New drug therapies for hypertension.

# New drug therapies for hypertension *The Lancet 2026* Therapeutics New drug therapies for hypertension Michel Azizi, Katherine R Tuttle, Jenifer M Brown, Daniel L Piskorz, Kazuomi Kario, Bryan Williams Despite the availability of eective antihypertensive therapies, global blood pressure control rates remain unacceptably Published Online low. Contributing factors, such as low treatment adherence, therapeutic inertia, and rising multimorbidity, underscore February 10, 2026 the need for innovative approaches to improve hypertension care. New antihypertensive drug therapies that act on https://doi.org/10.1016/ S0140-6736(25)02064-1 physiological pathways beyond those targeted by conventional drug classes are emerging. These therapies include Hypertension Department, small interfering RNA agents that inhibit angiotensinogen synthesis as a novel approach to inhibit the renin– INSERM CIC1418, Hôpital angiotensin system, and new strategies to more selectively modulate aldosterone, such as aldosterone synthase Européen Georges Pompidou inhibitors and non-steroidal mineralocorticoid receptor antagonists. There is also growing interest in therapies to APHP, Université Paris Cité, enhance the action of the natriuretic peptide system. Although these innovations present valuable therapeutic Paris, France (Prof M Azizi MD); Division of Nephrology and opportunities, their benefits must be carefully balanced against considerations of safety, cost, clinical outcomes, and Kidney Research Institute, equitable access—all of which are crucial to reducing the residual burden of cardiovascular and chronic kidney University of Washington disease. School of Medicine, Seattle, WA, USA (Prof K Tuttle MD); Providence Medical Research Introduction inhibiting the translation of the angiotensinogen mRNA, Center, Providence Inland Arterial hypertension aects an estimated 25–30% of resulting in almost complete suppression of hepatic Northwest Health, Spokane, adults worldwide1 and remains the leading contributor to angiotensinogen production. Angiotensinogen is the WA, USA (Prof K Tuttle); Division of Cardiovascular cardiovascular morbidity and mortality.2 However, Medicine, Department of despite the widespread availability of eective, low-cost Medicine, Brigham and antihypertensive drugs, including single-pill comb- Search strategy and selection criteria Women’s Hospital, Harvard inations,3–6 global control rates of arterial hypertension Medical School, Boston, MA, We searched MEDLINE, Current Contents, PubMed, and USA (J M Brown MD); Instituto remain unacceptably low.1 Multiple factors underlie this references from relevant articles using the search terms de Cardiología, Sanatorio treatment gap, including low adherence to recommended “antihypertensive drug(s)”, “blood pressure-lowering Británico, Rosario, Santa Fe, lifestyle changes and medications, therapeutic inertia, drug(s)”, “randomised controlled trials”, “meta-analysis”, Argentina (D L Piskorz MD); target organ damage, rising obesity and multimorbidity, Division of Cardiovascular “systematic review”, “zilebesiran”, “IONIS-AGT-LRx”, Medicine, Department of population ageing, and socioeconomic inequalities.7,8 “osilodrostat”, “baxdrostat”, “lorundrostat”, “dexfadrostat Medicine, Jichi Medical The complex and multifactorial pathophysiology of phosphate”, “BI 690517 OR vicadrostat”, “esaxerenone”, University School of Medicine, hypertension9 means that existing pharmacological “ocedurenone”, “finerenone”, “aprocitentan”, “M-atrial Tochigi, Japan (Prof K Kario MD); classes, even in combination, fail to address all contri- University College London natriuretic peptide”, “XXB750”, “REGN5381”, “sacubitril/ Institute of Cardiovascular buting mechanisms, particularly in patients with valsartan”, “soluble guanylate cyclase stimulators”, and Science and National Institute resistant hypertension, chronic kidney disease, or “firibastat”. Abstracts and reports from meetings were for Health Research UCL diabetes.7 These challenges have led to renewed eorts to included only when they related directly to previously Hospitals Biomedical Research develop drugs targeting novel pathways to improve blood Centre, London, UK published work. Only articles published in English between (Prof B Williams MD) pressure control in individuals with hypertension. In the Jan 1, 2015, and Sept 1, 2025, were included, but we did not Correspondence to: past 10 years, novel therapeutic approaches have entered exclude commonly referenced older publications. We Prof Michel Azizi, Hypertension clinical develop ment, targeting well characterised excluded the endothelin receptor antagonists sparsentan, Department, INSERM CIC1418, pathways such as the renin–angiotensin–aldosterone avosentan, atrasentan, and zibozentan, which—although Hôpital Européen Georges system, endothelin receptors, and natriuretic peptide Pompidou APHP, Université Paris exerting mild blood pressure-lowering effects—have been Cité, Paris F-75015, France signalling. Further more, innovative strategies for drug evaluated only in proteinuric kidney diseases. Drugs michel.azizi@aphp.fr delivery, such as RNA interference-based