Optimal Dose of Lorundrostat in Uncontrolled Hypertension: A Dose Response Meta-Analysis

Abstract

Background

Lorundrostat, an aldosterone synthase inhibitor, shows promise for hypertension management, though optimal dosing strategies remain poorly defined.

Aims

To evaluate the efficacy, safety, and dose-response effects of Lorundrostat to identify the optimal therapeutic dose.

Methods

We searched PubMed, Embase, Scopus, and ClinicalTrials.gov systematically for relevant RCTs. Using a random-effects model, data were pooled to calculate mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CIs). Dose-response modeling was performed using “dosresmeta” and “rcs” packages in R (v4.4.3).

Results

Three RCTs (n=1568) were included. Lorundrostat significantly reduced systolic BP at 4–8 weeks (MD: –7.66 mmHg, 95% CI: –10.42 to –4.89) and 12 weeks (MD: –10.19 mmHg, 95% CI: –13.57 to –6.82). Diastolic BP also decreased significantly (MD: –3.81). Sub-group analysis based on background medication count showed no significant differences (P=0.80). Aldosterone levels were significantly reduced (MD: –4.39). Dose-response modeling identified 60 mg as the optimal dose, with diminishing returns thereafter. While hyperkalemia risk increased (RR: 3.19), no significant differences were found in serious adverse events.

Conclusion

Lorundrostat effectively lowers BP with a manageable safety profile. The modeling-based insights suggest 60 mg as the optimal dose, delineating a clearer therapeutic window.

Graphical Abstract

Keywords

lorundrostat hypertension systolic blood pressure diastolic blood pressure dose-response meta-analysis

1. Introduction

Hypertension is a major global health burden, affecting an estimated 1.4 billion adults worldwide and contributing substantially to cardiovascular morbidity and mortality. It is a complex, multifactorial disorder shaped by genetic, metabolic, and iatrogenic factors such as corticosteroid use, and psychosocial determinants including stress, poor diet, and sedentary lifestyle.¹ Standard management combines lifestyle modification with pharmacological agents such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), thiazide diuretics, and beta-blockers. However, only about one in five patients with hypertension achieve target blood pressure levels globally.² Uncontrolled hypertension confers a markedly increased risk of end-organ damage and premature cardiovascular and all-cause mortality. The reasons for suboptimal control are multifactorial, including poor medication adherence, clinical inertia, lifestyle factors, comorbidities, inadequate follow-up, and resistant hypertension.³ The latter, defined as persistent blood pressure above target despite treatment with at least three antihypertensive agents of different classes, including a diuretic, affects up to 10% of treated patients.⁴ Increasing evidence suggests that aldosterone dysregulation is a key driver of resistant hypertension. Both primary aldosteronism and secondary causes of aldosterone excess, such as obesity, contribute significantly to persistent hypertension.^5,6 Furthermore, 30–40% of patients on long-term ACEi or ARB therapy develop aldosterone breakthrough, a phenomenon in which aldosterone levels, initially suppressed by RAAS blockade, return to or exceed baseline within months of treatment.⁷

Currently, mineralocorticoid receptor antagonists (MRAs) are the only widely available aldosterone-targeted agents, but they are typically reserved as fourth-line add-on therapy in both European and US guidelines.⁸ Their limited use, coupled with the high prevalence of aldosterone dysregulation and breakthrough, underscores the urgent need for novel, effective, and well-tolerated aldosterone-directed therapies.

Lorundrostat (MLS-101), a selective aldosterone synthase inhibitor (ASI), represents such an approach. By directly inhibiting aldosterone synthesis, Lorundrostat reduces sodium and water retention, thereby lowering blood pressure.^9-11 Unlike conventional RAAS blockers, it targets aldosterone production at its source. Early clinical trials, including the TARGET-HTN study, have demonstrated meaningful reductions in systolic blood pressure with once-daily dosing.¹² Furthermore, the recent TARGET-HTN and ADVANCE-HTN randomized controlled trials have confirmed the effectiveness of this novel aldosterone inhibitor, lorundrostat, in reducing both systolic and diastolic blood pressures among patients with uncontrolled hypertension, showing especially strong benefits in obese individuals and with suppressed levels of renin^10,13.

Given the role of Lorundrostat in uncontrolled hypertension, a dose-response meta-analysis of available randomized trials is warranted. Our study focuses on a dose-response meta-analysis (DRMA) for Lorundrostat in uncontrolled hypertension, focusing on systolic blood pressure, diastolic blood pressure, and serum aldosterone and renin levels. Further, by synthesizing dose-response effects and evaluating the optimal doses of Lorundrostat that balance its clinical benefit and tolerability from recent randomized controlled trials (RCTs), this meta-analysis aims to strengthen the clinical understanding of Lorundrostat’s therapeutic potential and supports evidence-based decision-making in uncontrolled hypertension.

