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NEJM 2025 May 8;392(18):1813-1823.doi: 10.1056/NEJMoa2501440. Epub 2025 Apr 23
Lorundrostat Efficacy and Safety in Patients with Uncontrolled Hypertension
L.J. Laffin, B. Kopjar, C. Melgaard, K. Wolski, J. Ibbitson, S. Bhikam, M.R. Weir, E.O. Ofili, R. Mehra, J.M. Luther, D.L. Cohen, A. Sarraju, M.J. Wilkinson, J.M. Flack, D. Rodman, and S.E. Nissen, for the Advance-HTN Investigators*
PMID: 40267417
Introduction
Uncontrolled hypertension is a major contributor to cardiovascular and renal adverse events worldwide. Patients with elevated blood pressure, either in-office or at-home (so-called masked uncontrolled hypertension or MUCH, equivalent to ‘white-coat normotension’), face an even higher risk of cardiovascular events and mortality compared to those with controlled hypertension (Pierdomenico et al, Hypertension 2018). Even within the subset of patients with true uncontrolled hypertension (definitions in the figure below), risk of cardio-vascular, cerebrovascular, and renal adverse events differs noticeably, as seen from one of the largest database studies of resistant hypertension (Sim et al, KI, 2015). Both primary and secondary prevention in this group of patients clearly improve outcomes (Zhou et al, Sci Rep 2018, Sim et al, Kidney Int 2015). Coupled with the fact that hypertension affects more than 1 billion people worldwide, clinicians face the entity of resistant hypertension more often today (Buso et al, Eur Cardiol 2024), with most considering this as one of the toughest challenges encountered in day-to-day practice (NephMadness 2025).
Box 1 from Fay and Cohen AJKD 2021
So why do so many patients still miss their BP targets? To get to the heart of this problem, let’s recount our clinic encounters and spell out the rough algorithm. We rule out ‘pseudohypertension’, an essential everyday exercise, that may account for some of this supposedly uncontrolled hypertension. Accurate BP measurement (AOBP style used in SPRINT, ACCORD) matters, and so does checking for medication adherence. Possibly a third of patients might not take their prescribed meds (Bourque et al, Am J HT 2023). A multi-factorial issue related to cost, pill burden, side-effects, behavioral traits, ignorance, education, poor social support, and addressing medication non-compliance may call for multi-disciplinary teams to step in. Next, we track down the contributors (salt intake, obesity, smoking, alcohol intake, stress, and lifestyle factors) and modify them, addressing another significant proportion of uncontrolled hypertension.
These two steps lead us to a tedious list of ‘secondary causes’ to investigate- sleep disorders and OSA, endocrine disease, renal parenchymal or vascular involvement. Drugs, substances, and other ‘miscellaneous’ entities may be sabotaging BP control sneakily, and need to be sought earnestly (Fay and Cohen, AJKD 2021; Buso et al, Eur Cardiol 2024; Cluett and William, AJKD 2024). Thereafter, the next major consideration in uncontrolled hypertension (and now we know, in all hypertension) is the pivotal role of aldosterone dysregulation and breakthrough (NephJC 2025), which sustains and dials up the pathology of sodium and water retention, vascular inflammation, and vascular and cardiac remodeling. Nephrologists and hypertensive specialists are in urgent need of reliable, novel methods to treat patients with resistant hypertension.
When BP stays elevated despite a triple regimen, what’s next? Although there are many and varied choices for a fourth medication, mineralocorticoid receptor antagonists (MRAs), like spironolactone, are a common choice for patients with cardiovascular and CKD risk factors. Landmark studies like ASPIRANT and PATHWAY-2 excluded patients with eGFR <40 ml/min/m2, making it tricky to generalize findings on our patients with advanced CKD. Its magical effect was pointed out both on NephJC’s spironolactone primer and 2023 Nephmadness. Maybe the real love-hate story: spironolactone is good enough, until potassium climbs, eGFR dips, or some other side effect appears, and limits its use. As Swap reminded us last year, “spironolactone remained the neglected step child”.