therapies, are developed for other indications (eg, diabetes, obesity, heart in late-phase trials (eg, zilbesiran [NCT07181109 failure, and chronic kidney disease)—notably SGLT2 inhibitors NCT04936035, NCT05103332, and NCT06272487] and and incretin therapies, GLP-1 receptor agonists, and dual QCZ484 [NCT06857955]). GLP-1–glucose dependent insulinotropic polypeptide We herein review new drug therapies for hypertension receptor agonists with complementary actions in lowering in the context of targeting specific physiological systems. blood pressure—are not covered here because none of these Device-based therapies for uncontrolled hypertension7,8 drugs are currently licensed or recommended as are beyond the scope of this Therapeutics review, but antihypertensive agents. Finally, drugs that have only reached have been recently reviewed elsewhere.10 phase 1 trials (eg, REGN5381), are in phase 2 trials for indications other than hypertension (eg, soluble guanylate RNA-based therapies for hypertension cyclase stimulators), or initially showed promise in lowering RNA-based therapies have successfully been developed for blood pressure but did not show efficacy versus placebo in conditions such as hypercholesterolaemia through phase 2 or 3 trials (eg, IONIS-AGT-LRx, osilodrostat, selective targeting of the RNA transcription of specific ocedurenone, and firibastat) are reported only in the proteins in the liver.11,12 These approaches now oer a new appendix (p 3). See Online for appendix therapeutic framework for hypertension by selectively www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 1 Therapeutics unique substrate for renin, and its cleavage by renin to of the renin–angiotensin system than conventional generate angiotensin 1 represents the rate-limiting step of oral angiotensin-converting enzyme (ACE) inhibitors the renin–angiotensin system cascade.11–13 AGT gene and angiotensin receptor blockers (ARBs), and could expression can be silenced by either synthetic double- improve adherence compared with daily oral therapies. stranded small interfering RNAs (siRNAs) or single- Zilebesiran has been evaluated in patients with mild- stranded antisense oligonucleotides, both of which, to-moderate hypertension who were either untreated or through distinct mechanisms, cleave the complementary receiving a stable regimen of up to two antihypertensive mRNA, thereby reducing protein translation.14,15 The first- agents in the phase 2, dose-ranging, KARDIA-1 trial.18 At generation antisense oligonucleotide-targeting hepatic month 3, various subcutaneous injection doses of angiotensinogen mRNA16 therapy was discontinued for zilebesiran (150–600 mg every 6 months) had clinically lack of blood pressure-lowering ecacy (appendix p 3). significant reductions in 24 h ambulatory systolic blood pressure relative to placebo—of about 15 mm Hg Small interfering RNAs throughout the circadian cycle—and suppression in Zilebesiran is the first-in-class trivalent serum angiotensinogen (>90%); the antihypertensive N-acetylgalactosamine ligand-conjugated siRNA eect of zilebesiran was durable at 6 months (table 1).18 targeting hepatic angiotensinogen production, with In the phase 2 KARDIA-2 trial, a single 600 mg other agents such as QCZ484 in development subcutaneous injection dose of zilebesiran as an add-on (eg, NCT06857955). Zilebesiran is administered via therapy to monotherapies (indapamide, amlodipine, or subcutaneous injection11,12,17 and is sequestered in late olmesartan) led to clinically significant 24 h systolic hepatic endosomes, from which it is released slowly, blood pressure reductions at 3 months, particularly with resulting in sustained suppression of angiotensinogen indapamide and amlodipine (table 1).19 However, the production (a single administration can maintain ecacy phase 2 KARDIA-3 trial (NCT06272487), evaluating for at least 6 months; figure).11,12 This approach zilebesiran as an add-on therapy in patients with might provide more complete and durable inhibition uncontrolled hypertension and high cardiovascular risk, Zilbesiran Hepatocyte ASGPR ASGPR Recycling of ASGPR ASGPR Endosome Cleavage and degradation ASGPR of the angiotensinogen Internalisation of the RISC mRNA Degradation of the GalNAc siRNA after GalNAc moiety binding to the ASGPR mRNA cleavage Release of Removal of the passenger angiotensinogen (sense) strand siRNA RISC RISC RISC Hybridisation of the guide (antisense) strand with angiotensinogen mRNA Angiotensinogen mRNA Transcription Genomic DNA 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. 