2. Methods

This systematic review and meta-analysis was conducted according to the Cochrane Handbook for Systematic Review of Interventions and reported according to the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ (PRISMA) checklist.^14,15 This systematic review and meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD 420261304380).

2.1. Information Sources and Search Strategy

A comprehensive search was conducted across three electronic databases, PubMed, Cochrane Library, and Embase, and a clinical trial registry (ClinicalTrials.gov) to identify relevant studies published or registered up to September 20, 2025. The systematic review and meta-analysis was conducted between September 2025 and November 2025. No restrictions were applied to language, publication status, or publication date to ensure maximal inclusivity. All studies included in this meta-analysis were published in English, and therefore, no language translations were required.

The search strategy combined free-text terms and database-specific controlled vocabulary related to “Hypertension” and “Lorundrostat”. Boolean operators (AND/OR) and truncation symbols were used to refine results. For example, searches combined terms for the condition (e.g., “hypertension”) with the intervention “Lorundrostat”. The full search syntax for each database and registry is provided in the Supplementary file (Table S1).

2.2. Eligibility Criteria

Studies were eligible for inclusion if they met the following criteria¹: the study design had to involve human participants and be a controlled trial, including randomized controlled trials (RCTs) to ensure direct comparison of Lorundrostat against placebo, or standard care²; study population had to include individuals with uncontrolled or resistant hypertension³; the intervention had to involve treatment with Lorundrostat (MLS-101) at any dose (12.5, 25, 50 and 100 mg administered for daily⁴; studies were required to report at least one predefined outcome of interest, including reporting of systolic blood pressure (SBP) changes, diastolic blood pressure changes, serum aldosterone, serum renin and AEs, or serious adverse events (SAEs) at different dosage levels.

Studies were excluded for the following reasons¹: non-randomized controlled studies (e.g., prospective or retrospective cohort studies)²; evaluation of Lorundrostat in combination with other hypertensive treatments³; failure to report outcomes or participant data separately for treatment and control groups, which would preclude meaningful meta-analysis⁴; lack of accessible data, such as ongoing trials without published results, conference abstracts lacking analyzable datasets, or studies with outcomes irrelevant to this review (e.g., pharmacokinetic analyses without clinical endpoints)⁵; duplication of patient cohorts across multiple studies, in which case only the most recent or comprehensive publication was retained to avoid data redundancy; and⁶ absence of any predefined efficacy or safety outcomes, rendering the study unsuitable for addressing the objectives.

2.3. Study Selection Process

The retrieved references were screened by three independent authors (M.S, O.V & S.S) based on title and abstracts and assessed for eligibility using predefined inclusion and exclusion criteria. The same authors performed secondary full-text screening independently. A fourth independent reviewer (O.A.G.) resolved any conflicts.

2.4. Outcomes Assessment

The primary outcomes for this systematic review and meta-analysis were carefully selected to evaluate clinical efficacy of Lorundrostat in patients with uncontrolled or resistant hypertension. The primary efficacy outcomes included change in systolic and diastolic BP at different follow ups or time points, analyzed by pooling mean differences (MD) with corresponding 95% confidence intervals and evaluation of the optimal dosages of Lorundrostat for systolic BP and diastolic BP, with maximum predicted values for each measure reported as EDmax with 95% CI. Moreover the estimated doses to produce 50% (ED₅₀) and 80% (ED₈₀) of the predicted maximum effects for each BP parameter (systolic and diastolic) were calculated. In addition, sub-group analysis based on the number of hypertensive medications taken by patients at baseline were conducted to assess systolic BP differences if any. To assess efficacy in terms of serum biomarkers; serum aldosterone and renin changes were evaluated, and expressed as mean differences (MD) along with 95% CI (pre-treatment and post-treatment). Secondary outcomes focused on mechanistic and safety endpoints. These included incidence of hyponatremia, hyperkalemia and serious adverse events.

All outcomes were selected based on their clinical relevance and consistent reporting across trials in this therapeutic area, ensuring robust data synthesis and meaningful clinical interpretation.

2.5. Data Extraction

Two independent reviewers (O.A. and M.S.) systematically extracted data from the full text and supplementary materials of each included study using a standardized data extraction form. Any discrepancies were resolved through discussion and consensus, with re-evaluation of the original full text and supplementary sources when necessary.

The extracted data included¹: study identification details (first author, year of publication, country, and setting)²; study design characteristics (type, duration, and methodology)³; patient demographics and clinical characteristics (age, sex distribution, treatment duration, and dosage regimens); and⁴ quantitative and qualitative data for all predefined outcomes of interest. For studies involving treatment switches (e.g., crossover designs or sequential therapies), data from each distinct treatment phase were extracted and analyzed separately to maintain intervention-specific accuracy. Participants whose outcomes were not reported at the time of treatment transition were excluded from the corresponding outcome analysis to prevent data misclassification. This approach ensured methodological consistency and minimized bias in the synthesis of evidence across studies.