Figure 22, from ESC Hypertension Guidelines, 2024
As spotlighted in NephJC 2023, meet the "-stats", the aldosterone synthase inhibitors (ASI). These emerging oral therapies, unlike MRAs, ASIs, directly inhibit aldosterone synthase. This means no gynecomastia, potentially less hyperkalemia, and no direct effect on cortisol.
Figure 1. Inhibition of ASIs, from Ando H, Hypertens Res, 2023
Previously, NephJC discussed that vicadrostat (BI 690517), when combined with flozins, showed promising albuminuria reduction (Tuttle et al, Lancet 2024, NephJC summary). Baxdrostat is another ASI in development for hypertension and CKD (e.g. BrigHTN trial, Freeman et al, NEJM 2022). Lorundrostat, like these second generation ASIs, is highly selective for CYP11B2, reducing the risk of off-target cortisol suppression and possibly improving the side-effect profile. In fact, it made headlines in the Target-HTN RCT, JAMA 2023 where it significantly reduced office BP in patients with uncontrolled hypertension with some intriguing signal in people with higher BMI, and established the dose of 50 mg daily.
Now, the Advance-HTN trial is taking the spotlight, evaluating lorundrostat’s efficacy and safety in patients with uncontrolled hypertension on ambulatory BP (ABPM) in a larger set of patients.
The Study
Methods
Study design: Advanced-HTN was a phase 2b, multi-center, randomized, double-blinded, placebo-controlled trial conducted in 103 sites in the United States.
Inclusion criteria: Adults over 18 years, with resistant HTN, defined as SBP 140-180 mmHg or DBP 90-110 mmHg on 2-5 stable antihypertensives.
Key exclusion criteria: eGFR <45, K > 5 mmol/L, hyponatremia (Na < 135 mmol/L), recent cardiovascular events (last 6 months), uncontrolled diabetes (HbA1c> 9%), or cortisol abnormalities.
Run-in and randomization: All participants switched to a standardized regimen (olmesartan + indapamide/ HCTZ ± amlodipine) during a single-blind period for 3 weeks. The randomization (1:1:1) was placebo vs lorundrostat 50 mg daily vs lorundrostat increased dose 100 mg (if BP ≥ 130 mmHg at week 4, and normal electrolytes/ eGFR).
Figure S1. Study design, from Laffin et al, NEJM, 2025
The primary endpoint was represented by the change in 24-hour ABPM systolic blood pressure (baseline to week 12).
Key secondary endpoints were represented by week 4 ABPM SBP change (pooled lorundrostat groups) and the proportion with ABPM SBP <125 mmHg.
Statistical methods
The study employed a prespecified, covariate-adjusted analysis to evaluate lorundrostat’s efficacy. The primary end-point was analyzed using an ANCOVA model with treatment group, number of baseline antihypertensives (2 vs 3), interaction term, and baseline ABPM SBP as covariates. The Kenward-Roger adjustment accounted for small-sample bias. To control multiplicity, each lorundrostat dose group was tested at a stricter two-sided α=0.025, preserving an overall family-wise error rate of 0.05. (fig S2)
For missing data, the trial implemented a hierarchical imputation strategy. Discontinuations due to adverse events (non-random missingness, were handled via treatment policy imputation, leveraging observed data from participants who discontinued treatment but completed follow-up (“retrieved dropouts”). If this approach failed, a jump-to-reference (J2R) method was used, assuming dropouts reverted to placebo-like responses. The single death was imputed using the worst 5% of outcomes across all groups. The remaining missing data were treated as missing at random and imputed between treatment arms.
Secondary endpoints were analyzed via ANCOVA and logistic regression. Subgroup analyses (obesity, number of baseline medications) were tested for treatment-effect heterogeneity. The trial was powered at 90% to detect a 7 mmHg difference (SD 14 mmHg).
BP measuring
Office BP was measured by the Microlife Watch BP (average 4/5 readings) to reduce the white-coat effect. Ambulatory blood pressure monitoring was done using Mobil-O-Graph (3/hour/daytime, 2/hour/nighttime measurements).
