Efficacy and safety outcomes of aldosterone synthase inhibitors for resistant hypertension: A meta-analysis of randomized controlled trials

Abstract

Introduction

Aldosterone synthase inhibitors (ASIs) have emerged as a promising therapeutic approach for blood pressure (BP) management.

Materials and Methods

We searched the PubMed, Web of Science, EMBASE and Cochrane Library databases until July 11, 2025. We expressed continuous outcome data as mean differences (MDs) with 95% confidence intervals (CIs) and dichotomous outcome data as risk ratios (RRs) with 95% CIs.

Results

Five randomized controlled trials involving 1958 patients (mean age, 60 years; 54% men) were included. The pooled results showed that ASIs significantly reduced SBP compared with placebo, with a mean difference of −7.08 mmHg (95% CI: −9.24 to −4.93). There was no significant difference between patients assigned to ASIs treatment and placebo on serious adverse events (RR,1.16; 95% CI,0.47–2.88). Additionally, significant reductions were observed among patients receiving ASIs treatment compared with receiving placebo on the change in diastolic blood pressure (DBP), with a mean difference of −2.96 mmHg (95% CI: −4.6 to −1.32).

Conclusions

ASIs effectively reduce SBP and DBP in patients with resistant hypertension (RHT) and demonstrate a generally favorable safety profile, although the increased risk of hyperkalemia and other adverse events warrants consideration. These results support the potential of ASIs as a therapeutic option for RHT, requiring confirmation in larger-scale studies.

Keywords

aldosterone synthase inhibitors resistant hypertension blood pressure meta-analysis renin–angiotensin–aldosterone system

Introduction

Hypertension affects 1.56 billion (29.2%) individuals globally and is the leading modifiable risk factor for cardiovascular diseases (CVD), disability, stroke, and premature mortality worldwide, which are the leading causes of mortality.^1–3 Resistant hypertension (RHT) is defined as uncontrolled blood pressure (at or above 130/80 mmHg) when on four or more classes of antihypertensive medication, including a diuretic.^3,4 First-line pharmacotherapy for RHT typically comprises a triple combination of agents, including a renin–angiotensin system blocker, a dihydropyridine calcium channel blocker, and a thiazide or thiazide-like diuretic.^5,6 Despite the wide availability of antihypertensive medications, blood pressure control rates are far from ideal.⁷ Inadequate management of RHT is associated with an increased risk of major adverse cardiovascular events (MACE) and end-organ damage, contributing to significant morbidity and mortality.⁸

Aldosterone is a mineralocorticoid hormone that controls body fluid and electrolyte balance, which plays a crucial role in the pathogenesis of RHT.^9,10 Blockade of the renin–angiotensin–aldosterone system (RAAS) is one of the key therapeutic targets in patients with hypertension.¹¹ Although mineralocorticoid receptor antagonists (MRAs) are effective in lowering blood pressure in patients with elevated aldosterone levels, particularly those with resistant hypertension, their use and efficacy may be constrained by hormonal adverse effects and by aldosterone's nongenomic actions that increase vascular stiffness and sympathetic activation.¹² Aldosterone synthase inhibitors (ASIs) are a novel class of antihypertensive agents that lower blood pressure by inhibiting aldosterone synthesis.¹¹ Pharmacokinetic profiles and clinical evidence indicate that ASIs are a promising therapeutic strategy for improving blood pressure control in patients with RHT.¹³ Although several randomized controlled trials (RCTs) have demonstrated promising efficacy and safety outcomes, the overall effectiveness and safety of ASIs for RHT remain uncertain due to the limited scope and inconsistent findings of these studies.^14–16

This systematic review and meta-analysis provide a more comprehensive understanding of ASIs’ efficacy and safety. By synthesizing data from multiple randomized controlled trials, we aim to increase statistical power for detecting both therapeutic efficacy and adverse events. Our objective is to provide a clearer understanding of the potential role of ASIs in hypertension management, thereby informing future research and clinical practice.

Methods

The meta-analysis was conducted based on a pre-registered protocol in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD420251109962). The methodological approach, including study identification and selection, adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁷

Data sources and search strategy

A comprehensive systematic search was performed in four major databases—PubMed, Embase, Web of Science, and the Cochrane Library—to identify relevant studies published up to July 2025, with no restrictions on publication language. The search strategy was developed based on the PICOS framework, focusing primarily on two key components: individuals with uncontrolled hypertension and treatment with ASIs, including osilodrostat, lorundrostat, and baxdrostat. Full details of the search terms and strategy are provided in Supplementary Table 1.