2.6. Risk of Bias Assessment

The methodological quality and risk of bias of included randomized controlled trials were independently evaluated by two reviewers using the revised Cochrane Risk of Bias tool (RoB 2.0). This tool systematically assesses five domains¹: randomization process,² deviations from intended interventions,³ missing outcome data,⁴ measurement of outcomes, and⁵ selection of reported results. Each domain was judged as having “low risk,” “some concerns,” or “high risk” of bias based on the criteria outlined in the RoB 2.0 guidelines. Discrepancies between reviewers were resolved through discussion or by consulting a third reviewer when necessary.

2.7. Statistical Analysis

All statistical analyses were performed using RevMan (version 5.4, Cochrane Collaboration) and R Studio version 4.4.3 (Posit PBC, Boston, USA). We pooled mean differences (MD) with 95% confidence intervals (CIs) using inverse variance weighting for continuous outcomes like systolic and diastolic BPs, and serum markers, etc. Dichotomous outcomes like incidence of hyperkalemia, hyponatremia and serious adverse events, etc., were analyzed using pooled risk ratios (RR) with 95% CIs, employing the Mantel-Haenszel (M-H) method. When studies reported continuous data as medians and interquartile ranges, we estimated means and standard deviations using validated transformation methods to ensure compatibility with meta-analytic techniques. Heterogeneity was assessed using the Cochrane Q test (significance threshold: p < 0.10) and quantified with the I² statistic, where values >50% indicated substantial heterogeneity. Given anticipated clinical and methodological variability across studies, we employed a DerSimonian and Laird random-effects model for all primary analyses to account for between-study variance. Subsequently, a dose-response meta-analysis was performed using R Studio version 4.4.3 (Posit PBC, Boston, USA), using the “dosresmeta”¹⁶ and “rcs” packages.¹⁷ We examined the single dose of Lorundrostat injection, standardizing each dose of Lorundrostat administered daily, without considering simultaneous calculations for up-titration or down-titration. The initial dose-response relationship was examined using a linear mixed-effects regression model. Subsequently, we conducted a dose-response meta-analysis through the one-stage or two-stage approach depending on data availability. A restricted cubic spline model with knots at the 10th, 50th, and 90th percentiles of Lorundrostat dosages (12.5, 25, 50, and 100mg) was applied within a restricted maximum likelihood random-effects model (REML).¹⁸ Further, we validated this standardized placement by the Akaike Information Criterion (AIC) to ensure the most robust model fit relative to the specific dose-density of the included studies in each outcome.

ED50, ED80, and EDmax were derived from the predicted pooled spline function and represent the doses achieving 50%, 80%, and 100% of the maximal expected treatment effect. The reference for the dose-response meta-analysis was set to 0, with no a priori assumptions about the shape of the association. All statistical tests were two-tailed, with α = 0.05 defining significance.

3. Results

3.1. Study Selection Process

A comprehensive database search resulted in 255 studies, of which 42 were removed as duplicates. The remaining 213 studies were assessed based on their titles and abstracts. A total of 3 studies fulfilling the predefined inclusion and exclusion criteria were included in this meta-analysis. The detailed study selection process is depicted in the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flow diagram as shown in Figure 1.

Figure 1.

Prisma flowsheet

3.2. Baselines Characteristics and Patients’ Demographics

The mean age of participants was consistent, averaging between 59.1 and 65.7 years, with standard deviations close to 11.3, indicating minimal age variability. The study population included a slightly higher proportion of males, accounting for 53.2% of participants across studies, reflecting both disease prevalence and efforts toward balanced trial recruitment. Baseline systolic blood pressure or BP at randomization ranged from 135.3 to 143.5 mmHg, while baseline diastolic blood pressure ranged from 78.5 to 85.6 mmHg (Table 1).

Table 1.

