Novas Terapias para Hipertensão

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Therapeutics
1www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1
Published Online 
February 10, 2026 
https://doi.org/10.1016/ 
S0140-6736(25)02064-1
Hypertension Department, 
INSERM CIC1418, Hôpital 
Européen Georges Pompidou 
APHP, Université Paris Cité, 
Paris, France (Prof M Azizi MD); 
Division of Nephrology and 
Kidney Research Institute, 
University of Washington 
School of Medicine, Seattle, 
WA, USA (Prof K Tuttle MD); 
Providence Medical Research 
Center, Providence Inland 
Northwest Health, Spokane, 
WA, USA (Prof K Tuttle); 
Division of Cardiovascular 
Medicine, Department of 
Medicine, Brigham and 
Women’s Hospital, Harvard 
Medical School, Boston, MA, 
USA (J M Brown MD); Instituto 
de Cardiología, Sanatorio 
Británico, Rosario, Santa Fe, 
Argentina (D L Piskorz MD); 
Division of Cardiovascular 
Medicine, Department of 
Medicine, Jichi Medical 
University School of Medicine, 
Tochigi, Japan (Prof K Kario MD); 
University College London 
Institute of Cardiovascular 
Science and National Institute 
for Health Research UCL 
Hospitals Biomedical Research 
Centre, London, UK 
(Prof B Williams MD)
Correspondence to: 
Prof Michel Azizi, Hypertension 
Department, INSERM CIC1418, 
Hôpital Européen Georges 
Pompidou APHP, Université Paris 
Cité, Paris F-75015, France 
michel.azizi@aphp.fr
New drug therapies for hypertension
Michel Azizi, Katherine R Tuttle, Jenifer M Brown, Daniel L Piskorz, Kazuomi Kario, Bryan Williams
Despite the availability of effective antihypertensive therapies, global blood pressure control rates remain unacceptably 
low. Contributing factors, such as low treatment adherence, therapeutic inertia, and rising multimorbidity, underscore 
the need for innovative approaches to improve hypertension care. New antihypertensive drug therapies that act on 
physiological pathways beyond those targeted by conventional drug classes are emerging. These therapies include 
small interfering RNA agents that inhibit angiotensinogen synthesis as a novel approach to inhibit the renin–
angiotensin system, and new strategies to more selectively modulate aldosterone, such as aldosterone synthase 
inhibitors and non-steroidal mineralocorticoid receptor antagonists. There is also growing interest in therapies to 
enhance the action of the natriuretic peptide system. Although these innovations present valuable therapeutic 
opportunities, their benefits must be carefully balanced against considerations of safety, cost, clinical outcomes, and 
equitable access—all of which are crucial to reducing the residual burden of cardiovascular and chronic kidney 
disease.
Introduction
Arterial hypertension affects an estimated 25–30% of 
adults worldwide1 and remains the leading contributor to 
cardiovascular morbidity and mortality.2 However, 
despite the widespread availability of effective, low-cost 
antihypertensive drugs, including single-pill comb-
inations,3–6 global control rates of arterial hypertension 
remain unacceptably low.1 Multiple factors underlie this 
treatment gap, including low adherence to recommended 
lifestyle changes and medications, therapeutic inertia, 
target organ damage, rising obesity and multimorbidity, 
population ageing, and socioeconomic inequalities.7,8
The complex and multifactorial pathophysiology of 
hypertension9 means that existing pharmacological 
classes, even in combination, fail to address all contri-
buting mechanisms, particularly in patients with 
resistant hypertension, chronic kidney disease, or 
diabetes.7 These challenges have led to renewed efforts to 
develop drugs targeting novel pathways to improve blood 
pressure control in individuals with hypertension. In the 
past 10 years, novel therapeutic approaches have entered 
clinical develop ment, targeting well characterised 
pathways such as the renin–angiotensin–aldosterone 
system, endothelin receptors, and natriuretic peptide 
signalling. Further more, innovative strategies for drug 
delivery, such as RNA interference-based therapies, are 
in late-phase trials (eg, zilbesiran [NCT07181109 
NCT04936035, NCT05103332, and NCT06272487] and 
QCZ484 [NCT06857955]).
We herein review new drug therapies for hypertension 
in the context of targeting specific physiological systems. 
Device-based therapies for uncontrolled hypertension7,8 
are beyond the scope of this Therapeutics review, but 
have been recently reviewed elsewhere.10
RNA-based therapies for hypertension
RNA-based therapies have successfully been developed for 
conditions such as hypercholesterolaemia through 
selective targeting of the RNA transcription of specific 
proteins in the liver.11,12 These approaches now offer a new 
therapeutic framework for hypertension by selectively 
inhibiting the translation of the angiotensinogen mRNA, 
resulting in almost complete suppression of hepatic 
angiotensinogen production. Angiotensinogen is the 
Search strategy and selection criteria
We searched MEDLINE, Current Contents, PubMed, and 
references from relevant articles using the search terms 
“antihypertensive drug(s)”, “blood pressure-lowering 
drug(s)”, “randomised controlled trials”, “meta-analysis”, 
“systematic review”, “zilebesiran”, “IONIS-AGT-LRx”, 
“osilodrostat”, “baxdrostat”, “lorundrostat”, “dexfadrostat 
phosphate”, “BI 690517 OR vicadrostat”, “esaxerenone”, 
“ocedurenone”, “finerenone”, “aprocitentan”, “M-atrial 
natriuretic peptide”, “XXB750”, “REGN5381”, “sacubitril/
valsartan”, “soluble guanylate cyclase stimulators”, and 
“firibastat”. Abstracts and reports from meetings were 
included only when they related directly to previously 
published work. Only articles published in English between 
Jan 1, 2015, and Sept 1, 2025, were included, but we did not 
exclude commonly referenced older publications. We 
excluded the endothelin receptor antagonists sparsentan, 
avosentan, atrasentan, and zibozentan, which—although 
exerting mild blood pressure-lowering effects—have been 
evaluated only in proteinuric kidney diseases. Drugs 
developed for other indications (eg, diabetes, obesity, heart 
failure, and chronic kidney disease)—notably SGLT2 inhibitors 
and incretin therapies, GLP-1 receptor agonists, and dual 
GLP-1–glucose dependent insulinotropic polypeptide 
receptor agonists with complementary actions in lowering 
blood pressure—are not covered here because none of these 
drugs are currently licensed or recommended as 
antihypertensive agents. Finally, drugs that have only reached 
phase 1 trials (eg, REGN5381), are in phase 2 trials for 
indications other than hypertension (eg, soluble guanylate 
cyclase stimulators), or initially showed promise in lowering 
blood pressure but did not show efficacy versus placebo in 
phase 2 or 3 trials (eg, IONIS-AGT-LRx, osilodrostat, 
ocedurenone, and firibastat) are reported only in the 
appendix (p 3). See Online for appendix
http://crossmark.crossref.org/dialog/?doi=10.1016/S0140-6736(25)02064-1&domain=pdf
Therapeutics
www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-12
unique substrate for renin, and its cleavage by renin to 
generate angiotensin 1 represents the rate-limiting step of 
the renin–angiotensin system cascade.11–13 AGT gene 
expression can be silenced by either synthetic double-