Study selection

This study aimed to identify and include RCTs assessing the efficacy of ASIs versus placebo in the management of uncontrolled hypertension. Eligible studies met the following criteria: (1) adult patients aged ≥18 years; (2) prospective randomized clinical trial design; and (3) availability of outcome data, including changes in systolic and diastolic blood pressure and the occurrence of deaths or adverse events. The exclusion criteria were: (1) studies involving patients under 18 years of age; (2) non-randomized study designs; and (3) trials lacking a control arm.

Two independent reviewers (QS and XT) screened the titles and abstracts of all retrieved articles using NoteExpress v3.9.0 (AegeanSoftware Corp, Beijing, China), followed by full-text assessments to determine eligibility. Any discrepancies were resolved through discussion and consensus with a third reviewer (HT).

Data extraction and quality appraisal

Two researchers (QS and XT) independently extracted data from selected studies using Microsoft Excel 2017 (Microsoft, Redmond, WA, USA) and adhered to a structured data extraction form. The form included study characteristics (author, study design, study region, study population, duration of study, follow-up duration, primary endpoint), baseline characteristics (mean age, sex, body mass index (BMI), hypertension, diabetes, baseline blood pressure, estimated glomerular-filtration-rate, eGFR), intervention (aldosterone synthase inhibitors, drug dosage and drug duration), and outcome measures (Impact on systolic blood pressure and diastolic blood pressure). Two researchers (QS and XT) evaluated the quality of each included trial using the Cochrane Risk of Bias Tool 1 (ROB1).¹⁸ We resolved discrepancies by mutual consensus with a third researcher (QT).

Clinical outcomes

The objective was to evaluate the efficacy and safety of oral ASIs on blood pressure compared with placebo in the treatment of RHT. The primary efficacy outcome was the change in SBP. The primary safety outcome was serious adverse events. The secondary outcomes included changes in DBP, overall adverse events, adverse events of special interest, hyperkalemia, hypernatremia, and reduction in eGFR.

Statistical analysis

A conventional pairwise meta-analysis was performed to compare ASIs treatment with placebo in individuals with uncontrolled hypertension. The risk ratio (RR) and their corresponding 95% CIs were used as the primary effect estimate for synthesizing dichotomous outcome data and mean differences (MDs) with 95% CIs for synthesizing continuous outcome data. Given the anticipated clinical and methodological heterogeneity among the included studies, a random-effects model was employed to provide a more conservative estimate of the pooled effect size. The heterogeneity of the effect size across the studies was tested using the Q statistic (p < 0.05 was considered heterogeneous) and I² statistic (I² < 25% indicating low heterogeneity, 25% to 50% indicating moderate heterogeneity, or I² > 50% indicating high heterogeneity). Additionally, we conducted two sensitivity analyses to explore potential sources of heterogeneity. First, we performed subgroup analysis based on the type and dosage of ASIs. Second, A leave-one-out sensitivity analysis was also conducted, excluding one study at a time and repeating the analysis. To assess potential publication bias, we applied both visual and statistical approaches. Given the relatively small sample size, we utilized contour-enhanced funnel plots to evaluate the symmetry of effect estimates and to distinguish between asymmetry caused by publication bias and that arising from other factors such as heterogeneity or chance. In addition, we performed Egger's regression test to provide a quantitative assessment of small-study effects. A p-value < 0.05 was considered indicative of significant asymmetry. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of the overall evidence for the results in our analysis. GRADEpro was employed for drafting the GRADE tables. The quality of evidence ranged from very low certainty to high certainty. Publication bias was evaluated using funnel plots.

Meta-analyses were conducted using Review Manager 5.3 software (Cochrane Collaboration, Copenhagen, Denmark) and R4.3.3 software (R Foundation for Statistical Computing, Vienna, Austria). The “metafor” package was used to perform contour-enhanced funnel plots and Egger's regression test of the meta-analysis, and statistically significant results were defined as two-sided P values of < 0.05.