Baseline Characteristics of Included Studies

Study ID	Group	Sample size (n)	Age (mean ±SD)	Male, n (%)	BMI, (mean ±SD)	Baseline systolic BP (mean ±SD)	Baseline diastolic BP (mean ±SD)	eGFR (mean ±SD)
Advance-HTN trial, 2025	Placebo	95.0	59.1 (10.5)	62 (65)	32.2 (4.8)	141.7 (14.0)	85.5 (10.3)	73.6 (18.0)
	Lorundrostat 50mg	94.0	61.3 (9.6)	56 (60)	31.2 (4.6)	141.8 (14.4)	84.3 (9.4)	76.6 (17.8)
	Lorundrostat 50mg then 100mg	96.0	60.9 (10.2)	54 (56)	32.4 (5.4)	143.5 (12.8)	85.6 (10.2)	76.4 (19.4)
Target-HTN trial, 2025	Lorundrostat 50 mg and then100mg	270.0	61.4 (10.3)	142 (52.6)	32.8 (6.7)	146.6 (11.1)	86.3 (9.2)	92.8 (17.6)
	Lorundrostat 50 mg	541.0	61.7 (10.6)	294 (54.3)	33.0 (6.9)	149.0 (12.2)	87.8 (9.0)	90.1 (17.8)
	Placebo	272.0	61.8 (10.4)	139 (51.1)	32.6 (7.4)	148.8 (12.2)	87.1 (9.1)	91.2 (16.4)
Launch-HTN trial, 2025 (Cohort 1)	Lorundrostat (100 mg once daily)	30.0	68.7 (8.9)	12 (40.0)	30.4 (5.5)	142.2 (13.4)	78.5 (10.0)	77.4 (14.0)
	Lorundrostat (50 mg once daily)	28.0	64.7 (9.5)	13 (46.4)	32.0 (5.0)	140.0 (12.1)	84.7 (7.0)	77.2 (14.1)
	Lorundrostat (25 mg twice daily)	30.0	64.8 (9.7)	11 (36.7)	30.6 (5.5)	142.8 (13.1)	80.1 (9.3)	80.9 (12.4)
	Lorundrostat (12.5 mg twice daily)	22.0	68.1 (10.1)	8 (36.4)	32.0 (5.2)	142.6 (13.3)	81.6 (9.4)	81.7 (16.3)
	Lorundrostat (12.5 mg once daily)	23.0	65.2 (11.3)	11 (47.8)	30.6 (4.9)	142.9 (13.7)	80.3 (12.0)	77.9 (18.7)
	Placebo	30.0	62.6 (10.7)	13 (43.3)	31.9 (5.0)	142.9 (10.7)	83.8 (9.5)	81.6 (17.3)
Launch-HTN trial, 2025 (Cohort 2)	Lorundrostat (100 mg once daily)	31.0	66.6 (10.6)	10 (32.3)	30.5 (4.4)	139.8 (9.1)	78.6 (10.0)	79.9 (13.1)
Launch-HTN trial, 2025 (Cohort 2)	Placebo	6.0	62.7 (12.3)	2 (33.3)	32.0 (3.9)	135.3 (5.5)	81.5 (7.9)	83.9 (18.6)

Data is presented as n (%) or mean ± SD. Abbreviation: NR, not reported.

3.3. Outcomes

3.3.1. Change in Systolic Blood Pressure at 4–6 Weeks

Three studies,^10,11,13 encompassing 1,324 patients (930 in the Lorundrostat group and 394 in the placebo group), reported the change in systolic blood pressure at 4–6 weeks of follow-up. Lorundrostat (50 mg daily) demonstrated a significant reduction in systolic AOBP, with a mean difference of –7.66 mmHg (95% CI: –10.42 to –4.89; P < 0.00001) compared with placebo (Figure 2A).

Figure 2.

Forest plots of: (A) “Change in Systolic BP at 4-6 weeks”; and (B) “Change in Systolic BP in Lorundrostat-treated Patients versus Placebo at 12 weeks” using the mean difference (MD)

3.3.2. Change in Systolic Blood Pressure at 12 Weeks

The pooled analysis demonstrated treatment with Lorundrostat 50 mg once daily resulted in a significant reduction in systolic AOBP compared with placebo, with a mean difference of –10.19 mmHg (95% CI: –13.57 to –6.82; P < 0.00001; I² = 10%) (Figure 2B).

3.3.3. Change in Diastolic Blood Pressure at 12 Weeks

The pooled analysis demonstrated treatment with Lorundrostat 50 mg once daily resulted in a significant reduction in diastolic blood pressure, with a mean difference of –3.81 mmHg (95% CI: –6.09 to –1.52; P= 0.001; I² = 0%) compared with placebo (Figure 3A).

Figure 3.

Forest plots of: (A) “Change in Diastolic BP”; (B) “Change in Serum Aldosterone Levels”; and (C) “Change in Serum Renin Levels” in Lorundrostat-treated Patients versus Placebo using the mean difference (MD)

3.3.4. Change in Plasma Aldosterone Levels at 12 Weeks

The pooled analysis demonstrated treatment with Lorundrostat 50 mg once daily resulted in a significant reduction in aldosterone levels, with a mean difference of –4.39 (95% CI: –5.54 to –3.25; P < 0.00001; I² = 79%) compared with placebo. Despite the significant heterogeneity, the results remain statistically robust with a highly significant p-value, reinforcing the strength of the observed effect (Figure 3B).