stranded small interfering RNAs (siRNAs) or single- 
stranded antisense oligonucleotides, both of which, 
through distinct mechanisms, cleave the complementary 
mRNA, thereby reducing protein translation.14,15 The first-
generation antisense oligonucleotide-targeting hepatic 
angiotensinogen mRNA16 therapy was discontinued for 
lack of blood pressure-lowering efficacy (appendix p 3).
Small interfering RNAs
Zilebesiran is the first-in-class trivalent 
N-acetylgalactosamine ligand-conjugated siRNA 
targeting hepatic angiotensinogen production, with 
other agents such as QCZ484 in development 
(eg, NCT06857955). Zilebesiran is administered via 
subcutaneous injection11,12,17 and is sequesteredglomerular filtration rate. *The triple 
combination in a single pill included hydrochlorothiazide, valsartan, and amlodipine. †Responder rates and use of rescue antihypertensive medications have not been reported. ‡In a subset of 281 patients.
Table 4: Blood pressure-lowering effects and key safety issues with aprocitentan in phase 2 and 3 trials in hypertension
Therapeutics
11www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1
also common, reflecting a combination of haemodilution, 
diminished endothelin-1-mediated erythropoiesis, and 
possibly increased hepcidin levels.76 Hepatotoxicity, 
prominent with first-generation agents, is uncommon 
with newer ERAs, although liver function monitoring 
remains advisable.
Natriuretic peptide system and cyclic guanosine 
monophosphate signalling-targeted therapies
The natriuretic peptides—atrial natriuretic peptide and 
B-type natriuretic peptide—are released from the atria 
and ventricles, respectively, in response to wall stretch due 
to volume, pressure overload, or both. Their biological 
action to promote natriuresis, diuresis, vasodilation, 
suppression of renin, aldosterone, and the sympathetic 
nervous system, as well as antifibrotic, anti-inflammatory, 
and antihypertrophic effects, are principally mediated via 
binding to the atrial natriuretic peptide receptor 1.85
The challenge is that natriuretic peptides have a short 
half-life of only minutes in the systemic circulation, due 
to rapid degradation by enzymes such as neprilysin and 
clearance by the natriuretic peptide clearance receptor. 
Upon binding to the atrial natriuretic peptide receptor 1, 
atrial natriuretic peptide and B-type natriuretic peptide 
activate cyclic guanosine monophosphate signalling, 
which mediates the aforementioned action of the 
natriuretic peptides.86 Strategies have been developed to 
exploit the potential of the natriuretic peptide system to 
treat hypertension, such as augmenting the natural 
natriuretic peptide system by inhibiting the degradation 
of atrial natriuretic peptide and B-type natriuretic 
peptide, or by direct activation of the atrial natriuretic 
peptide receptor 1.
Augmenting the natriuretic peptide system: neprilysin 
inhibitors
Inhibition of neprilysin to augment the circulating levels 
of atrial natriuretic peptide and B-type natriuretic 
peptide, and prolong their half-life, has the potential to 
substantially lower blood pressure, especially when 
combined with renin–angiotensin system inhibition. 
The blood pressure-lowering potential of dual inhibition 
of both ACE and neprilysin was originally confirmed 
with omapatrilat, but its develop ment was discontinued 
because it was associated with a higher risk of angio-
oedema than ACE inhibition alone,87 probably due to 
concomitant inhibition of neprilysin, ACE, and 
aminopeptidase P, all of which participate in the 
breakdown of bradykinin.88 Subsequently, a sacubitril–
valsartan combination was developed, which combined 
the neprilysin inhibitor sacubitril with the ARB valsartan 
in a single oral tablet.89 When used at higher doses than 
in heart failure (ie, 400 mg/day), this dual-acting 
combination therapy was shown to be effective at 
lowering blood pressure in patients with mild-to-
moderate hypertension when compared with each of its 
components given alone89 and versus the ARB olmesartan 
given alone.90,91 Despite the efficacy of sacubitril–valsartan 
at lowering blood pressure, subsequent development and 
licensing of this drug primarily focused on patients with 
heart failure.92 A recent systematic review showed that 
sacubitril–valsartan (200 mg or 400 mg orally) is more 
effective than a conventional ARB or ACE inhibitor at 
lowering blood pressure when combined with a thiazide 
and a calcium channel blocker in patients with resistant 
hypertension;93 this superiority was also confirmed in 
patients of Black African ancestry.94 Furthermore, after 
52 weeks of treatment, one trial95 found that sacubitril–
valsartan reduced diffuse interstitial fibrosis and 
favourably decreased left ventricular mass in hypertensive 
patients with left ventricular hypertrophy, compared with 
valsartan alone, when both regimens were titrated and 
combined with other antihypertensives to reach a systolic 
blood pressure target of less than 140 mm Hg. Sacubitril–
valsartan is not approved for the treatment of 
hypertension in Europe and the USA.
Direct natriuretic peptide system activators
Intravenous recombinant natriuretic peptides are 
approved for decompensated heart failure, but their 
short half-life and route of administration limits broader 
use.85 Modified forms of the atrial natriuretic peptide, 
designed as ANP mimetics, are engineered to be more 
resistant to enzymatic degradation and renal clearance. A 
proof-of-concept study96 confirmed that a single 
subcutaneous injection lowered blood pressure, 
increased cyclic guanosine mono phosphate 
concentrations, and was not associated with serious 
adverse events, but the plasma half-life of ANP was only 
extended to around 1 h and the blood pressure effect 
waned substantially by 24 h.96,97 The short duration of 
action and the need for daily subcutaneous injection 
would be challenging for its adoption as a long-term 
treatment.
Conclusions
There has been renewed interest in the development of 
new antihypertensive medications; however, how these 
treatments will be integrated with established, low-cost 
generic antihypertensive drugs remains uncertain. 
Moreover, combining these novel agents into single-pill 
combination products would also be challenging given 
regulatory requirements for outcomes-based trials and the 
poor uptake of existing single-pill products, despite their 
increasing endorsement in clinical guidelines worldwide. 
Furthermore, in low-income and middle-income countries, 
where the availability, accessibility, and affordability of care 
and therapies remain constrained, demonstration of cost-
effectiveness will be essential to establish the feasibility 
and the potential global effect of these new therapeutic 
approaches. Thus, it could be argued that the focus should 
be on developing more effective systems of care to enhance 
adherence to existing low-cost treatments. However, this 
approach has proved challenging, and despite multiple 
Therapeutics
www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-112
iterations of guidelines and various models of care, overall 
global blood pressure control rates have not improved 
substantially. Moreover, recent advances in other medical 