Outcomes

A total of 2017 articles were identified in the literature search, with 1846 remaining after duplicate removal. After thorough screening of titles, abstracts, and full texts, 5 articles comprising 5 RCTs were ultimately included in the analysis (Figure 1).^19–22

Characteristics of the eligible trials

All studies were prospective, multicentre RCTs designed to assess the efficacy and safety of ASIs therapy in patients with RHT. All the trials were conducted in developed countries, including the USA, Australia, and European countries. These trials collectively included 1958 participants and were the basis for our primary analyses. Specifically, three studies compared lorundrostat treatment with a placebo, and one study compared LCI699 with placebo. Additionally, one study evaluated baxdrostat treatment against a placebo. The average double-blind treatment duration across the trials was 10 weeks, varying between 8 to 12 weeks. The main study characteristics are shown in Table 1.

Table 1.

Characteristics of included trials.

Trial ID	Trial type	Country	No of centers	No. of patients	Duration of study	Duration of study (wk)	Follow-up duration in days	Primary endpoint	Secondary endpoint
Adam, 2013	Multicenter	USA	38	155	12 weeks, comprising a 2 -week single-blind run-in, an 8-week double-blind period, and concluding with a 2-week randomized withdrawal.	12	14	Impact on msSBP	Impact on msDBP
Luke, 2023	Multicenter	USA	43	200	14 weeks, comprising a 2-week of prescreening, a 2-week single-blind run-in, an 8-week double-blind period, and concluding with a 2-week randomized withdrawal.	12	14	Impact on mean systolic AOBP	Impact on mean diastolic AOBP
Mason, 2023	Multicenter	USA	NA	275	up to 8 weeks for pre-screening, screening, a 2-week single-blind run-in, followed by a 12-week double-blind treatment phase, and a 1-week follow up period.	24	7	Impact on systolic blood pressure	Impact on diastolic blood pressure
Laffin, 2025	Multicenter	USA	103	285	up to 4 weeks for pre-screening, screening, and placebo run-in, followed by an 8- week double-blind treatment phase, and a 4-week follow up period.	20	28	Impact on systolic blood pressure	Impact on diastolic blood pressure
Manish, 2025	Multicenter	multiple countries	159	1083	16 weeks, starting with a 2-week run-in phase, a 12-week double-blind period, and ending with a 2-week follow-up.	10	14	Impact on systolic blood pressure	Impact on diastolic blood pressure

AOBP: automated office blood pressure; msSBP: mean sitting systolic blood pressure; msDBP: mean sitting diastolic blood pressure.

A total of 1958 participants were included across the five trials. Of these, 1468 (75%) were allocated to an ASIs intervention group, while the remaining 490 (25%) were part of a placebo group. The mean age of participants ranged from 56 to 66 years, with 54% men (1057) and 46% women (901). Over 80% of participants primarily received ACE (Angiotensin-Converting Enzyme) inhibitors or ARBs (Angiotensin Receptor Blockers), and ≈ 90% underwent diuretic therapy, with a distribution of 55% to 100% in the intervention group and 56% to 100% in the control group. The baseline characteristics are presented in Table 2.

Table 2.

Baseline of included trials.

Trial ID	ASIs treatment	Comparator (s)	Age mean (SD)	Male sex, n (%)	BMI, mean (SD), kg ⁄ m²	Diabetes, n (%)	Baseline BP, mm Hg	eGFR, mean (SD), mL/min per 1.73 m²	Diagnostic criteria	ASIs treatment (Drug dosage)
Adam, 2013	Osilodrostat	Placebo	60 (10)	97(62)	33(6)	37(24)	153/90	81(17)	Systolic automated office blood pressure of 130 mm Hg or greater while taking 3 or more antihypertensive medications for at least 4 weeks at maximally tolerated doses	Osilodrostat, 0.25 mg BID or 1 mg QD or 0.5 mg BID titrated to 1 mg BID
Luke, 2023	Lorundrostat	Placebo	66 (10)	80(40)	30(4)	79(40)	143/84	84(19)	Systolic automated office blood pressure of 130 mm Hg or greater while taking 2 or more antihypertensive medications for at least 4 weeks at maximally tolerated doses	Lorundrostat, 12.5 mg, 50 mg, or 100 mg QD or 12.5 mg or 25 mg BID
Mason, 2023	Baxdrostat	Placebo	61 (11)	153(55)	32(5)	105(38)	149/88	86(18)	Mean seated blood pressure of at least 130/80 mm Hg while receiving stable doses of at least three antihypertensive medications, one of which was a diuretic	CIN-107 (Baxdrostat), 0.5 or 1 or 2 mg QD
Laffin,2025	Lorundrostat	Placebo	60 (10)	172(60)	32(5)	119(42)	142/86	80(17)	Systolic automated office blood pressure of 130 mm Hg or greater while taking 2 or more antihypertensive medications for at least 4 weeks at maximally tolerated doses	Lorundrostat, 12.5 or 50 or 100 mg QD or 12.5 or 25 mg BID
Manish, 2025	Lorundrostat	Placebo	62 (10)	575(53)	33(7)	338(31)	149/87	91(16)	Mean systolic BP ≥135 and ≤180 mm Hg and mean diastolic BP ≥65 and ≤110 mm Hg while taking stable doses of 2 to 5 prescribed antihypertensive medications	Lorundrostat, 50 or 100 mg QD