Funding: The trial was funded and co-designed by Mineralys Therapeutics, the drug’s developer, in collaboration with the Cleveland Clinic’s C5Research. An independent data and safety monitoring committee provided oversight, and C5Research verified statistical analyses which were performed by the sponsor.
Results
Of the 2617 screen participants, 926 entered the placebo run-in, with only 285 being randomized. Almost 2/3rd of the patients were excluded during the run-in period, mostly because they did not meet ABPM criteria (lower BP values than expected) with the standardized therapy (olmesartan + indapamide/HCTZ +/- amlodipine).
Figure S3. Trials flow, from Laffin et al, NEJM, 2025
The mean age was 60 years, and 53% of the patients were Black. The mean office SBP was 155 mmHg, and 24-hour average ambulatory SBP at randomization was 140 mmHg. More than 40% of the included patients had diabetes, and about 5% had sleep apnea. More than 60% of the patients had the two-drug standard regimen (olmesartan+ indapamide/ HCTZ).
Table 1. Baseline characteristics, from Laffin et al, NEJM, 2025
Efficacy outcomes
Primary endpoint
Placebo-adjusted 24-hour SBP reduction was significantly lower with lorundrostat.
Stable-dose (50 mg): −7.9 mmHg (97.5% CI −13.3 to −2.6).
Dose-adjustment (50→100 mg): −6.5 mmHg (97.5% CI −11.8 to −1.2).
Placebo group: −7.4 mmHg (97.5% CI −11.4 to −3.4).
Table 2. BP changes with lorundrostat, from Laffin et al, NEJM, 2025
Secondary endpoints
There was a significantly early BP reduction with lorundrostat, showing a pooled -5.3 mmHg (95% CI, -8.4 to -2.3, p< 0.001) reduction in 24-hour systolic BP versus placebo at week 4, with 41% of treated participants achieving BP <125 mmHg compared to 18% on placebo (OR 3.3, 98.75% CI 1.4-7.8). Participants escalated to 100 mg showed particularly robust responses (-17.5 mmHg office SBP reduction at week 12), with greater efficacy observed in those taking 2 versus 3 baseline antihypertensives (Fig. S4). No differential effect was seen based on BMI status.
Figure 1. Changes in blood pressure, from Laffin et al, NEJM, 2025
Exploratory analysis showed a similar BP reduction in Black/White participants (fig S5).
Of interest, and as expected, serum aldosterone levels decreased, and renin activity increased, with lorundrostat as compared to placebo.
Table S5: Efficacy and safety biomarkers
Safety
Hyperkalemia represented the most significant concern, confirmed serum potassium > 6 mmol/L occurred in 2% of stable-dose and 3% of dose-adjustment patients, while transient elevations > 6.5 mmol/L were observed in 1% and 2%, respectively.
Table S6. Hyperkalemia rates, from Laffin et al, NEJM, 2025
The eGFR decline was higher in active treatment (13-15%) vs placebo (3%) at 12-weeks. The rate of eGFR-driven dose modification was also higher with higher doses of lorundrostat (7 vs. 3% placebo). Partial recovery occurred after a 4 week washout, suggesting hemodynamic effects of the medication on changes in eGFR. The changes in cystatin C are helpful to consider given that lorundrostat (similar to cimetidine or trimethoprim) has an effect on the tubular secretion of creatinine.
Table 3. Effect of lorundrostat on eGFR calculated with cystatin C (2C) and serum creatinine (2D), from Laffin et al, NEJM, 2025
Hyponatremia affected 9-11% of participants on lorundrostat versus 6% on placebo (note that all participants were also on thiazide diuretics). Symptomatic hypotension was similar in both lorundrostat groups (9%, respectively 8%), but higher than in the placebo group (3%).