fields challenge the assumption that we already have all of 
the treatments we need. The advent of SGLT2 inhibitors 
and GLP-1 receptor agonists has transformed the 
management of patients with high cardiovascular risk, 
chronic kidney disease, diabetes, obesity, and heart 
failure—conditions once considered adequately treated 
with existing therapies. These developments highlight the 
potential for innovative antihypertensive drugs to improve 
standards of care and address residual disease risk, even in 
a therapeutic landscape dominated by inexpensive generic 
drugs.
Unlike many drug developments in medicine, the new 
antihypertensive therapies we have discussed have the 
potential to transform hypertension management. RNA 
silencing therapies offer the potential to deliver the first 
always-on blood pressure-lowering treatment, lasting for 
at least 6 months after a single subcutaneous injection, 
overcoming the substantial problem of low treatment 
adherence. How this therapy would affect patient 
outcomes is unknown but, at a population level, even a 
modest sustained blood pressure reduction could prevent 
thousands of cardiovascular events per year.98 Furthermore, 
better targeting of disease pathophysiology with novel 
treatments such as ASIs has the potential to transform the 
treatment of blood pressure in the many millionsof 
people with (often unrecognised) aldosterone 
dysregulation as the underlying cause of their so-called 
essential hypertension.99 Together with the re-emergence 
of interest in the natriuretic peptide system as a target for 
novel therapies, these treatments could deliver the first 
new generation of targeted diuretic therapies for 
hypertension for over 70 years. As newer therapies target 
the underlying pathophysiology of hypertension more 
precisely, blood pressure control rates could improve, 
potentially reducing the number of medications required 
per patient, and with some of those treatments delivered 
as injectables in the future.
Many of these treatments will be approved for the 
treatment of hypertension simply on the basis of their 
efficacy in lowering blood pressure, once their efficacy and 
safety are adequately confirmed. However, to move beyond 
use in niche cohorts—in countries and for patients with 
the resources to deploy them—and to provide a compelling 
case for more widespread use, evidence from 
cardiovascular outcome trials would likely also be needed 
to justify their cost relative to widely available evidence-
based generic therapies. Such trials would establish 
whether these novel therapies can improve outcomes for 
the hundreds of millions of patients with uncontrolled 
hypertension, and in so doing, close the treatment gap that 
has frustrated existing treatment strategies.
Contributors
MA and BW were responsible for conceptualisation, literature search, 
and supervision. All authors contributed to creation of the figure, writing 
and revision of the manuscript, and had final responsibility for the 
decision to submit for publication.
Declaration of interests
MA reports institutional grants from Novartis, Recor Medical, 
AstraZeneca, and Sonivie; consulting fees from Novartis, Recor Medical, 
AstraZeneca, Alnylam, Medtronic, and Sonivie; honoraria for lectures 
from Servier, NovoNordisk, Boehringer Ingelheim, and Alnylam; and 
travel support from Novartis. KRT reports investigator-initiated grant 
support from Travere, Bayer, Benaroya Research Institute, and the 
Doris Duke Charitable Foundation; consultancy fees from Boehringer 
Ingelheim, Eli Lilly, Novo Nordisk, Roche–Genentech, AstraZeneca, and 
ProKidney; speaker fees from Novo Nordisk, Bayer, and Boehringer 
Ingelheim; travel support from Bayer and Novo Nordisk; is chair of data 
safety monitoring boards for the National Institute of Diabetes and 
Digestive and Kidney Disease and for the George Clinical Institute; is a 
member of the data safety monitoring board for AstraZeneca; is chair for 
the Diabetic Kidney Disease Collaborative for the American Society of 
Nephrology and for the Kidney Week 2025 Program Committee; and is a 
member of the American Heart Association/American College of 
Cardiology Cardiovascular–Kidney–Metabolic Guideline Committee. 
JMB reports consulting fees from AstraZeneca, Bayer, and Recordati 
Rare Diseases; and funding from the American Heart Association 
(grant 21CDA852429) and US National Institutes of Health/National 
Heart, Lung, and Blood Institute (grant K23HL159279). DLP reports 
consulting fees, honoraria, participation on an advisory board, and travel 
support from Novo Nordisk. KK reports research grants from Otsuka 
Pharmaceutical, Daiichi Sankyo, Sumitomo Pharma, and Nippon 
Boehringer Ingelheim; consulting fees from Sanwa Kagaku Kenkyusho; 
honoraria from Otsuka Pharmaceuticals, Daiichi Sankyo, Novartis 
Pharma, and Viatris; and participation on advisory boards for Daiichi 
Sankyo and Novartis Pharma. BW is Chief Scientific and Medical Officer 
of the British Heart Foundation; reports consulting fees from Novartis, 
AstraZeneca, Alnylam, and Antlia; and reports honoraria from 
Medtronic.
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Copyright © 2026 Elsevier Ltd. All rights reserved, including those for 
text and data mining, AI training, and similar technologies.
	New drug therapies for hypertension
	Introduction
	RNA-based therapies for hypertension
	Small interfering RNAs
	Clinical considerations for RNA-based therapies for hypertension
	Aldosterone-targeted therapies
	Aldosterone synthase inhibitors
	Non-steroidal mineralocorticoid receptor antagonists
	Clinical considerations for ASIs and MRAs for hypertension
	Endothelin-targeted therapy
	Clinical implications for ERAs for hypertension
	Natriuretic peptide system and cyclic guanosine monophosphate signalling-targeted therapies
	Augmenting the natriuretic peptide system: neprilysin inhibitors
	Direct natriuretic peptide system activators
	Conclusions
	Referencesin late 
hepatic endosomes, from which it is released slowly, 
resulting in sustained suppression of angiotensinogen 
production (a single administration can maintain efficacy 
for at least 6 months; figure).11,12 This approach 
might provide more complete and durable inhibition 
of the renin–angiotensin system than conventional 
oral angiotensin-converting enzyme (ACE) inhibitors 
and angiotensin receptor blockers (ARBs), and could 
improve adherence compared with daily oral therapies.
Zilebesiran has been evaluated in patients with mild-
to-moderate hypertension who were either untreated or 
receiving a stable regimen of up to two antihypertensive 
agents in the phase 2, dose-ranging, KARDIA-1 trial.18 At 
month 3, various subcutaneous injection doses of 
zilebesiran (150–600 mg every 6 months) had clinically 
significant reductions in 24 h ambulatory systolic blood 
pressure relative to placebo—of about 15 mm Hg 
throughout the circadian cycle—and suppression in 
serum angiotensinogen (>90%); the antihypertensive 
effect of zilebesiran was durable at 6 months (table 1).18 
In the phase 2 KARDIA-2 trial, a single 600 mg 
subcutaneous injection dose of zilebesiran as an add-on 
therapy to monotherapies (indapamide, amlodipine, or 
olmesartan) led to clinically significant 24 h systolic 