ASIs: aldosterone synthase inhibitors; BP: blood pressure.

The assessment of bias risk in each study is presented in Supplementary Figure 1. The allocation concealment was not reported in the included trials except the Launch-HTN trial, which was judged as unclear risk of bias. Blinding of outcome assessment was not reported in Launch-HTN and targetHTN, and was not feasible in BrigHTN, which was judged as high risk of bias.

Primary outcome

The primary efficacy outcome in our analysis was the change in SBP. The pooled results showed that ASIs significantly reduced SBP compared to placebo, with a mean difference of −7.08 mmHg (95% CI: −9.24 to −4.93; I² = 0%) (Figure 2(a)). The certainty of evidence was deemed moderate (Supplementary Table 2). A contour-enhanced funnel plot was visually inspected to assess potential publication bias. The plot showed a roughly symmetric distribution of studies, with most studies located in the non-significant (p > 0.05) regions (Supplementary Figure 2). No strong indication of publication bias was observed. This finding was consistent with the results of Egger's test (p = 0.075) (Supplementary Table 3). In subgroup analysis stratified by specific type of ASIs, lorundrostat (MD = −7.90 mmHg, 95% CI −10.62 to −5.17) and baxdrostat (MD = −7.20 mmHg, 95% CI −11.58 to −2.82) were both associated with significant reductions in SBP, while osilodrostat showed a smaller and non-significant effect (MD = −3.00 mmHg, 95% CI −8.94 to 2.94) (Supplementary Figure 3). There was no significant difference across subgroups (p = 0.34). Subgroup analysis stratified by specific dosage of ASIs revealed a consistent blood pressure–lowering effect at high doses (MD = −7.55 mmHg, 95% CI −10.11 to −5.00) and intermediate doses (MD = −8.51 mmHg, 95% CI −10.96 to −6.05), whereas low-dose therapy did not demonstrate a statistically significant effect. The test for subgroup differences suggested a modest dose–response relationship (p = 0.04) (Supplementary Figure 4). The leave-one-out sensitivity analysis showed no significant alteration in the effect estimate (Supplementary Table 4).

The primary safety outcome was serious adverse events. There was no significant difference between patients assigned to ASIs treatment and placebo on serious adverse events (RR,1.16; 95% CI,0.47–2.88; I² = 19%) (Figure 3(a)). The certainty of evidence was deemed low (Supplementary Table 2). The contour-enhanced funnel plot revealed a generally symmetrical distribution of the included studies, with no substantial evidence of small-study effects or publication bias. Most studies fell within areas of statistical significance (p < 0.05), suggesting that potential asymmetry, if present, is unlikely to be solely attributable to publication bias (Supplementary Figure 5). This finding was consistent with the results of Egger's test (p = 0.334) (Supplementary Table 3). Subgroup analyses stratified by specific types or dosages of ASIs and leave-one-out sensitivity analysis demonstrated consistent risk ratios for serious adverse events (Supplementary Figure 6,7, and Table 5). No fatalities were reported in the included studies.