3.3.5. Change in Plasma Renin Levels at 12 Weeks

Two studies reported the mean change in plasma renin levels in both groups (Lorundrostat 50 mg and placebo). The pooled analysis demonstrated there was a statistically significant difference between Lorundrostat and placebo (MD: 3.39, 95% CI 1.12 to 5.65, I² = 0%, P=0.003 (Figure 3C).

3.3.6. Incidence of Serious Adverse Events

There was an 11% higher risk of severe adverse events in the Lorundrostat group, though this difference was not statistically significant (RR 1.11, 95% CI 0.53-2.32, P=0.78, I²=57%), with moderate heterogeneity among studies as shown in Figure 4.

Figure 4.

Forest plot of the Pooled Relative Risk (RR) for Serious Adverse Events in Lorundrostat-treated Patients versus Placebo

3.3.7. Incidence of Hyperkalaemia (>5.5-6.0 mmol/L)

The incidence of hyperkalaemia (>5.5-60 mmol/L) in the Lorundrostat group (50 mg daily) was significantly higher (RR 3.19, 95% CI 1.02-10.02, P=0.05, I²=29%) when compared to placebo. The heterogeneity among the studies was low as shown in Figure 5.

Figure 5.

Forest plot of the Pooled Relative Risk (RR) for Incidence of Hyperkalaemia in Lorundrostat-treated Patients versus Placebo

3.3.8. Incidence of Hyponatremia

The pooled analysis suggested a possible greater risk of hyponatremia with Lorundrostat compared with placebo (RR 1.79, 95% CI 1.00–3.22; P = 0.05; I² = 0%). However, this estimate was based on only two studies and lay at the threshold of statistical significance; therefore, it should be interpreted cautiously (Figure 6).

Figure 6.

Forest plot of the pooled relative risk (RR) for incidence of hyponatremia in lorundrostat-treated patients versus placebo

3.3.9. Sub-Groups Analysis

The change in systolic BP was stratified in patients taking two hypertensive medications and three hypertensive medications at baseline. In the patient taking two hypertensive medications at baseline, the mean difference in systolic BP was -6.96 (95% CI: -9.92, -4.01) when compared to placebo. In the patients taking three hypertensive medications at baseline, the mean difference in systolic BP was -6.64 (95% CI: -10.07, -3.20) when compared to placebo. The change in systolic BP was significant in both hypertensive groups when compared to the placebo, however, there was no significant difference in the change of systolic BP in the sub-groups (stratified by hypertensive medications), Chi2 = 0.02, P=0.89, I²=0 as shown in Figure 7.

Figure 7.

Forest Plot of Sub-groups Analysis of Change in Systolic BP of Patients taking two Hypertensive Medications and three Hypertensive Medications at Baseline

3.4. Dose-Response Analysis

3.4.1. Systolic Blood Pressure

Initially, a linear model showed significant results. However, further evaluation was carried out using a spline model with cubic knots positioned at the 10th, 50th, and 90th percentiles of Lorundrostat dosages. The spline model demonstrated a superior log-likelihood to the linear model, indicating a better fit to the data (Chi2 model: X2 = 42.43, P=0.0000). In the spline model, the first spline term (spline dose 1) showed a significantly negative coefficient for doses below 60 mg/day (-0.26; 95 % CI: -0.35 to -0.18, p = 0.0000), indicating that as the dose increased up to approximately 60 mg, the MD consistently decreased. For doses above 60 mg, the relationship between dose and MD shifted, with the second spline term (spline dose 2) having a positive coefficient (0.37; 95 % CI: 0.21 to 0.54, p = 0.0000). These results indicated a statistically significant positive association between increasing doses of Lorundrostat. However, the effects of the intervention plateaued after 60 mg/day as shown in Figure 8.

Figure 8.

Pooled Dose-Response Association between Lorundrostat and mean change in Systolic Blood Pressure (SBP). Lorundrostat Dosage was modelled with restricted cubic splines in a random-effects model. Dash lines represent the 95 % confidence intervals. The dose corresponding to the maximum predicted effect (Xmax) was 56.6 mg/day, at which the estimated maximum MD in systolic BP was -10.52 (95% CI: -13.69 to -7.34). The doses required to achieve 50% and 80% of this maximum predicted effect were ED50 = 19.9 mg/day and ED80 = 33.3 mg/day, respectively. Complete predicted dose–response estimates are presented in Table 2

3.4.2. Diastolic Blood Pressure

For accessing the dose response effect on diastolic BP, initially, again a linear model was employed. However, further evaluation was carried out using a spline model with cubic knots positioned at the 10th, 50th, and 90th percentiles of Lorundrostat dosages. The spline model demonstrated a superior log-likelihood to the linear model, indicating a better fit to the data. In the spline model, the first spline term (spline dose 1) showed a significantly negative coefficient for doses till 60 mg/day (-0.093; 95 % CI: -0.14 to -0.04, p = 0.0005), showing that as the dose increased up to approximately 60 mg, the MD consistently decreased. For doses above 60 mg, the relationship between dose and MD shifted, with the second spline term (spline dose 2) having a positive coefficient (0.12; 95 % CI: -0.01 to 0.27, p = 0.08). These results indicated a statistically significant positive association between increasing doses of Lorundrostat. However, the effects of the intervention plateaued after 60 mg/day as shown in Figure 9.