blood pressure reductions at 3 months, particularly with 
indapamide and amlodipine (table 1).19 However, the 
phase 2 KARDIA-3 trial (NCT06272487), evaluating 
zilebesiran as an add-on therapy in patients with 
uncontrolled hypertension and high cardiovascular risk, 
Figure: Mechanism of action of zilebesiran (double-stranded siRNA conjugated to trivalent GalNAc targeting angiotensinogen mRNA)
Zilebesiran is a first-in-class siRNA targeting hepatic angiotensinogen production.11,12 Zilebesiran has been chemically modified to optimise its pharmacokinetic, 
pharmacodynamic, and safety profiles and is conjugated to trivalent GalNAc, which binds to ASGPR on hepatocytes, enabling targeted liver delivery. After receptor-
mediated endocytosis, siRNA escapes from endosomes into the cytosol and is incorporated into the RISC. The guide strand directs RISC to angiotensinogen mRNA, 
leading to its cleavage (depicted by the thunderbolt symbol) and suppression of hepatic angiotensinogen synthesis. A single administration maintains efficacy for up 
to 6 months.11,12 ASGPR=asialoglycoprotein receptor. GalNAc=N-acetylgalactosamine. RISC=RNA-induced silencing complex. siRNA=small interfering RNA.
Zilbesiran
ASGPR
ASGPR
ASGPR
ASGPR
Hepatocyte
Endosome
Degradation of the
GalNAc moiety
Recycling of ASGPR
Release of 
angiotensinogen 
siRNA
RISC RISCRISC
RISC
Hybridisation of the guide
(antisense) strand with
angiotensinogen mRNA
Cleavage and degradation
of the angiotensinogen
mRNAInternalisation of the
GalNAc siRNA after
binding to the ASGPR 
Removal of the passenger
(sense) strand
Genomic DNA
Transcription
Angiotensinogen
mRNA
mRNA cleavage
Therapeutics
3www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1
did not meet its primary blood pressure endpoint at 
3 months, probably due to a larger placebo effect than 
in the earlier trials (table 1).20 Adverse events were 
infrequent, mild, and reversible across the KARDIA 
trials (table 1).
On the basis of the KARDIA-3 trial, the zilebesiran 
cardiovascular outcome study in hypertension phase 3 
trial was designed to compare zilebesiran (300 mg via 
subcutaneous injection every 6 months) with placebo in 
around 11 000 patients with uncontrolled hypertension 
and high cardiovascular disease risk.21
Clinical considerations for RNA-based therapies for 
hypertension
An siRNA that specifically targets the degradation of 
angiotensinogen mRNA in the hepatocyte offers a funda-
mentally new approach to manage hypertension with 
potential for twice-yearly dosing, particularly in patients 
KARDIA-1 (phase 2, dose-ranging),18 n=394 KARDIA-2 (phase 2, add-on therapy),19 n=663 KARDIA-3 (phase 2, add-on therapy),20 n=663
Patient 
population
Patients with mild-to-moderate hypertension either 
untreated or receiving a stable regimen of up to 
two antihypertensive medications; daytime 
ambulatory systolic blood pressure of 135–160 mm Hg 
following washout of background antihypertensive 
medications
Patients with uncontrolled hypertension despite receiving 
one or two antihypertensive medications; 24 h ambulatory systolic 
blood pressure of 130–160 mm Hg following washout of 
background antihypertensive medications and a 4-week run-in 
open-label treatment with indapamide 2·5 mg/day, amlodipine 
5 mg/day, or olmesartan 20–40 mg/day*
Patients with established cardiovascular 
disease, high cardiovascular risk or eGFR 
≥30 to 90% 
(300 mg or 600 mg by month 6)
Change in office systolic blood pressure at month 3 (difference 
vs placebo): −18·5 mm Hg (−22·8 to −14·2) with indapamide, 
−10·2 mm Hg (−13·4 to −6·9) with amlodipine, and −6·7 mm Hg 
(−10·2 to −3·3) with olmesartan; time-adjusted change in 24 h 
ambulatory systolic blood pressure through 6 months (difference 
vs placebo): −11·0 mm Hg (−14·7 to −7·3) with indapamide, 
−7·9 mm Hg (−10·6 to −5·3) with amlodipine, and −1·8 mm Hg 
(−4·6 to 1·0) with olmesartan; responder rate at month 6§: 
64·2% with indapamide vs 14·0% with placebo, 39·8% with 
amlodipine vs 13·7% with placebo, and 26·0% with olmesartan 
vs 17·2%with placebo; rescue antihypertensive medications at 
month 6: 15·5% with indapamide vs 41·7% with placebo, 
25·2% with amlodipine vs 48·7% with placebo, 42·5% with 
olmesartan vs 54·0% with placebo; angiotensinogen 
reduction: >95% (all groups)
Change in 24 h ambulatory systolic blood 
pressure at month 3‡ (difference vs placebo): 
−3·6 mm Hg (−7·7 to 0·4) with 300 mg and 
−2·6 mm Hg (−6·7 to 1·6) with 600 mg; change 
in 24 h ambulatory systolic blood pressure at 
month 6‡ (difference vs placebo): −5·5 mm Hg 
(−9·4 to −1·5) with 300 mg and −7·4 mm Hg 
(−11·3 to −3·4) with 600 mg; responder rate at 
month 6: not reported; rescue antihypertensive 
medications at month 6: not reported; 
angiotensinogen reduction: not reported
Key safety 
observations
Hyperkalaemia: 6·3% in all zilebesiran groups vs 2·7% 
with placebo; acute kidney failure: 1·0% in all 
zilebesiran groups vs 0% with placebo; eGFR change at 
month 6: −1·5% with 150 mg, −2·9% every 6 months 
and −2·7% every 3 months with 300 mg, −3·0% with 
600 mg, and −2·4% with placebo; hypotension: 4·0% in 
all zilebesiran groups vs 0% with placebo; injection-site 
reactions: 6·3% in all zilebesiran groups vs 1·0% with 
placebo
Hyperkalaemia >5·5 mmol/L: 6·1% in all zilebesiran groups vs 1·2% 
with placebo (indapamide: 3·2%; amlodipine: 6·8%; and 
olmesartan: 6·7%); ≥30% decrease in eGFR: 8·5% in all zilebesiran 
groups vs 3·0% with placebo (indapamide: 12·7%; 
amlodipine: 8·5%; and olmesartan: 6·8%); eGFR change at 
month 6: not reported; hypotension: 4·3% in all zilebesiran groups 
vs 2·1% with placebo (indapamide: 0%; amlodipine: 5·9%; and 
olmesartan: 4·7%); injection-site reactions: 3·0% in all zilebesiran 
groups vs 0·3% with placebo (indapamide: 6·3%; amlodipine: 1·7%; 
and olmesartan: 2·7%)
Hyperkalaemia >5·5 mmol/L‡: 4·4% with 
300 mg, 8·8% with 600 mg; and 4·5% with 
placebo; eGFR decrease ≥30% and 300 mg/g were preferentially assigned to olmesartan; the olmesartan dose was 20 mg for patients with eGFR ≤60 mL/min per 1·73 m² in countries 
other than the USA. †Every 6 months or every 3 months dosing combined. ‡Cohort A only. §Defined as reaching a 24 h ambulatory systolic blood pressurein patients with chronic kidney disease, diabetes, or 
when combined with other medications); hyponatraemia, hypotension, and reduced 
eGFR; contraindicated during pregnancy; specific adverse events risk with aldosterone 
synthase inhibitors: hypocortisolism or hypercortisolism, and other unexpected adverse 
events
Endothelin 1 receptor antagonists 
(aprocitentan‡)
Patients with resistant hypertension who are either intolerant 
of MRAs or for whom MRAs are contraindicated
Fluid retention, peripheral oedema, or both (caution is warranted in individuals with a 
history of heart failure); contraindicated during pregnancy
Sacubitril–valsartan§ Patients with resistant hypertension not responding to a 
conventional ARB included in a triple antihypertensive therapy 
including a diuretic; and patients with hypertension and heart 
failure with low ejection fraction
Risk of adverse events shared with all other renin–angiotensin system blockers: excessive 
hypotension and renal failure when blood pressure and renal function are renin-