Secondary outcomes

Significant reductions were observed among patients receiving ASIs treatment compared with receiving placebo on the change in DBP, with a mean difference of −2.96 mmHg (95% CI: −4.6 to −1.32; I² = 0%) (Figure 2(b)). As for the safety outcomes, a significant increasing was observed among patients receiving ASIs treatment compared with receiving placebo treatment on overall adverse events (RR,1.31; 95% CI,1.10–1.56; I² = 47%) ( Figure 3(b) ), and adverse events of special interest (RR,1.76; 95% CI,1.29–2.39; I² = 0%) (Figure 3(c)). No strong indication of publication bias was observed (Supplementary Figure 8–10). This finding was consistent with the results of Egger's test (Supplementary Table 3). The certainty of evidence was judged as moderate for the pooled outcomes of change in DBP, overall adverse events and adverse events of special interest.

Additionally, as to the adverse events of special interest, the risk of hyperkalemia (RR, 7.34; 95% CI, 2.07–25.98; I² = 0%) and hypernatremia (RR, 2.03; 95% CI, 1.19–3.47; I² = 0%) were significantly higher in ASIs therapy compared with placebo. The ASIs group was more associated with the risk of experiencing hypotension as compared to placebo (RR, 2.68; 95% CI, 1.05–6.85; I² = 0%). Regarding the worsening renal function outcome (defined as an increase in serum Cr of ≥0.5 mg/dL from baseline and a decrease in eGFR of 25% from baseline), two studies were included in the pooled analysis, comprising a total of 1333 participants (997 in the ASIs group and 336 in the placebo group). Results showed no clear evidence that ASIs treatment affected the worsening renal function outcome (OR = 2.52, 95% CI 0.97–6.50) (Supplementary Figure 1 1).

Discussion

Before this meta-analysis, there was strong evidence of the benefits of ASIs in patients with hypertension; however, uncertainty remained about the efficacy of ASIs in patients with RHT,¹ especially since osilodrostat had not shown a significant benefit for RHT.²³ With completion of the Target-HTN trial using lorundrostat and the BrigHTN trial using baxdrostat, there is now evidence that suppressing hormone synthesis with ASIs provides therapeutic benefit in patients with RHT.^15,24 To our knowledge, this is the first meta-analysis that has sought to examine the effectiveness of ASIs in patients with RHT. A previous systematic review has summarized the BP-lowering effects of all available ASIs, but only among patients with hypertension and only including data from the studies by Calhoun et al.,²⁵ Freeman et al.,²⁴ and Laffin et al.^1,15 Our study introduces the latest research on lorundrostat.^14,16 This analysis rigorously evaluated the efficacy and safety of ASIs in the management of RHT. The findings demonstrate a statistically significant reduction in SBP and DBP with ASIs compared to placebo. Treatment with ASIs was generally well tolerated, suggesting a favorable safety and efficacy profile for the management of RHT.

Excess aldosterone is a cardiovascular risk factor for RHT.⁹ Current treatments for hypertension in patients with high aldosterone levels often involve using MRAs, which effectively lower blood pressure, especially in those with RHT.¹² However, MRA use and efficacy may be limited due to hormonal adverse effects as well as enhancement of the nongenomic effects of aldosterone, which include increasing vascular stiffness and sympathetic nervous system activation.²⁶ The BrigHTN trial, reinforcing the role of aldosterone as a key mediator of treatment-resistant hypertension (TRH), demonstrated dose-dependent reductions in both blood pressure and markers of aldosterone secretion.²⁴ ASIs led to substantial reductions in SBP and DBP in patients with TRH.²⁴

The comprehensive analysis of primary efficacy outcomes, integrating data from all included studies, revealed significant patterns in SBP changes. These results are consistent with those of previous studies.¹ There was no evidence of heterogeneity between the studies in changes in SBP and DBP. This reduction underscores the potential of ASIs as an effective therapeutic strategy for the management of RHT. Confidence in these findings is supported by the overall high methodological quality of the included studies and the low statistical heterogeneity observed across studies and subgroups. This study evaluated and compared the antihypertensive efficacy of lorundrostat, baxdrostat, and osilodrostat in patients with RHT. Osilodrostat was the only drug that resulted in inferiority to another in head-to-head comparison (lorundrostat and baxdrostat), whereas there was no significant difference versus placebo.²⁷ This is primarily due to the limited specificity of osilodrostat for aldosterone synthase inhibition. CYP11B2, which encodes aldosterone synthase, shares more than 93% sequence homology with CYP11B1, the gene encoding 11-β-hydroxylase, the rate-limiting enzyme in cortisol biosynthesis.¹⁵ Owing to this high degree of similarity, ASIs with insufficient selectivity, such as osilodrostat, inevitably inhibit cortisol synthesis as well. Furthermore, osilodrostat markedly increases the production of 11-deoxycorticosterone, a potent mineralocorticoid receptor agonist, thereby compounding its off-target effects.^25,28 In contrast, baxdrostat and lorundrostat exhibit reduced off-target effects due to their highly selective action. Their targeted approach may prevent the potential onset of adrenal insufficiency and the reduction in effectiveness of blood-pressure-lowering activity.^24,29