2 www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 Therapeutics did not meet its primary blood pressure endpoint at around 11 000 patients with uncontrolled hypertension 3 months, probably due to a larger placebo eect than and high cardiovascular disease risk.21 in the earlier trials (table 1).20 Adverse events were infrequent, mild, and reversible across the KARDIA Clinical considerations for RNA-based therapies for trials (table 1). hypertension On the basis of the KARDIA-3 trial, the zilebesiran An siRNA that specifically targets the degradation of cardiovascular outcome study in hypertension phase 3 angiotensinogen mRNA in the hepatocyte oers a funda- trial was designed to compare zilebesiran (300 mg via mentally new approach to manage hypertension with subcutaneous injection every 6 months) with placebo in 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 Patients with mild-to-moderate hypertension either Patients with uncontrolled hypertension despite receiving Patients with established cardiovascular population untreated or receiving a stable regimen of up to one or two antihypertensive medications; 24 h ambulatory systolic disease, high cardiovascular risk or eGFR two antihypertensive medications; daytime blood pressure of 130–160 mm Hg following washout of ≥30 to <60 mL/min per 1·73 m² and ambulatory systolic blood pressure of 135–160 mm Hg background antihypertensive medications and a 4-week run-in uncontrolled hypertension on two to following washout of background antihypertensive open-label treatment with indapamide 2·5 mg/day, amlodipine four antihypertensive medications (including a medications 5 mg/day, or olmesartan 20–40 mg/day* calcium channel blocker or a diuretic); 24 h ambulatory systolic blood pressure of 140–170 mm Hg; cohort A eGFR ≥45 mL/min per 1·73 m²; and cohort B eGFR 30 mL/min per 1·73 m² to <45 mL/min per 1·73 m² (ongoing) Intervention Zilebesiran (subcutaneous injection) 150 mg every Zilebesiran (subcutaneous injection) 600 mg vs placebo as a single Cohort A: zilebesiran (subcutaneous injection) 6 months, 300 mg every 6 months or every 3 months, dose 300 mg or 600 mg vs placebo as a single dose; or 600 mg every 6 months, vs placebo cohort B: zilebesiran (subcutaneous injection) 150 mg, 300 mg or 600 mg vs placebo, as a single dose (ongoing) Trial duration 6 months 6 months 6 months Primary Change in 24 h ambulatory systolic blood pressure at Change in 24 h ambulatory systolic blood pressure at month 3: Change in office systolic blood pressure at endpoint month 3: −7·3 mm Hg with 150 mg, −10·0 mm Hg† −15·7 mm Hg with indapamide, −10·5 mm Hg with amlodipine, month 3†: −12·3 mm Hg with with 300 mg, −8·9 mm Hg with 600 mg, and −7·7 mm Hg with olmesartan, and −3·7 mm Hg, −0·7 mm Hg, and 300 mg,−10·6 mm Hg with 600 mg, and 6·8 mm Hg with placebo; difference vs placebo: −3·2 mm Hg with placebo, respectively; difference vs placebo: −7·3 mm Hg with placebo; difference −14·1 mm Hg (−19·2 to −9·0) with 150 mg, −12·1 mm Hg (−16·5 to −7·6) with indapamide, −9·7 mm Hg vs placebo‡: −5·0 mm Hg (−9·9 to −0·2) with −16·7 mm Hg (−21·2 to −12·3)† with 300 mg, and (−12·9 to −6·6) with amlodipine, and −4·5 mm Hg (−8·2 to −0·8) 300 mg and −3·9 mm Hg (−8·2 to 1·0) with −15·7 mm Hg (−20·8 to −10·6) with 600 mg with olmesartan 600 mg Additional Change in office systolic blood pressure at month 3 Change in office systolic blood pressure at month 3 (difference Change in 24 h ambulatory systolic blood endpoints (difference vs placebo): −9·6 mm Hg (−13·8 to −5·3) vs placebo): −18·5 mm Hg (−22·8 to −14·2) with indapamide, pressure at month 3‡ (difference vs placebo): with 150 mg, −12·0 mm Hg (−15·7 to −8·3)† with −10·2 mm Hg (−13·4 to −6·9) with amlodipine, and −6·7 mm Hg −3·6 mm Hg (−7·7 to 0·4) with 300 mg and 300 mg, and −9·1 mm Hg (−13·4 to −4·8) with 600 mg; (−10·2 to −3·3) with olmesartan; time-adjusted change in 24 h −2·6 mm Hg (−6·7 to 1·6) with 600 mg; change change in 24 h ambulatory systolic blood pressure at ambulatory systolic blood pressure through 6 months (difference in 24 h ambulatory systolic blood pressure at 6 months (difference vs placebo): −11·1 mm Hg vs placebo): −11·0 mm Hg (−14·7 to −7·3) with indapamide, month 6‡ (difference vs placebo): −5·5 mm Hg (−15·8 to −6·4) with 150 mg, −14·5 mm Hg −7·9 mm Hg (−10·6 to −5·3) with amlodipine, and −1·8 mm Hg (−9·4 to −1·5) with 300 mg and −7·4 mm Hg (−19·1 to −9·9)† with 300 mg, and −14·2 mm Hg (−4·6 to 1·0) with olmesartan; responder rate at month 6§: (−11·3 to −3·4) with 600 mg; responder rate at (−18·9 to −9·5) with 600 mg; responder rate at 64·2% with indapamide vs 14·0% with placebo, 39·8% with month 6: not reported; rescue antihypertensive month 6§: 30·8% with 150 mg, 50·7% every 6 months amlodipine vs 13·7% with placebo, and 26·0% with olmesartan medications at month 6: not reported; and 38·7% every 3 months with 300 mg, 47·4% with vs 17·2% with placebo; rescue antihypertensive medications at angiotensinogen reduction: not reported 600 mg, and 6·7% with placebo; add-on use of at least month 6: 15·5% with indapamide vs 41·7% with placebo, one antihypertensive medication through 6 months: 25·2% with amlodipine vs 48·7% with placebo, 42·5% with 32·1% with 150 mg, 20·5% every 6 months and 26·7% olmesartan vs 54·0% with placebo; angiotensinogen every 3 months with 300 mg, 27·6% with 600 mg, and reduction: >95% (all groups) 52·0% with placebo; angiotensinogen reduction: >90% (300 mg or 600 mg by month 6) Key safety Hyperkalaemia: 6·3% in all zilebesiran groups vs 2·7% Hyperkalaemia >5·5 mmol/L: 6·1% in all zilebesiran groups vs 1·2% Hyperkalaemia >5·5 mmol/L‡: 4·4% with observations with placebo; acute kidney failure: 1·0% in all with placebo (indapamide: 3·2%; amlodipine: 6·8%; and 300 mg, 8·8% with 600 mg; and 4·5% with zilebesiran groups vs 0% with