dependent*, hyperkalaemia, ionic disturbances in patients with chronic kidney disease or 
when combined with other medications, haematocrit decrease or anaemia in patients 
with chronic kidney disease, pregnancy, and with other unexpected adverse events; 
specific adverse events risks: angioedema (more in Black patients) especially if combined 
with ACE inhibitors or dipeptidyl peptidase IV inhibitors
eGFR=estimated glomerular filtration rate. ACE=angiotensin converting enzyme. ARB=angiotensin receptor blocker. MRAs=mineralocorticoid receptor antagonists. *For example: elderly patients, salt depletion, 
hypovolaemia, heat wave, use of cyclo-oxygenase enzyme inhibitors, presence of renal artery stenosis, anaesthetic induction, urgent surgery, haemorrhage, septic shock, or myocardial infarction. †Alone or in 
combination with a SGLT2 inhibitor. ‡Aprocitentan is approved for the treatment of hypertension inadequately controlled by at least three antihypertensive medications in the USA, Europe, and the UK. 
§Sacubitril–valsartan is approved for the treatment of hypertension only in Japan, China, and Russia.
Table 2: Potential indications and risks of new drug therapies for hypertension
Therapeutics
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higher pre-treatment serum potassium concentrations, 
diabetes, or concomitant use of mineralocorticoid 
receptor antagonists (MRAs) or conventional renin–
angiotensin system inhibitors, necessitating more 
regular monitoring of serum potassium concentrations 
in these populations.28 In the KARDIA trials, which 
enrolled patients with a mean baseline eGFR of 
approximately 80 mL/min per 1·73 m², zilebesiran was 
associated with a mild initial decline in eGFR, similar to 
that observed with conventional renin–angiotensin 
system blockers.29 As an upstream renin–angiotensin 
system inhibitor, this effect reflects a renal haemodynamic 
mechanism: reduced intraglomerular pressure due to 
decreased transmission of elevated systemic blood 
pressure into the afferent arteriole resulting from 
improved hypertension control, together with efferent 
arteriolar vasodilatation due to angiotensin 2 
suppression.30 The long-term consequences of this early 
eGFR decline in patients with lower baseline eGFR are 
yet to be established.31
A unique clinical challenge with the long-lasting, 
siRNA-mediated inhibition of the renin–angiotensin 
system is the inability to expediently reverse the siRNA 
mechanism and resulting renin–angiotensin system 
suppression in emergencies in which the renin–
angiotensin system is usually activated to maintain blood 
pressure and circulating volume (eg, in patients with 
shock or acute volume depletion).32 In these emergency 
situations, countermeasures should include intravenous 
fluids and intravenous angiotensin 2 or vasopressor 
administration if required. Moreover, administration of 
zilebesiran to patients with undetected renal artery 
stenosis could pose a risk of acute kidney injury, similar 
to that observed with ACE inhibitors and ARBs, but less 
reversible due to the long-acting nature of the therapy—
underscoring the need for a reliable reversal strategy for 
this kind of scenario. Preclinical studies have shown that 
a complementary REVERSIR subcutaneous injection—a 
specific siRNA designed to hybridise with and inactivate 
the RISC-loaded siRNA—can restore angiotensinogen 
mRNA production and blood pressure within 48 h in 
rats.33 Although this complementary treatment will not 
be of use in an emergency setting (because the onset of 
reversal takes too long), reversal agents could be of use 
for patients in whom long-lasting renin–angiotensin 
system inhibition is no longer desirable.
Pregnancy represents another crucial concern. 
Angiotensinogen concentrations rise during pregnancy 
to support uteroplacental blood flow and maternal blood 
pressure regulation,34 and an siRNA targeting angio-
tensinogen could theoretically pose risks of maternal 
hypotension and placental insufficiency. Effective 
contraception should be recommended for women of 
childbearing potential when receiving an siRNA targeting 
angiotensinogen.
Given these considerations, careful patient selection 
and attention to baseline and post-treatment serum 
creatinine and potassium will be required to ensure safe 
and effective use of siRNAs targeting angiotensinogen. 
Their use will also necessitate thorough patient 
education, including regular use of self-measurement of 
blood pressure at home, specific precautions especially 
in case of volume depletion or pregnancy, and 
contingency plans to manage acute scenarios. If ongoing 
phase 2 and 3 trials (eg, NCT06423352, NCT06905327, 
NCT06864104, and NCT07181109) confirm the long-term 
efficacy and safety of zilebesiran and other treatments in 
this new class of therapy, they have the potential to offer 
a durable, infrequent injection-based therapy for 
hypertension, potentially reshaping future treatment 
frameworks.
Aldosterone-targeted therapies
Aldosterone is a mineralocorticoid hormone mainly 
produced by the glomerulosa cells of the outer zone of 
the adrenal cortex in response to multiple stimuli 
including hypotension, hyperkalaemia, angiotensin 2, 
and adrenocorticotrophic hormone.35,36 In the kidney, 
aldosterone acts via its mineralocorticoid receptor to 
enhance reabsorption of sodium and fluid and increase 
potassium excretion.35,36 In addition, aldosterone 
activates expression of multiple pro-inflammatory and 
profibrotic mediators in the kidneys and heart.35,36 
Aldosterone also can mediate non-genomic and 
mineralocorticoid receptor-independent mechanisms 
that contribute to endothelial dysfunction, vascular 
stiffness, and systemic vasoconstriction.37 In treatment-
resistant hypertension characterised by a blood pressure 
level remaining above threshold despite a triple 
combination antihypertensive therapy at maximally 
tolerated doses including a diuretic, the steroidal MRA 
spironolactone is recommended as a preferred fourth-
line therapy if eGFR is above 30 mL/min per 1·73 m² 
and serum potassium is below 4·5 mmol/L,7,8,38 and its 
benefits in heart failure with reduced ejection fraction 
are well recognised.39,40 However, spironolactone is 
underused due to concerns over hyperkalaemia 
(especially in chronic kidney disease)41 and anti-
androgenic and progestogenic adverse events.42 Another 
steroidal MRA, eplerenone, which does not interfere 
with progesterone or androgen receptors, can be used 
alternatively,7,8 but is less effective in lowering blood 
pressure than spironolactone.43 However, there has been 
an increasing recognition among clinicians and 
researchers that many patients with hypertension are 
likely to have some degree of aldosterone dysregulation 
(ie, renin-independent aldosterone production that is 
excessive relative to the sodium status of the patient). 
This dysregulation spansa spectrum, with increasing 
severity associated with a higher prevalence of difficult-
to-control and resistant hypertension; overt primary 
aldosteronism represents the extreme end of this 
spectrum.44–46 Therefore, the need to effectively target the 
aldosterone–mineralocorticoid receptor pathway to 
Therapeutics
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mitigate hypertension and to preserve organ function in 