We also performed more detailed subgroup analyses, which focused on the impact of different doses (low, intermediate, and high dosages). With regard to the primary endpoints, the intermediate-dose and high-dose groups performed better than the low-dose group.^15,30 In our meta-analysis, low doses of lorundrostat and baxdrostat did not result in a significantly greater reduction in SBP; intermediate-dose and high-dose of lorundrostat and baxdrostat led to improvements in SBP. Most of the included studies focused on intermediate-dose and high-dose groups, and few studies examined low-dose group.^14,31 Increasing the 50 mg/d dose of lorundrostat to 100 mg/d provided no additional benefit to participants who did not reach the goal BP using the 50 mg/d dose.¹⁴ In an initial dose-finding trial of lorundrostat, participants taking 100 mg had no greater reduction in blood pressure than those taking 50 mg.¹⁵ The results of this meta-analysis support this observation and suggest that maximal blood-pressure reduction is achieved with a daily dose of 50 mg of lorundrostat, and that the risk of adverse events is lower with this dose. Notably, while the high dose significantly reduced blood pressure statistically, there was no clear incremental benefit over the intermediate doses. This observation suggests a flattened dose-response curve, where higher doses do not proportionally increase efficacy.^15,24 Our meta-analysis findings align with those of the earlier study.³² Higher doses of osilodrostat lead to suppression of ACTH-induced cortisol release.³³

Both lorundrostat and baxdrostat demonstrated significant dose-dependent reductions in blood pressure, particularly in patients with RHT and crucially, with a minimal impact on cortisol levels.³⁴ Because the analysis of the low-dose group was based on very few studies with wide confidence intervals, these results should be considered exploratory, and definitive dose-response conclusions for individual ASIs will require direct, head-to-head comparisons in larger trials.

No significant difference in serious adverse events was observed between patients receiving ASIs treatment and those receiving placebo, suggesting a robust safety profile, notably for first-generation ASIs. This is likely attributable to the strict inclusion criteria of early studies, which predominantly involved patients with lower cardiovascular risk and few hypertension-related complications. This finding is consistent with previous ASIs intervention studies across diverse cohorts, including healthy volunteers and patients with uncontrolled or RHT.^25,30,35 However, the incidence of overall adverse events was significantly higher in the ASIs group compared with the placebo group. Treatment with ASIs may be associated with an increased risk of hyperkalemia, hyponatremia, and hypotension.

It is noteworthy that the overall risk of hyperkalemia was approximately seven times higher in the intervention group compared with the placebo group, a risk generally manageable through dose reduction or drug discontinuation.³⁶ Moreover, this risk increased with higher ASIs dosages.¹⁴ Hyperkalemia occurred more frequently with lorundrostat than with placebo, and this effect was likely amplified by concomitant treatment with an angiotensin receptor blocker.¹⁶ Lorundrostat at a once-daily dose of 50 mg was generally well tolerated, with treatment-emergent adverse events being predominantly mild, transient, and self-limiting.¹⁴ Owing to its relatively short half-life, once-daily administration of lorundrostat (50 mg) was associated with a 25% lower mean increase in serum potassium compared with twice-daily administration (25 mg, bid).¹⁵ In the BrigHTN trial, recurrent hyperkalemia was uncommon among patients treated with baxdrostat, and elevations in serum potassium resolved rapidly without the need for dose adjustment or interventions beyond standard dietary counseling.²⁴ Lorundrostat and baxdrostat are expected to cause modest initial declines in eGFR.^14,24 The acute decline in eGFR reflects a lowering of intraglomerular pressure that predicts long-term kidney protection when it coincides with BP reduction.³⁷ There were no lorundrostat-treated participants with confirmed glucocorticoid deficiency.¹⁴ Overall, this finding further supports the safety profile of ASIs in the management of hypertension.