Figure 9.

Pooled Dose-Response Association between Lorundrostat and mean change in Diastolic Blood Pressure (DBP). Lorundrostat dosage was modelled with restricted cubic splines in a random-effects model, the EDmax at 54.2mg/day. Dash lines represent the 95 % confidence intervals for the spline model

The maximum predicted effect (Xmax) occurred at a dose of 60mg/day, corresponding to an estimated MD in diastolic BP of -3.83 (95% CI: -5.73 to -1.93). The doses estimated to achieve 50% and 80% of this effect were ED50 = 20.5 mg/day and ED80 = 34.5 mg/day, respectively. The complete predictive values of the dose-response effect are available in (Table 2).

Table 2.

Prediction Values of Dose-Response Meta-Analysis of Systolic BP, Diastolic BP and Serum Aldosterone Levels Using Cubic Restricted Spline Model

Prediction values of dose-response analysis of systolic blood pressure
Dose (mg)	Prediction value	Lower CI	Upper CI
20	-5.29	-6.99	-3.59
40	-9.51	-12.5	-6.53
60	-10.48	-13.64	-7.33
80	-9.3	-12.43	-6.17
100	-7.57	-11.38	-3.76
Prediction values of dose-response analysis of diastolic blood pressure
Dose (mg)	Prediction value	Lower CI	Upper CI
20	-1.87	-2.91	-0.82
40	-3.38	-5.16	-1.6
60	-3.83	-5.73	-1.93
80	-3.57	-6.22	-0.92
100	-3.13	-7.28	1.02
Prediction values of dose-response analysis of serum aldosterone levels
Dose (mg)	Prediction value	Lower CI	Upper CI
20	-2.01	-3.23	-0.8
40	-3.7	-5.94	-1.47
60	-4.39	-7.06	-1.72
80	-4.42	-7.2	-1.64
100	-4.28	-7.14	-1.41

Data is presented as mean, Abbreviation: CI; Confidence interval, mg; milligrams.

3.4.3. Serum Aldosterone Levels

The dose–response effect of Lorundrostat on serum aldosterone levels was evaluated using a restricted cubic spline model with knots placed at the 10th, 50th, and 90th percentiles of Lorundrostat dosages. The first spline term demonstrated a statistically significant negative association between dose and mean difference (MD) in aldosterone levels up to approximately 70 mg/day (coefficient = –0.10; 95% CI: –0.16 to –0.04; p = 0.001), indicating a progressive reduction in aldosterone concentrations with increasing dose within this range. Beyond this point, the slope of the dose–response curve began to flatten, as reflected by the positive coefficient of the second spline term (0.11; 95% CI: 0.04 to 0.19; p = 0.002), suggesting attenuation of the treatment effect at higher doses rather than further reduction as shown in Figure 10.

Figure 10.

Pooled Dose-Response Association between Lorundrostat and mean change in Serum Aldosterone Levels. Lorundrostat dosage was modelled with restricted cubic splines in a random-effects model. Dash lines represent the 95 % confidence intervals for the spline model. From the pooled spline prediction function, the dose associated with the maximum estimated reduction in aldosterone levels (EDmax) was 70.3 mg/day, corresponding to a mean difference of –4.45 (95% CI: –7.2 to –1.7). The doses required to achieve 50% and 80% of this maximum predicted effect were ED50 = 22.1 mg/day and ED80 = 37.8 mg/day, respectively. Complete predicted dose–response estimates are presented in Table 2

3.5. Risk of Bias Assessment

The risk of bias in the included studies was evaluated using RoB 2.0 software by the Cochrane Collaboration in five domains, i.e., selection bias, performance bias, detection bias, attrition bias, and reporting bias. We found an overall ‘low risk’ of bias but there were ‘some concerns’ in Saxena at el., 2025 regarding missing outcome data, measurement of outcome and selection of reported results as shown in Figures 11 and 12.

Figure 11.

Traffic light plot summarizing the risk of bias assessment for individual studies, evaluated using the Cochrane RoB 2.0 tool across five domains: selection bias, performance bias, detection bias, attrition bias, and reporting bias

Figure 12.

Summary plot of the risk of bias for included studies, showing an overall assessment of studies with “low risk,” “some concerns,” or “high risk” of bias

3.6. Sensitivity Analysis

To evaluate the robustness of the primary pooled estimates, leave-one-out sensitivity analyses were performed for all outcomes comprising data from at least three independent trials.