patients with heart failure and chronic kidney disease, 
while improving tolerability of therapy, has motivated 
the development of two classes of aldosterone-targeted 
therapies: aldosterone synthase (CYP11B2) inhibitors 
and non-steroidal MRAs, as well as their use in 
combination with SGLT2 inhibitors for patients with, or 
at risk of, heart failure or chronic kidney disease.
Aldosterone synthase inhibitors
Aldosterone escape is a well recognised compensatory 
response to chronic inhibition of the renin–angiotensin 
system by ACE inhibitors or ARBs, and mineralcorticoid 
receptor bloackade due, in part, to the counter-regulatory 
increase in renin levels induced by all these drugs via 
different mechanisms (eg, interruption of the 
angiontensin 2 feedback loop on renin secretion for both 
ACE inhibitors and ARBs, and sodium depletion induced 
by MRAs), which partly counteracts their beneficial 
actions.47 Inhibition of aldosterone synthase in the adrenal 
cortex is an attractive therapeutic strategy, as it could 
circumvent aldosterone escape and enhance efficacy by 
attenuating both genomic and non-genomic actions of 
aldosterone.37 The pharmacological challenge has been 
overcoming the close homology (>93%) between 
aldosterone synthase (CYP11B2) and cortisol synthase 
(CYP11B1), to enable selective inhibition of the former 
without inhibiting the latter.48
Second-generation aldosterone synthase inhibitors 
(ASIs) developed to augment selectivity for aldosterone 
synthase (CYP11B2) over cortisol synthase (CYP11B1) 
include baxdrostat, lorundrostat, defaxadrostat, and 
vicadrostat.48 These ASIs have completed phase 2 and 3 
trials,49–59 although another compound (LY3045697) failed 
to move forward because of the loss of its effects with 
multiple dosing.60
Both baxdrostat and lorundrostat (which have CYP11B2 
and CYP11B1 selectivity ratios of 100 and 374, 
respectively)48 have been evaluated for the treatment of 
uncontrolled and resistant hypertension in placebo-
controlled phase 2 and 3 trials over a large dose range 
(table 3).49–55 When added to a background therapy 
of two or more antihypertensive medications, the 
placebo-corrected blood pressure-lowering effects of both 
drugs (at 6, 8, or 12 weeks) were consistent and clinically 
relevant (table 3), with the exception of the HALO trial of 
baxdrostat,50,56 which did not meet its primary blood 
pressure endpoint, possibly because of a large placebo 
effect (NCT05137002; results presented50 but not yet 
published at the time of writing). Both baxdrostat and 
lorundrostat also produced dose-dependent decreases in 
serum aldosterone concentrations (table 3) and increases 
in plasma renin activity, but did not decrease basal serum 
cortisol levels.49–55 Of note, in the phase 3 BaxHTN trial,54 
systolic blood pressure continued to decline during an 
8-week randomised withdrawal period with baxdrostat 
(increasing slightly with placebo), indicating a long 
duration of action, slow offset, and no rebound effect 
upon withdrawal. In patients with chronic kidney disease 
(with a mean eGFR 44 mL/min per 1·73 m² and median 
urinary albumin-to-creatinine ratio [UACR] 714 mg/g) 
and uncontrolled hypertension, baxdrostat lowered both 
office systolic blood pressure and UACR compared with 
placebo, but at the cost of high rates of hyperkalaemia 
(appendix p 7).55 Finally, in a small phase 2a open-label 
study in 15 patients with primary aldosteronism,57 
baxdrostat reduced systolic blood pressure and excessive 
aldosterone production and corrected hypokalaemia 
(appendix p 7).
Adverse events with baxdrostat or lorundrostat were 
mild, infrequent, and reversible across the trials, and 
were predictable on the basis of the anticipated effects of 
aldosterone synthase inhibition, including hyperkalaemia 
and hyponatraemia (table 3).49,51–54 Hyperkalaemia rates 
were much higher in patients with chronic kidney 
disease (41%) compared with patients in the placebo 
group (5%; appendix p 7).55 No cases of hypercortisolism 
or adrenal insufficiency were reported in the baxdrostat 
or lorundrostat trials.49,51–54
Another ASI, dexfadrostat phosphate (which has a 
CYP11B2-to-CYP11B1 selectivity ratio of 9),48 was 
assessed in a small, proof-of-concept study in patients 
with primary aldosteronism.58 Dexfadrostat phosphate 
reduced the aldosterone–renin ratio, aldosterone levels, 
and both ambulatory and office systolic blood pressure 
(appendix p 7).58 To our knowledge, at the time of 
writing, no further trials with this aldosterone synthase 
inhibitor are planned.
After a small phase 1 proof-of-concept study,61 vicadrostat 
(BI 690517), another highly selective ASI (CYP11B2-to-
CYP11B1 selectivity ratio of 250),62 was evaluated in a 
phase 2, placebo-controlled study assessing the efficacy 
and safety of multiple oral doses alone or in combination 
with the SGLT2 inhibitor empagliflozin in participants 
with chronic kidney disease (mean eGFR 52 mL/min per 
1·73 m² and median UACR 426 mg/g), with or without 
type 2 diabetes, receiving stable background ARB or ACE 
inhibitor (appendix p 7).59 Vicadrostat alone reduced the 
UACR and systolic blood pressure at 14 weeks in a dose-
dependent manner, with more pronounced effects 
observed when combined with empagliflozin (appendix 
p 7). Adverse events were infrequent (appendix p 7), 
although smaller increases in serum potassium 
concentrations occurred with vicadrostat in combination 
with empagliflozin, compared with vicadrostat alone.59
There are ongoing phase 3 trials of ASIs in hypertension 
(appendix p 10). Moreover, large, phase 3 outcome trials 
currently in progress for chronic kidney disease and 
heart failure are testing combinations of an ASI plus an 
SGLT2 inhibitor (appendix p 10).
Non-steroidal mineralocorticoid receptor antagonists
Mineralocorticoid receptor antagonists include 
two distinct classes: steroidal MRAs (eg, spironolactone 
Therapeutics
7www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1
Br
ig
H
TN
⁵⁵ 
(p
ha
se
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), 
n=
27
5
H
AL
O
 tr
ia
l⁵⁶
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ha
se
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n=
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(p
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se
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n=
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va
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(p
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n=
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83
Pa
tie
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te
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th
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clu
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 o
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 p
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ite
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th
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ur
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 b
ot
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se
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ce
 