placebo; eGFR change at olmesartan: 6·7%); ≥30% decrease in eGFR: 8·5% in all zilebesiran placebo; eGFR decrease ≥30% and <60 mL/min month 6: −1·5% with 150 mg, −2·9% every 6 months groups vs 3·0% with placebo (indapamide: 12·7%; per 1·73 m²‡: 5·5% with 300 mg, 8·8% with and −2·7% every 3 months with 300 mg, −3·0% with amlodipine: 8·5%; and olmesartan: 6·8%); eGFR change at 600 mg, and 1·1% with placebo; eGFR change 600 mg, and −2·4% with placebo; hypotension: 4·0% in month 6: not reported; hypotension: 4·3% in all zilebesiran groups at month 6: not reported; hypotension‡: all zilebesiran groups vs 0% with placebo; injection-site vs 2·1% with placebo (indapamide: 0%; amlodipine: 5·9%; and 3·3% with 300 mg; 4·4% with 600 mg; reactions: 6·3% in all zilebesiran groups vs 1·0% with olmesartan: 4·7%); injection-site reactions: 3·0% in all zilebesiran 3·4% with placebo; injection-site reactions: not placebo groups vs 0·3% with placebo (indapamide: 6·3%; amlodipine: 1·7%; reported and olmesartan: 2·7%) Changes in blood pressure are expressed as means, and differences vs placebo are expressed as mean (95% CI), unless otherwise stated. eGFR=estimated glomerular filtration rate. *Patients with eGFR <45 mL/min per 1·73 m² or urine albumin–creatinine ratio >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 pressure <130 mm Hg, a ≥20 mm Hg reduction from baseline, or both, without rescue medication. Table 1: Blood pressure-lowering effects, angiotensinogen suppression, and key safety issues with zilebesiran in three phase 2 trials conducted in patients with hypertension www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 3 Therapeutics for whom sustained and long-term blood pressure control concentrations, even in the setting of elevated plasma is crucial but dicult to achieve with conventional renin.23 Furthermore, zilebesiran does not increase plasma medications (appendix p 5). A key additional advantage to angiotensin 1–7 or activate the bradykinin–nitric oxide– this approach is sustained adherence to treatment because cyclic guanosine monophosphate pathway, which have therapy remains active for at least 6 months (appendix p 5). been speculated to contribute to the benefits of treatment However, most patients would still require additional daily with ACE inhibitors or ARBs beyond their eect on blood antihypertensive medications for optimal blood pressure pressure (appendix p 6)11,12 and to the bradykinin-dependent control, as zilebesiran alone achieves 24 h ambulatory adverse eects of ACE inhibitors, notably cough,24 and, blood pressure control in only about 50% of patients more rarely, angio-oedema.25 Finally, zilebesiran and other (increasing to approximately 65% when combined with RNA-based therapies targeting angiotensinogen, which indapamide; table 1). Even in patients with low adherence induce sustained angiotensin 2 suppression, might not to conventional treatment, zilebesiran alone would still have the neuroprotective benefits specifically attributed to provide an improvement in blood pressure control. The ARBs as compared with ACE inhibitors.26 The prolonged duration of action of zilebesiran and consistent neuroprotective eects of ARBs have been attributed to 24 h ecacy for up to 24 weeks could make this treatment increased angiotensin 2 and redirected signalling to type-2 approach suitable for various types of patients with and type-4 angiotensin 2 receptors (appendix p 6), which hypertension (table 2).11,12 A final point for consideration is have been shown experimentally to mitigate oxidative the consequence of upstream inhibition of the renin– stress and neuroinflammation, improve cerebral angiotensin system with siRNA targeting angiotensinogen perfusion, and reduce amyloid β accumulation and tau (appendix p 6). Conventional renin–angiotensin system hyperphosphorylation.27 blockers provoke a counter-regulatory rise in plasma renin The eects of zilebesiran on serum potassium concentration by disrupting angiotensin 2-mediated concentrations and estimated glomerular filtration rate negative feedback at the level of the juxtaglomerular (eGFR) have been predictable and consistent with those apparatus.22 In the presence of physiological circulating expected from renin–angiotensin system inhibition concentrations of angiotensinogen, the compensatory rise (table 1). The risk of mild and reversible hyperkalaemia, in renin can partly restore angiotensin 1 and 2 levels, as reported in the KARDIA trials, is similar to that from blunting ecacy of oral conventional therapies. In conventional renin–angiotensin system inhibitors and contrast, sustained depletion of angiotensinogen by a will be dependent on the patient population, and siRNA prevents the increase in all angiotensin peptide increased in individuals with chronic kidney disease, Potential indications Potential risks RNA-based therapies targeting Patients with elevated cardiovascular and renal risk; patients Risk of adverse events shared with all other renin–angiotensin system blockers: excessive angiotensinogen with very low adherence to treatment; patients with ACE hypotension and renal failure when blood pressure and renal function are renin- inhibitor-related