Limitations

Our analysis has several limitations. First, our study included a relatively small number of trials. Additionally, given that ASIs were in the early phase of clinical development at the time this study was initiated, the duration of follow-up was limited to a maximum of 12 weeks. The long-term safety profile of ASIs, including sustained risks such as hyperkalemia and potential adrenal insufficiency, as well as the durability of their antihypertensive effect, remains unknown. Therefore, further large-scale and long-term Phase III trials are warranted to confirm the safety and efficacy of ASIs. Second, although heterogeneity was low for most endpoints, moderate heterogeneity was observed for safety outcomes, including serious and overall adverse events (I²: 19%–47%). This variability may reflect differences in baseline patient risk, ASIs type and dosage, definitions of adverse events, and follow-up duration across studies. Such clinical and methodological differences could have influenced the pooled safety estimates and should be taken into account when interpreting our findings. Third, although this study included high-quality randomized controlled trials, their findings may have limited generalizability due to small sample sizes, heterogeneity in study designs, diverse patient populations, differences in patient characteristics and treatment duration, and variations in the doses and types of ASIs used. In addition, the possibility of confounding related to concomitant RAAS blocker and diuretic use warrants consideration. Despite subgroup analyses based on the doses and types of ASIs, the limited statistical power resulting from small subgroup sample sizes may have led to false-negative findings; therefore, the absence of significant differences should be interpreted with caution. Finally, as with all meta-analyses, our study is subject to potential publication bias and other inherent biases, as well as the limitations of the data reported in the included RCTs.

Conclusions

Supplemental Material

sj-docx-1-jra-10.1177_14703203251411193 - Supplemental material for Efficacy and safety outcomes of aldosterone synthase inhibitors for resistant hypertension: A meta-analysis of randomized controlled trials

Supplemental material, sj-docx-1-jra-10.1177_14703203251411193 for Efficacy and safety outcomes of aldosterone synthase inhibitors for resistant hypertension: A meta-analysis of randomized controlled trials by Xiaokang Tu, Qingchun Song, Qinwei Tang, Haoyu Tan, Hao Zhang and Chengming Fan in Journal of the Renin-Angiotensin-Aldosterone System

Supplemental Material

sj-docx-2-jra-10.1177_14703203251411193 - Supplemental material for Efficacy and safety outcomes of aldosterone synthase inhibitors for resistant hypertension: A meta-analysis of randomized controlled trials

Supplemental material, sj-docx-2-jra-10.1177_14703203251411193 for Efficacy and safety outcomes of aldosterone synthase inhibitors for resistant hypertension: A meta-analysis of randomized controlled trials by Xiaokang Tu, Qingchun Song, Qinwei Tang, Haoyu Tan, Hao Zhang and Chengming Fan in Journal of the Renin-Angiotensin-Aldosterone System

Footnotes

Acknowledgements

Everyone who contributed significantly to the work has been listed.

ORCID iDs

Xiaokang Tu

Qingchun Song

Chengming Fan

Ethical approval and informed consent statements

This article does not contain any studies with human participants performed by any of the authors.

Consent to participate

Not applicable

Consent for publication

Not applicable

Authorship contributions

CF is the corresponding author. QS, XT and CF had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: QS, XT and CF. Acquisition and interpretation of data: QS, HZ, QT and XT. Statistical analysis: QS, XT, CF and QT. Drafting of the manuscript: QS, XT and QT. Critical revision of the manuscript for important intellectual content: HT, HZ and CF. Study supervision: CF. All authors have read, provided critical feedback on intellectual content and approved the final manuscript.

Funding

This work was financially supported by Hunan Provincial Health High-Level Talent Scientific Research Project (R2023017 to CF), the Scientific Research Launch Project for new employees of the Second Xiangya Hospital of Central South University.

Declaration of conflicting interests

Chengming Fan is a member of the Editorial Board of JRAAS and has no further conflicts to declare. The author did not take part in the peer review or decision-making process for this submission.

Data accessibility statement

This meta-analysis used only data extracted from publicly available RCTs. All data are available in the published articles cited in the manuscript.

Supplemental material

Supplemental material for this article is available online.

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