sy
st
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ic 
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 m
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 H
g 
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 p
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 p
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ite
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 tw
o 
an
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ax
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st
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 ≥
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 H
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 p
lu
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nt
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 re
sis
ta
nt
 
hy
pe
rt
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n 
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ite
 tw
o 
to
 
fiv
e 
an
tih
yp
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e 
m
ed
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ns
; 2
4 
h 
am
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la
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sy
st
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ic 
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oo
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13
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 H
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4 
h 
am
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la
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 d
ia
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ic 
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oo
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 >
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 m
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 H
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ee
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 p
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on
 
pl
ac
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o 
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us
 st
an
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rd
ise
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an
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yp
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te
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(ie
, o
lm
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us
 a
 th
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ic 
w
ith
 o
r w
ith
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t 
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Un
co
nt
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 re
sis
ta
nt
 
hy
pe
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en
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ite
 tw
o 
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 fi
ve
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nt
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yp
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te
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ffi
ce
 
sy
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ic 
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re
 
13
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 H
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d 
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as
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 b
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re
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 m
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as
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 b
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 p
re
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 m
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 H
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te
r 
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ee
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ru
n-
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 p
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on
 
pl
ac
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o 
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us
 b
ac
kg
ro
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an
tih
yp
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te
ns
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In
te
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Ba
xd
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st
at
: 0
·5
 m
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g 
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ily
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r 2
 m
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ily
 
vs
 p
la
ce
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Ba
xd
ro
st
at
: 0
·5
 m
g 
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ily
, 1
 m
g 
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ily
, o
r 2
 m
g 
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ily
 vs
 p
la
ce
bo
Ba
xd
ro
st
at
: 1
 m
g 
da
ily
 o
r 2
 m
g 
da
ily
 vs
 p
la
ce
bo
Lo
ru
nd
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st
at
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5 
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g 
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ily
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2·
5 
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g 
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ice
 
da
ily
, 2
5 
m
g 
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ice
 d
ai
ly
, 5
0 
m
g 
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ily
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r 1
00
 m
g 
da
ily
 vs
 p
la
ce
bo
Lo
ru
nd
ro
st
at
: 5
0 
m
g 
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ily
 fo
r 
12
 w
ee
ks
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r 5
0 
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g 
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ily
 fo
r 
4 
w
ee
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 w
ith
 ti
tr
at
io
n 
to
 
10
0 
m
g 
da
ily
 fo
r 8
 w
ee
ks
 
(lo
ru
nd
ro
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at
 w
ith
 d
os
e 
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ju
st
m
en
t)
 vs
 p
la
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bo
Lo
ru
nd
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st
at
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0 
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ily
 fo
r 1
2 
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ee
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, o
r 
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 m
g 
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ily
 fo
r 6
 w
ee
ks
 
w
ith
 ti
tr
at
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to
 1
00
 m
g 
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ily
 fo
r 6
 w
ee
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(lo
ru
nd
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at
 w
ith
 d
os
e 
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st
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en
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 vs
 p
la
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Tr
ia
l d
ur
at
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n
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rim
ar
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12
 w
ee
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8 
w
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ks
12
 w
ee
ks
8 
w
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ks
12
 w
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ks
6 
w
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ks
Pr
im
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en
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nt
Ch
an
ge
 in
 o
ffi
ce
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st
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ic 
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oo
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es
su
re
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·1
 m
m
 H
g 
w
ith
 
ba
xd
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st
at
 0
·5
 m
g,
 
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7·
5 
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m
 H
g 
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ith
 b
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t 
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3 
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 H
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ith
 
ba
xd
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st
at
 2
 m
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 a
nd
 
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·4
 m
m
 H
g 
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ith
 p
la
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bo
; 
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ffe
re
nc
e 
vs
 p
la
ce
bo
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·0
 m
m
 H
g 
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6 
to
 2
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w
ith
 b
ax
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ta
t 0
·5
 m
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 m
m
 H
g 
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13
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 to
 −
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8)
 
w
ith
 b
ax
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ta
t 1
 m
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 a
nd
 
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1·
0 
m
m
 H
g 
(−
16
·4
 to
 −
5·
5)
 
w
ith
 b
ax
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ta
t 2
 m
g
Ch
an
ge
 in
 o
ffi
ce
 sy
st
ol
ic 
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oo
d 
pr
es
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re
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·0
 m
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 H
g 
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ith
 
ba
xd
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 0
·5
 m
g;
 −
16
·0
 m
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 H
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ith
 b
ax
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t 1
 m
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9·
8 
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 H
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ith
 b
ax
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t 
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nd
 −
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 m
m
 H
g 
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ith
 
pl
ac
eb
o;
 d
iff
er
en
ce
 vs
 p
la
ce
bo
 
(m
ea
n 
[S
E]
)†
: −
0·
5 
m
m
 H
g 
(±
2·
21
) 
w
ith
 b
ax
dr
os
ta
t 0
·5
 m
g,
 
0·
6 
m
m
 H
g 
(±
2·
20
) w
ith
 
ba
xd
ro
st
at
 1
 m
g,
 a
nd
 −
3·
2 
m
m
 H
g 
(±
2·
23
) w
ith
 b
ax
dr
os
ta
t 2
 m
g
Ch
an
ge
 in
 o
ffi
ce
 sy
st
ol
ic 
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oo
d 
pr
es
su
re
: –
14
·5
 m
m
 H
g 
w
ith
 
ba
xd
ro
st
at
 1
 m
g,
 –1
5·
7 
m
m
 H
g 
w
ith
 b
ax
dr
os
ta
t 2
 m
g,
 a
nd
 
–5
·8
 m
m
 H
g 
w
ith
 p
la
ce
bo
; 
di
ffe
re
nc
e 
vs
 p
la
ce
bo
: 
–8
·7
 m
m
 H
g 
(−
 1
1·
5 
to
 −
5·
8)
 
w
ith
 b
ax
dr
os
ta
t 1
 m
g,
 a
nd
 
–9
·8
 m
m
 H
g 
(−
 1
2·
6 
to
 −
7·
0)
 
w
ith
 b
ax
dr
os
ta
t 2
 m
g
Ch
an
ge
 in
 o
ffi
ce
 sy
st
ol
ic 
bl
oo
d 
pr
es
su
re
: 
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·6
 m
m
 H
g 
w
ith
 lo
ru
nd
ro
st
at
 1
2·
5 
m
g,
 