The trial reported no cortisol-related adverse events leading to discontinuation. There was one death in the higher lorundrostat group, which the authors did not attribute to the study drug. However, the overall adverse event profile revealed 6-8% serious adverse events with lorundrostat versus 2% with placebo. Severe adverse events were notably more common with dose escalation (11%- higher dose group, 3-5% in others), mostly driven by hyperkalemia and hypotension.
Table 3. Adverse events, from Laffin et al, NEJM, 2025
Discussion
Resistant hypertension is familiar, often frustrating, and occasionally misdiagnosed. Advance-HTN doesn’t resolve that tension, but it maps it with precision. In contrast to the dose-ranging, mechanism-focused Target-HTN (Laffin et al, JAMA, 2023), which tested five lorundrostat doses in aldosterone-stratified cohorts using office BP, Advance-HTN was a focused phase 2b trial testing two dose strategies (50 mg QD and 50→100 mg) against placebo. The trial used a standardized background antihypertensive regimen to minimize pharmacologic noise, and 24-hour ABPM to avoid the measurement errors/biases with office BP. At 12 weeks, lorundrostat reduced 24-hour SBP by -7.9 mmHg (50 mg QD) and -6.5 mmHg (titrated dose) compared with placebo. In Target-HTN, office SBP reductions were greater (- 9.6 mmHg for 50 mg; -7.8 mmHg for 100 mg), particularly in low-renin patients, but ABPM was not used, and population selection was different. Baxdrostat reported a similar -11 mmHg effect in BrighHTN, but trial design and patient characteristics complicate direct comparison (Freeman et al, NEJM, 2023).
Importantly, Advance-HTN screened over 2600 participants to randomize only 285. Most exclusions occurred during placebo run-in, primarily due to ABPM BP below entry threshold- patients initially labeled as resistant hyperstensives who, under structured care, turned out not to be. This finding reiterates the scale of pseudoresistance in clinical practice. Sensible pharmacology and good BP measurement fix most of ‘resistant’ hypertension. Safety outcomes followed a predictable RAAS-modulating pattern (hypotension, hyperkalemia, hypercreatininemia).
However, unlike the aprocitentan trial (Schlaich et al, Lancet 2022 | NephJC Summary), these ASI trials are choosing a softer hypertension target (mostly 2 drug hypertension) - not truly resistant hypertension, mostly because true resistant hypertension is so uncommon. Secondly, all these trials have excluded the true comparator that matters - spironolactone. Are these ASIs really superior to spironolactone for BP lowering? Talk about off-target effects of aldosterone, and lower hyperkalemia is just marketing malarkey until demonstrated in long-term clinical trials and head:head data.
Nevertheless, there is a huge interest in ASIs - with many completed and ongoing phase 3 trials, mostly targeting difficult-to-control hypertension, and proteinuric kidney disease. See below for a graphical summary of some of these data.
The risk of side effects was similar, independent of dose, type of ASI, or resistant hypertension or CKD.
Strengths
Prospectively registered with a prespecified statistical plan
Covariate-adjusted analysis and robust ABPM-defined endpoints
Sensitivity analyses upheld findings despite 11% missing data
Wider demographic representation (53% Black participants)
Limitations
Small sample (n=285), limiting power, and subgroup analysis (especially with renin and BMI)
The primary endpoint required multiple imputation
Secondary outcomes relied on office BP—still vulnerable to measurement bias
Exclusion of high-risk CKD/hyperkalemia patients limits real-world applicability
Placebo comparator avoiding spironolactone
Conclusion
ADVANCE-HTN confirms the BP-lowering efficacy of lorundrostat in uncontrolled and resistant hypertension. The trial adds to the growing evidence that ASIs as a promising strategy for tackling RH, offering a potential alternative to MRAs, particularly patients at risk of hyperkalemia or with poor MRA tolerance. Not “practice changing” yet, these findings mark an important step in the search for more targeted, better-tolerated antihypertensive options, especially in populations with CKD, proteinuria, and aldosterone-driven phenotypes. Spironolactone stans can stand by silently.
Summary by
Cristina Popa, Milagros Flores
Reviewed by
Brian Rifkin, Sayali Thakare, Swapnil Hiremath