3.6.1. Change in Systolic Blood Pressure at 4–6 Weeks

The primary finding of significant SBP reduction with Lorundrostat was highly robust to individual study influence. The pooled mean difference (MD) remained statistically significant (P < 0.001) across all iterations, with effect sizes ranging from -6.46 mmHg (95% CI, -10.26 to -2.65) when omitting the largest trial (Launch-HTN) to -9.14 mmHg (95% CI, -12.66 to -5.61) when omitting Advance-HTN. Notably, the omission of Target-HTN resulted in an increase in heterogeneity (I² = 31.6%), suggesting this trial played a stabilizing role in the primary analysis (Supplementary Figure 1).

3.6.2. Incidence of Hyperkalaemia (>5.5-60 mmol/L)

In contrast, the safety signal for hyperkalaemia demonstrated significant fragility. While the primary analysis indicated a three-fold increase in risk (RR 3.19; 95% CI, 1.02 to 10.02), this effect was found to be primarily driven by a single study. Omission of the Launch-HTN trial resulted in a non-significant relative risk of 1.78 (95% CI, 0.53 to 6.00; P = 0.35) and reduced between-study heterogeneity (I²) from 28.7% to 0%. Omission of Advance-HTN or Target-HTN maintained the direction of risk but resulted in wide confidence intervals, reflecting the limited number of events recorded in these smaller cohorts (Supplementary Figure 2).

4. Discussion

This systematic review and dose-response meta-analysis synthesized evidence from three randomized controlled trials (RCTs) evaluating Lorundrostat in patients with uncontrolled or resistant hypertension. Using a cubic restricted spline model, we demonstrated that Lorundrostat significantly reduced both systolic and diastolic blood pressure, with maximal predicted effects at approximately 60 mg/day. The pooled analysis confirmed consistent reductions in systolic blood pressure and diastolic blood pressure, alongside marked decreases in serum aldosterone levels. Importantly, while Lorundrostat was generally well tolerated, safety analyses revealed an increased risk of hyperkalemia and hyponatremia, though no significant differences in serious adverse events were observed. Collectively, these findings delineate a therapeutic window in which Lorundrostat achieves optimal efficacy without major safety concerns.

Uncontrolled hypertension remains a global challenge, affecting nearly one in five treated patients despite multidrug regimens.^19,20 Aldosterone dysregulation, including breakthrough during long-term ACEi or ARB therapy, contributes substantially to resistant hypertension.^7,21 Lorundrostat, as a selective aldosterone synthase inhibitor, directly targets aldosterone production,²² offering a mechanistically distinct approach compared to mineralocorticoid receptor antagonists (MRAs). The observed reductions in BP and aldosterone levels highlight its potential role as an adjunctive therapy in patients with resistant hypertension, particularly those with obesity or suppressed renin activity.²³ However, substantial heterogeneity was observed for the aldosterone outcome, likely reflecting differences in assay methodology, patient populations, baseline hormonal physiology, and trial design. The cubic spline model further refines dosing strategies, suggesting that 60 mg/day achieves near-maximal benefit, thereby guiding clinicians toward evidence-based titration.²⁴

Our findings align with early-phase trials such as TARGET-HTN and ADVANCE-HTN, which reported significant reductions in systolic BP with Lorundrostat.^12,25 The magnitude of BP reduction observed in our pooled analysis is comparable to that achieved with MRAs,²⁶ yet with potentially fewer tolerability issues. Notably, the dose–response plateau beyond 60 mg/day mirrors observations in other aldosterone-targeted therapies, where escalating doses confer diminishing returns.²⁷ Lorundrostat’s therapeutic window appears similarly well defined. However, unlike MRAs, Lorundrostat’s mechanism avoids direct receptor blockade, potentially mitigating off-target effects such as gynecomastia or menstrual irregularities.²⁸

The identification of 60 mg/day as the optimal dose has direct clinical utility. It provides a rational basis for dose selection in future trials and clinical practice, balancing efficacy with safety. The increased risk of hyperkalemia underscores the need for careful monitoring, particularly in patients with chronic kidney disease or concomitant RAAS blockade.²⁹

However, these safety findings should be interpreted with caution. The association with hyponatremia was borderline statistically significant (RR 1.79, 95% CI 1.00–3.22; P = 0.05), and the limited number of contributing studies may reduce the robustness of this estimate. Likewise, the increased risk of hyperkalemia (RR 3.19, 95% CI 1.02–10.02) was accompanied by a wide confidence interval, indicating imprecision likely related to small event counts and limited sample size. Therefore, larger adequately powered trials are warranted to better define the safety profile of Lorundrostat.