−1
1·
3 
m
m
 H
g 
w
ith
 lo
ru
nd
ro
st
at
 
12
·5
 m
g 
tw
ice
 d
ai
ly
, −
11
·1
 m
m
 H
g 
w
ith
 
lo
ru
nd
ro
st
at
 2
5 
m
g 
tw
ice
 d
ai
ly
, −
13
·7
 m
m
 H
g 
w
ith
 lo
ru
nd
ro
st
at
 5
0 
m
g,
 −
11
·9
 m
m
 H
g 
w
ith
 
lo
ru
nd
ro
st
at
 1
00
 m
g,
 −
4·
1 
m
m
 H
g 
w
ith
 
pl
ac
eb
o;
 d
iff
er
en
ce
 vs
 p
la
ce
bo
 (m
ea
n 
[9
0%
 C
I])
: 
−1
·5
 m
m
 H
g 
(−
8·
3 
to
 5
·3
) w
ith
 lo
ru
nd
ro
st
at
 
12
·5
 m
g,
 −
7·
2 
m
m
 H
g 
(−
14
·0
 to
 −
0·
4)
 w
ith
 
lo
ru
nd
ro
st
at
 1
2·
5 
m
g 
tw
ice
 d
ai
ly
, −
7·
0 
m
m
 H
g 
(−
13
·1
 to
 −
0·
8)
 w
ith
 lo
ru
nd
ro
st
at
 
25
 m
g 
tw
ice
 d
ai
ly
, −
9·
6 
m
m
 H
g 
(−
15
·8
 to
 −
3·
4)
 
w
ith
 lo
ru
nd
ro
st
at
 5
0 
m
g,
 a
nd
−7
·8
 m
m
 H
g 
(−
14
·1
 to
 −
1·
5)
 w
ith
 lo
ru
nd
ro
st
at
 1
00
 m
g
Ch
an
ge
 in
 2
4 
h 
am
bu
la
to
ry
 
sy
st
ol
ic 
bl
oo
d 
pr
es
su
re
: 
−1
5·
4 
m
m
 H
g 
w
ith
 
lo
ru
nd
ro
st
at
 5
0 
m
g,
 
−1
3·
9 
m
m
 H
g 
w
ith
 
lo
ru
nd
ro
st
at
 w
ith
 d
os
e 
ad
ju
st
m
en
t, 
an
d 
−7
·9
 m
m
 H
g 
w
ith
 p
la
ce
bo
; d
iff
er
en
ce
 
vs
 p
la
ce
bo
 (m
ea
n 
[9
7·
5%
 C
I])
: 
−7
·9
 m
m
 H
g 
(−
13
·3
 to
 −
2·
6)
 
w
ith
 lo
ru
nd
ro
st
at
 5
0 
m
g,
 a
nd
 
−6
·5
 m
m
 H
g 
(−
11
·8
 to
 −
1·
2)
 
w
ith
 lo
ru
nd
ro
st
at
 w
ith
 d
os
e 
ad
ju
st
m
en
t
Ch
an
ge
 in
 o
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primary aldosteronism, 
chronic kidney disease, or heart failure (table 2). How 
ASIs compare with MRAs in terms of efficacy, tolerability, 
and safety is unknown due to the absence of head-to-
head trials across various clinical conditions.74
Endothelin-targeted therapy
Endothelin-1 is one of the most potent vasoconstrictors 
implicated in the pathogenesis of both hypertension and 
chronic kidney disease.75,76 Endothelin-1 exerts its effects 
through two G protein-coupled receptors widely 
distributed across multiple organ systems: the 
endothelin receptor type A, primarily expressed on 
vascular smooth muscle cells, which mediates 
vasoconstriction and fibrosis; and the endothelin 
receptor type B, located on endothelial cells (where it 
promotes vasodilation via nitric oxide release) and on 
kidney tubular epithelial cells and vascular smooth 
muscle.75,76 In the setting of hypertension and chronic 
kidney disease, endothelin-1 expression is upregulated, 
which provides a strong rationale for blockade of 
endothelin-1 signalling to reduce blood pressure and 
slow chronic kidney disease progression.75,76 Endothelin 
receptor antagonists (ERAs) can be either selective to the 
endothelin receptor type A, or act as antagonists to both 
the endothelin receptor type A and the endothelin 
receptor type B (dual ERAs).
Even though the first dual ERAs (ie, bosentan and 
darusentan) showed significant blood pressure 
reductions in patients with hypertension, their 
Therapeutics
www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-110
development was discontinued due to adverse events, 
including fluid overload, peripheral oedema, and 
hepatotoxicity.77,78
Aprocitentan, another dual ERA, was later developed 
for treatment of hypertension. After an 8-week, phase 2, 
dose-finding trial (table 4),79 aprocitentan was evaluated in 
a large phase 3 study conducted in patients with resistant 
hypertension, all of whom were maintained on a triple 
fixed-dose combination in a single pill of guideline-
directed therapy.80 At 4 weeks, systolic blood pressure was 
clinically significantly reduced with aprocitentan at 
12·5 mg and 25 mg versus placebo, and the reduction 
was sustained through 48 weeks at the 25 mg dose 
(table 4).
Clinical implications for ERAs for hypertension
Aprocitentan is approved in the USA, Europe, and 
the UK for the treatment of hypertension inadequately 
controlled by at least three antihypertensive 
medications.81–83 Patients with resistant hypertension who 
are either intolerant of MRAs or for whom MRAs are 
contraindicated could be candidates for this therapy 
(table 2).7 Given its teratogenic potential, aprocitentan is 
contraindicated during pregnancy. Caution is warranted 
in individuals with a history of heart failure.
Dose-related fluid retention (eg, peripheral oedema, 
weight gain, and heart failure) remains a key treatment-
limiting adverse effect of ERAs, particularly in patients 
with chronic kidney disease or pre-existing cardiovascular 
disease.76 Fluid retention, peripheral oedema, or both were 
the most frequently reported adverse events with 
aprocitentan (table 4),80 which is also a concern especially 
in the context of resistant hypertension, which is 
often a sodium-retaining state. The underlying mech-
anisms of fluid retention are multifactorial and 
incompletely understood. Management strategies include 
co-administration or increase in dose of diuretics as part of 
the background antihypertensive medications.80 In patients 
with chronic kidney disease, the lowest available dose of 
aprocitentan should be considered. Combining ERAs with 
SGLT2 inhibitors could offer additional benefit, mitigating 
fluid retention while enhancing reductions in albuminuria 
and blood pressure.76,84 When initiated, ERAs also induce a 
modest, reversible decline in eGFR (attributable to efferent 
arteriolar vasodilation).76 Monitoring for anaemia is 
recommended, as mild reductions in haemoglobin are 
PRECISION study⁸⁵ (phase 3), n=730 Dose-response study⁸⁴ (phase 2), n=490
Patient 
population
Patients with resistant hypertension despite three or more antihypertensive 
medications; unattended seated systolic blood pressure of ≥140 mm Hg 
despite at least 4 weeks of treatment with a triple combination in a single 
pill continued throughout the trial*
Patients with grade 1 to 2 hypertension; unattended seated diastolic blood pressure of 
≥90 mm Hg to