an active agent for lowering ambulatory systolic blood pressure in patients with uncontrolled, treatment‑resistant hypertension. Its effect size is clinically relevant and measurable early (by 4 weeks). However, the observed rates of marked hyperkalemia underline that this agent will require careful patient selection and laboratory monitoring if used in practice—particularly in patients with reduced kidney function, baseline hyperkalemia, or concomitant RAAS blockade that predisposes to elevated potassium.
Possible clinical roles include use as an alternative or adjunct for patients intolerant of MRAs or with persistent aldosterone‑driven hypertension despite other agents. However, given the safety signals and the lack of long‑term outcomes data, lorundrostat (or other ASIs) should be positioned as an investigational option pending more extensive efficacy and safety characterization.
Research implications and next steps
Key questions for future research include:
- Long‑term efficacy and durability of BP reduction and effects on cardiovascular outcomes (major adverse cardiovascular events, heart failure, progression of chronic kidney disease).
- Detailed characterization of hyperkalemia risk: timing, predictors (e.g., baseline eGFR, concomitant medications), and effective mitigation strategies (dose adjustment, potassium binders, monitoring intervals).
- Head‑to‑head comparisons with MRAs (spironolactone/eplerenone) to define relative efficacy and safety and to identify patient subgroups most likely to benefit.
- Mechanistic studies evaluating aldosterone suppression, adrenal steroidogenesis, and off‑target effects.
Expert commentary
Clinicians familiar with resistant hypertension will welcome a new mechanism of action aimed at aldosterone synthesis. The use of ambulatory blood pressure strengthening internal validity is important. However, the safety profile—especially hyperkalemia—needs careful adjudication. In practice, if lorundrostat becomes available, baseline and frequent early potassium and creatinine monitoring (for example, within 1–2 weeks after initiation and after dose changes) would be prudent, along with cautious use in patients with eGFR <45 mL/min/1.73 m2 and avoidance or dose reduction when combined with other agents that increase potassium.
Conclusion
The Advance‑HTN randomized trial demonstrates that lorundrostat reduces 24‑hour systolic ambulatory blood pressure modestly but significantly versus placebo in adults with uncontrolled, treatment‑resistant hypertension. The drug shows early efficacy, but the occurrence of clinically significant hyperkalemia in 5–7% of treated participants is a substantial safety signal that will influence clinical adoption. Longer trials with larger populations, head‑to‑head comparisons with MRAs, and outcome studies are required before lorundrostat can be integrated routinely into practice.
Funding and registration
Funded by Mineralys Therapeutics. ClinicalTrials.gov number: NCT05769608.
References
1. Laffin LJ, Kopjar B, Melgaard C, et al; Advance‑HTN Investigators. Lorundrostat Efficacy and Safety in Patients with Uncontrolled Hypertension. N Engl J Med. 2025 May 8;392(18):1813‑1823. doi:10.1056/NEJMoa2501440 IF: 78.5 Q1 .
2. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug‑resistant hypertension (PATHWAY‑2): a randomised, double‑blind, crossover trial. Lancet. 2015;386(10008):2059‑2068.