or ARB-related adverse events; patients with dependent* or when combined with conventional oral renin–angiotensin system renin–angiotensin system-dependent target organ damage blockers (dual renin–angiotensin system blockade), hyperkalaemia, ionic disturbances in such as left ventricular hypertrophy, endothelium dysfunction, patients with chronic kidney disease or when combined with other medications, or early kidney damage (eg, microalbuminuria); Black patients; haematocrit decrease, or anaemia in patients with chronic kidney disease, and other and patients with oestrogen-induced hypertension unexpected adverse events; contraindicated during pregnancy; specific adverse event risks: permanent and continuous renin–angiotensin system blockade and need for rapid reversal of the effect Aldosterone-targeted therapies Patients with difficult-to-control hypertension including Risk of adverse events shared between aldosterone synthase inhibitors and non-steroidal (aldosterone synthase inhibitors uncontrolled or resistant hypertension; patients with MRAs: hyperkalaemia (especially in patients with chronic kidney disease, diabetes, or and non-steroidal MRAs) aldosterone dysregulation; patients with primary when combined with other medications); hyponatraemia, hypotension, and reduced aldosteronism; patients with heart failure and low or preserved eGFR; contraindicated during pregnancy; specific adverse events risk with aldosterone ejection fraction†; and patients with diabetes, obesity, or synthase inhibitors: hypocortisolism or hypercortisolism, and other unexpected adverse chronic kidney disease and albuminuria† events Endothelin 1 receptor antagonists Patients with resistant hypertension who are either intolerant Fluid retention, peripheral oedema, or both (caution is warranted in individuals with a (aprocitentan‡) of MRAs or for whom MRAs are contraindicated history of heart failure); contraindicated during pregnancy Sacubitril–valsartan§ Patients with resistant hypertension not responding to a Risk of adverse events shared with all other renin–angiotensin system blockers: excessive conventional ARB included in a triple antihypertensive therapy hypotension and renal failure when blood pressure and renal function are renin- including a diuretic; and patients with hypertension and heart dependent*, hyperkalaemia, ionic disturbances in patients with chronic kidney disease or failure with low ejection fraction 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 4 www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 Therapeutics higher pre-treatment serum potassium concentrations, creatinine and potassium will be required to ensure safe diabetes, or concomitant use of mineralocorticoid and eective use of siRNAs targeting angiotensinogen. receptor antagonists (MRAs) or conventional renin– Their use will also necessitate thorough patient angiotensin system inhibitors, necessitating more education, including regular use of self-measurement of regular monitoring of serum potassium concentrations blood pressure at home, specific precautions especially in these populations.28 In the KARDIA trials, which in case of volume depletion or pregnancy, and enrolled patients with a mean baseline eGFR of contingency plans to manage acute scenarios. If ongoing approximately 80 mL/min per 1·73 m², zilebesiran was phase 2 and 3 trials (eg, NCT06423352, NCT06905327, associated with a mild initial decline in eGFR, similar to NCT06864104, and NCT07181109) confirm the long-term that observed with conventional renin–angiotensin ecacy and safety of zilebesiran and other treatments in system blockers.29 As an upstream renin–angiotensin this new class of therapy, they have the potential to oer system inhibitor, this eect reflects a renal haemodynamic a durable, infrequent injection-based therapy for mechanism: reduced intraglomerular pressure due to hypertension, potentially reshaping future treatment decreased transmission of elevated systemic blood frameworks. pressure into the aerent arteriole resulting from improved hypertension control, together with eerent Aldosterone-targeted therapies arteriolar vasodilatation due to angiotensin 2 Aldosterone is a mineralocorticoid hormone mainly suppression.30 The long-term consequences of this early produced by the glomerulosa cells of the outer zone of eGFR decline in patients with lower baseline eGFR are the adrenal cortex in response to multiple stimuli yet to be established.31 including hypotension, hyperkalaemia, angiotensin 2, A unique clinical challenge with the long-lasting, and adrenocorticotrophic hormone.35,36 In the kidney, siRNA-mediated inhibition of the renin–angiotensin aldosterone acts via its mineralocorticoid receptor to system is the inability to expediently reverse the siRNA enhance reabsorption of sodium and fluid and increase mechanism and resulting renin–angiotensin system potassium excretion.35,36 In addition, aldosterone suppression in emergencies in which the renin– activates expression of multiple pro-inflammatory and angiotensin system is usually activated to maintain blood profibrotic mediators in the kidneys and heart.35,36 pressure and circulating volume (eg, in