Subgroup analyses revealed consistent efficacy across patients on two or three antihypertensive agents, suggesting broad applicability in resistant hypertension.³⁰ Furthermore, reductions in aldosterone levels may translate into long-term cardiovascular benefits, given aldosterone’s role in vascular remodeling and fibrosis.^31,32 Thus, Lorundrostat may represent a valuable addition to the therapeutic armamentarium for resistant hypertension.

4.1. Strengths and Limitations

The strengths of this meta-analysis include adherence to PRISMA guidelines,¹⁵ rigorous risk-of-bias assessment,¹⁴ and the use of a cubic restricted spline model,¹⁸ which allowed precise characterization of the dose–response relationship. The inclusion of only RCTs enhances internal validity, while the pooling of biomarker outcomes provides mechanistic insights. However, limitations must be acknowledged. First, the number of included trials was small (n=3), limiting statistical power and generalizability. Second, because only a limited number of RCTs were available for clinical outcomes, we were unable to formally explore the sources of heterogeneity through sensitivity analysis or meta-regression. Third, follow-up durations were relatively short (≤12 weeks), limiting inference on long-term cardiovascular outcomes. Finally, safety data were constrained by small event counts, necessitating cautious interpretation of hyperkalemia and hyponatremia risks.

4.2. Future Directions

Future research should focus on large-scale, long-term RCTs to confirm the durability of BP reductions and assess cardiovascular outcomes such as major adverse cardiovascular events (MACE). Comparative trials against MRAs would clarify relative efficacy and tolerability.²⁶ Additionally, mechanistic studies exploring Lorundrostat’s effects on vascular remodeling, renal outcomes, and aldosterone breakthrough are warranted.^7,21 Real-world studies should evaluate its utility in diverse populations, including those with obesity, diabetes, and chronic kidney disease.²³ Finally, pharmacogenomic investigations may identify patient subgroups most likely to benefit, enabling precision medicine approaches in resistant hypertension.

5. Conclusion

This systematic review and cubic spline dose–response meta-analysis demonstrate that Lorundrostat effectively lowers systolic and diastolic blood pressure in patients with uncontrolled hypertension, with an optimal dose of approximately 60 mg/day. The drug exhibits a favorable safety profile, though vigilance for hyperkalemia and hyponatremia is required. By delineating a clear therapeutic window, our findings provide a foundation for clinical decision-making and future trial design. Lorundrostat thus emerges as a promising aldosterone-directed therapy, addressing a critical gap in the management of resistant hypertension.

Supplemental Material

Supplemental Material - Optimal Dose of Lorundrostat in Uncontrolled Hypertension: A Dose Response Meta-Analysis

Supplemental Material for Optimal Dose of Lorundrostat in Uncontrolled Hypertension: A Dose Response Meta-Analysis by Omar Abdullah Gill, Miguel Leonardo Salcedo Monterrubio, Ayeman Rashid, Erum Habib, Asma Yasin, Ahmad Alam, Azhar Khan, Ramesha Tahir, Savika Bansal, Olivia Benny, Shivani Sabarish, Lakshmi Sheethal Arvapalli, Devanshi Bhanderi, Salau Ibrahim Layi, Hafiz Muhammad Haris, and Dori Woldu in Dose-Response.

Footnotes

ORCID iD

Dori Woldu

Ethical Considerations

Due to the de-identified nature of the dataset, the need for informed consent and Institutional Review Board approval is waived.

Author Contributions

Gill OA, Monterrubio MLS, Rashid A, and Habib E, contributed to conceptualization, methodology, writing–original draft, formal analysis, writing–review and editing; Yasin A, Bansal S, and Khan A, contributed to investigation, data curation, software, data analysis, writing–review and editing; Tahir R, and Benny O, contributed to project administration, funding acquisition, writing–review and editing; Alam A, and Woldu D contributed to supervision, writing–review and editing; Sabarish S, Arvapalli LS, Bhanderi D, Layi SI, Haris Hafiz Muhammad, and Dori Woldu contributed to validation, writing–review and editing. Dori Woldu is also the corresponding author.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The complete dose response analysis code is available at .

Use of Generative AI and AI-Assisted Technologies

No AI tools or technologies were used in the preparation of any part of this manuscript.

Core Tip

Lorundrostat, a selective aldosterone synthase inhibitor, demonstrates clinically meaningful reductions in both systolic and diastolic blood pressure across randomized controlled trials. This meta-analysis not only evaluates its antihypertensive efficacy and favourable overall safety profile but also provides novel dose–response insights, identifying 60 mg as the optimal therapeutic dose beyond which additional benefits plateau. These findings help refine dosing strategies and support Lorundrostat’s emerging role as a targeted treatment option for patients with uncontrolled hypertension.

Supplemental Material

Supplemental material for this article is available online.

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