patients with Aldosterone also can mediate non-genomic and shock or acute volume depletion).32 In these emergency mineralocorticoid receptor-independent mechanisms situations, countermeasures should include intravenous that contribute to endothelial dysfunction, vascular fluids and intravenous angiotensin 2 or vasopressor stiness, and systemic vasoconstriction.37 In treatment- administration if required. Moreover, administration of resistant hypertension characterised by a blood pressure zilebesiran to patients with undetected renal artery level remaining above threshold despite a triple stenosis could pose a risk of acute kidney injury, similar combination antihypertensive therapy at maximally to that observed with ACE inhibitors and ARBs, but less tolerated doses including a diuretic, the steroidal MRA reversible due to the long-acting nature of the therapy— spironolactone is recommended as a preferred fourth- underscoring the need for a reliable reversal strategy for line therapy if eGFR is above 30 mL/min per 1·73 m² this kind of scenario. Preclinical studies have shown that and serum potassium is below 4·5 mmol/L,7,8,38 and its a complementary REVERSIR subcutaneous injection—a benefits in heart failure with reduced ejection fraction specific siRNA designed to hybridise with and inactivate are well recognised.39,40 However, spironolactone is the RISC-loaded siRNA—can restore angiotensinogen underused due to concerns over hyperkalaemia mRNA production and blood pressure within 48 h in (especially in chronic kidney disease)41 and anti- rats.33 Although this complementary treatment will not androgenic and progestogenic adverse events.42 Another be of use in an emergency setting (because the onset of steroidal MRA, eplerenone, which does not interfere reversal takes too long), reversal agents could be of use with progesterone or androgen receptors, can be used for patients in whom long-lasting renin–angiotensin alternatively,7,8 but is less eective in lowering blood system inhibition is no longer desirable. pressure than spironolactone.43 However, there has been Pregnancy represents another crucial concern. an increasing recognition among clinicians and Angiotensinogen concentrations rise during pregnancy researchers that many patients with hypertension are to support uteroplacental blood flow and maternal blood likely to have some degree of aldosterone dysregulation pressure regulation,34 and an siRNA targeting angio- (ie, renin-independent aldosterone production that is tensinogen could theoretically pose risks of maternal excessive relative to the sodium status of the patient). hypotension and placental insuciency. Eective This dysregulation spans a spectrum, with increasing contraception should be recommended for women of severity associated with a higher prevalence of dicult- childbearing potential when receiving an siRNA targeting to-control and resistant hypertension; overt primary angiotensinogen. aldosteronism represents the extreme end of this Given these considerations, careful patient selection spectrum.44–46 Therefore, the need to eectively target the and attention to baseline and post-treatment serum aldosterone–mineralocorticoid receptor pathway to www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 5 Therapeutics mitigate hypertension and to preserve organ function in duration of action, slow oset, and no rebound eect patients with heart failure and chronic kidney disease, upon withdrawal. In patients with chronic kidney disease while improving tolerability of therapy, has motivated (with a mean eGFR 44 mL/min per 1·73 m² and median the development of two classes of aldosterone-targeted urinary albumin-to-creatinine ratio [UACR] 714 mg/g) therapies: aldosterone synthase (CYP11B2) inhibitors and uncontrolled hypertension, baxdrostat lowered both and non-steroidal MRAs, as well as their use in oce systolic blood pressure and UACR compared with combination with SGLT2 inhibitors for patients with, or placebo, but at the cost of high rates of hyperkalaemia at risk of, heart failure or chronic kidney disease. (appendix p 7).55 Finally, in a small phase 2a open-label study in 15 patients with primary aldosteronism,57 Aldosterone synthase inhibitors baxdrostat reduced systolic blood pressure and excessive Aldosterone escape is a well recognised compensatory aldosterone production and corrected hypokalaemia response to chronic inhibition of the renin–angiotensin (appendix p 7). system by ACE inhibitors or ARBs, and mineralcorticoid Adverse events with baxdrostat or lorundrostat were receptor bloackade due, in part, to the counter-regulatory mild, infrequent, and reversible across the trials, and increase in renin levels induced by all these drugs via were predictable on the basis of the anticipated eects of dierent mechanisms (eg, interruption of the aldosterone synthase inhibition, including hyperkalaemia angiontensin 2 feedback loop on renin secretion for both and hyponatraemia (table 3).49,51–54 Hyperkalaemia rates ACE inhibitors and ARBs, and sodium depletion induced were much higher in patients with chronic kidney by MRAs), which partly counteracts their beneficial disease (41%) compared with patients in the placebo actions.47 Inhibition of aldosterone synthase in the adrenal group (5%; appendix p 7).55 No cases of hypercortisolism cortex is an attractive therapeutic strategy, as it could or adrenal insuciency were reported in the baxdrostat circumvent aldosterone escape and enhance ecacy by or lorundrostat trials.49,51–54 attenuating both genomic and non-genomic actions of Another ASI, dexfadrostat phosphate (which has a aldosterone.37 The pharmacological challenge has been CYP11B2-to-CYP11B1 selectivity ratio of 9),48 was overcoming the close homology (>93%) between assessed in a small, proof-of-concept study in patients aldosterone synthase (CYP11B2) and cortisol synthase with primary aldosteronism.58 Dexfadrostat phosphate (CYP11B1), to enable selective inhibition of the former reduced the aldosterone–renin ratio, aldosterone levels, without inhibiting the latter.48 and both ambulatory and oce systolic blood pressure Second-generation aldosterone synthase inhibitors (appendix p 7).58 To our knowledge, at the time of (ASIs) developed to augment selectivity for aldosterone writing, no further trials with this aldosterone synthase synthase (CYP11B2) over cortisol synthase (CYP11B1) inhibitor are planned. include baxdrostat, lorundrostat, defaxadrostat, and After a small phase 1 proof-of-concept study,61 vicadrostat vicadrostat.48 These ASIs have completed phase 2 and 3 (BI 690517), another highly selective ASI (CYP11B2-to- trials,49–59 although another compound (LY3045697) failed CYP11B1 selectivity ratio of 250),62 was evaluated in a to move forward because of the loss of its eects with phase 2, placebo-controlled study assessing the ecacy multiple dosing.60 and safety of multiple oral doses alone or in combination Both baxdrostat and lorundrostat (which have CYP11B2 with the SGLT2 inhibitor empagliflozin in participants and CYP11B1 selectivity ratios of 100 and 374, with chronic kidney disease (mean eGFR 52 mL/min per respectively)48 have been evaluated for the treatment of 1·73 m² and median UACR 426 mg/g), with or without uncontrolled and resistant hypertension in placebo- type 2 diabetes, receiving stable background ARB or ACE controlled phase 2 and 3 trials over a large dose range inhibitor (appendix p 7).59 Vicadrostat alone reduced the (table 3).49–55 When added to a background therapy UACR and systolic blood pressure at 14 weeks in a dose- of two or more antihypertensive medications, the dependent manner, with more pronounced eects placebo-corrected blood pressure-lowering eects of both observed when combined with empagliflozin (appendix drugs (at 6, 8, or 12 weeks) were consistent and clinically p 7). Adverse events were infrequent (appendix p 7), relevant (table 3), with the exception of the HALO trial of although smaller increases in serum potassium baxdrostat,50,56 which did not meet its primary blood concentrations occurred with vicadrostat in combination pressure endpoint, possibly because of a large placebo with empagliflozin, compared with vicadrostat alone.59 eect (NCT05137002; results presented50 but not yet There are ongoing phase 3 trials of ASIs in hypertension published at the time of writing). Both baxdrostat and (appendix p 10). Moreover, large, phase 3 outcome trials lorundrostat also produced dose-dependent decreases in currently in progress for chronic kidney disease and serum aldosterone concentrations (table 3) and increases heart failure are testing combinations of an ASI plus an in plasma renin activity, but did not decrease basal serum SGLT2 inhibitor (appendix p 10). cortisol levels.49–55 Of note, in the phase 3 BaxHTN trial,54 systolic blood pressure continued to decline during an Non-steroidal mineralocorticoid receptor antagonists 8-week randomised withdrawal period with baxdrostat Mineralocorticoid receptor antagonists include (increasing slightly with placebo), indicating a long two distinct classes: steroidal MRAs (eg, spironolactone 6 www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 Therapeutics www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 7 ,)3 esahp(⁹⁵NTH−hcnuaL ,)2 esahp( ⁸⁵NTH−ecnavdA 002=n ,)2 esahp( ⁷⁵NTH−tegraT 497=n ,)3 esahp( ⁰⁶NTHxaB 942=n ,)2 esahp( ⁶⁵lairt OLAH 572=n ,)2 esahp( ⁵⁵NTHgirB 3801=n 582=n tnatsiser ro dellortnocnU tnatsiser ro dellortnocnU noisnetrepyh dellortnocnU noisnetrepyh dellortnocnU elihw noisnetrepyh dellortnocnU noisnetrepyh tnatsiseR tneitaP owt etipsed noisnetrepyh ot owt etipsed noisnetrepyh evisnetrepyhitna owt tsael ta etipsed evisnetrepyhitna owt etipsed ro ,BRA ro rotibihni ECA na gnikat tsael ta etipsed noitalupop evisnetrepyhitna evfi ot evisnetrepyhitna evfi ;sesod detarelot mumixam ta snoitacidem tnatsiser ro snoitacidem a sulp BRA ro rotibihni ECA na evisnetrepyhitna eerht ecffio ;snoitacidem yrotalubma h 42 ;snoitacidem gH mm 031≥ erusserp doolb cilotsys ecffio tsael ta etipsed noisnetrepyh ECA na ro ,citeruid edizaiht a gnidulcni snoitacidem erusserp doolb cilotsys erusserp doolb cilotsys sulp obecalp no doirep ni-nur keew-2 retfa evisnetrepyhitna eerht muiclac a sulp BRA ro rotibihni erusserp doolb ecffio ;citeruid dna gH mm 081−531 h 42 ro gH mm 081−031 snoitacidem evisnetrepyhitna dnuorgkcab a gnidulcni ,snoitacidem cilotsys ecffio ;rekcolb lennahc keew-2 retfa gH mm 08/031≥ erusserp doolb cilotsaid doolb cilotsaid yrotalubma ecffio ;sesac htob ni citeruid retfa gH mm 041≥ erusserp doolb sulp obecalp no doirep ni-nur ro gH mm 011−56 retfa gH mm 08> erusserp erusserp doolb cilotsys obecalp no doirep ni-nur keew-4–2 evisnetrepyhitna dnuorgkcab erusserp doolb cilotsaid no doirep ni-nur keew-3 keew-2 retfa gH mm 531≥ evisnetrepyhitna dnuorgkcab sulp snoitacidem retfa gH mm 011−09 desidradnats sulp obecalp sulp obecalp no doirep ni-nur snoitacidem no doirep ni-nur keew-2 snoitacidem evisnetrepyhitna evisnetrepyhitna dnuorgkcab dnuorgkcab sulp obecalp edizaiht a sulp natrasemlo ,ei( snoitacidem evisnetrepyhitna tuohtiw ro htiw citeruid snoitacidem )enipidolma gm 05 :tatsordnuroL rof yliad gm 05 :tatsordnuroL eciwt gm 5·21 ,yliad gm 5·21 :tatsordnuroL gm 2 ro yliad gm 1 :tatsordxaB gm 1 ,yliad gm 5·0 :tatsordxaB ,yliad gm 5·0 :tatsordxaB noitnevretnI ro ,skeew 21 rof yliad rof yliad gm 05 ro ,skeew 21 gm 001 ro ,yliad gm 05 ,yliad eciwt gm 52 ,yliad obecalp sv yliad obecalp sv yliad gm 2 ro ,yliad yliad gm 2 ro ,yliad gm skeew 6 rof yliad gm ot noitartit htiw skeew 4 obecalp sv yliad obecalp sv gm 001 ot noitartit htiw skeew 8 rof yliad gm 001 skeew 6 rof yliad esod htiw tatsordnurol( esod htiw tatsordnurol( obecalp sv )tnemtsujda obecalp sv )tnemtsujda skeew skeew 21 skeew skeew skeew 8 skeew noitarud lairT )yramirp( cilotsys ecffio ni egnahC yrotalubma h 42 ni egnahC :erusserp doolb cilotsys ecffio ni egnahC doolb cilotsys ecffio ni egnahC doolb cilotsys ecffio ni egnahC doolb cilotsys ecffio ni egnahC yramirP :erusserp doolb :erusserp doolb cilotsys ,gm 5·21 tatsordnurol htiw gH mm 6·5− htiw gH mm 5·41– :erusserp htiw gH mm 0·71− :erusserp htiw gH mm 1·21− :erusserp tniopdne htiw gH mm 9·61− htiw gH mm 4·51− tatsordnurol htiw gH mm 3·11− gH mm 7·51– ,gm 1 tatsordxab gH mm 0·61− ;gm 5·0 tatsordxab ,gm 5·0 tatsordxab dna ,gm 05 tatsordnurol ,gm 05 tatsordnurol htiw gH mm 1·11− ,yliad eciwt gm 5·21 dna ,gm 2 tatsordxab htiw ,gm 1 tatsordxab htiw tatsordxab htiw gH mm 5·71− htiw gH mm 9·7− htiw gH mm 9·31− gH mm 7·31− ,yliad eciwt gm 52 tatsordnurol ;obecalp htiw gH mm 8·5– tatsordxab htiw gH mm 8·91− htiw gH mm 3·02−,gm ecnereffid ;obecalp esod htiw tatsordnurol htiw gH mm 9·11− ,gm 05 tatsordnurol htiw :obecalp sv ecnereffid htiw gH mm 6·61− dna ,gm 2 dna ,gm 2 tatsordxab gH mm 1·9− :obecalp sv gH mm 9·7− dna ,tnemtsujda htiw gH mm 1·4− ,gm 001 tatsordnurol )8·5− ot 5·11 −( gH mm 7·8– obecalp sv ecnereffid ;obecalp ;obecalp htiw gH mm 4·9− htiw )9·4− ot 3·31−( ecnereffid ;obecalp htiw :)]IC %09[ naem( obecalp sv ecnereffid ;obecalp dna ,gm 1 tatsordxab htiw )12·2±( gH mm 5·0− :†)]ES[ naem( :obecalp sv ecnereffid gm 05 tatsordnurol :)]IC %5·79[ naem( obecalp sv tatsordnurol htiw )3·5 ot 3·8−( gH mm 5·1− )0·7− ot 6·21 −( gH mm 8·9– ,gm 5·0 tatsordxab htiw *)7·2 ot 6·8−( gH mm 0·3− )6·2− ot 3·31−( gH mm 9·7− htiw )4·0− ot 0·41−( gH mm 2·7− ,gm 5·21 gm 2 tatsordxab htiw htiw )02·2±( gH mm 6·0 ,gm 5·0 tatsordxab htiw dna ,gm 05 tatsordnurol htiw gH mm 0·7− ,yliad eciwt gm 5·21 tatsordnurol gH mm 2·3− dna ,gm 1 tatsordxab )8·2− ot 5·31−( gH mm 1·8− )2·1− ot 8·11−( gH mm 5·6− tatsordnurol htiw )8·0− ot 1·31−( gm 2 tatsordxab htiw )32·2±( dna ,gm 1 tatsordxab htiw esod htiw tatsordnurol htiw )4·3− ot 8·51−( gH mm 6·9− ,yliad eciwt gm )5·5− ot 4·61−( gH mm 0·11− tnemtsujda gH mm 8·7−dna ,gm 05 tatsordnurol htiw gm 2 tatsordxab htiw gm 001 tatsordnurol htiw )5·1− ot 1·41−( rednopser erusserp doolB etar rednopser erusserp doolB doolb cilotsys( etar rednopser erusserp doolB etar rednopser erusserp doolB etar rednopser erusserp doolB rednopser erusserp doolB lanoitiddA doolb cilotsys( etar yrotalubma h 42( 4 keew ta htiw %1·62 :)gH mm 08/031< erusserp erusserp doolb cilotsys( erusserp doolb cilotsys( ni egnahc ;detroper ton :etar stniopdne :)gH mm 031< erusserp erusserp doolb cilotsys tatsordnurol htiw %8·13 ,gm 5·21 tatsordnurol htiw %4·93 :)gH mm 031< htiw %1·75 :)gH mm 031< –enoretsodla yraniru eht tatsordnurol htiw %1·44 htiw %0·14 :)gH mm 521< tatsordnurol htiw %3·34 ,yliad eciwt gm 5·21 htiw %0·04 ,gm 1 tatsordxab htiw %2·35 ,gm 5·0 tatsordxab g/gn 781− :oitar eninitaerc htiw %1·42 dna ,gm dna ,)deloop( tatsordnurol tatsordnurol htiw %9·24 ,yliad eciwt gm dna ,gm 2 tatsordxab htiw %7·17 ,gm 1 tatsordxab ,gm 5·0 tatsordxab htiw mures ni egnahc ;obecalp ni egnahc ;obecalp htiw %0·81 dna ,gm 001 tatsordnurol htiw %0·03 ,gm ni egnahc ;obecalp htiw %7·81 htiw %3·65 dna ,gm 2 tatsordxab tatsordxab htiw g/gn 081− ton :enoretsodla :enoretsodla mures mures ni egnahc ;obecalp htiw %3·32 :enoretsodla mures mures ni egnahc ;obecalp htiw g/gn 372− ,gm detroper tatsordnurol htiw %7·74− htiw %9·41− :4 keew ta enoretsodla ,gm 1 tatsordxab htiw %9·95− htiw %3·04− :enoretsodla g/gn 6 dna ,gm 2 tatsordxab htiw %7·55− ,gm 05 htiw %1·63− ,gm 5·21 tatsordnurol ,gm 2 tatsordxab htiw %4·56− htiw %3·14− ,gm 5·0 tatsordxab obecalp htiw esod htiw tatsordnurol htiw %6·15− ,yliad eciwt gm 5·21 tatsordnurol obecalp htiw egnahc on htiw %8·93− ,gm 1 tatsordxab htiw %5·22 dna ,tnemtsujda htiw %2·14− ,yliad eciwt gm 52 tatsordnurol htiw %7·01− dna ,gm 2 tatsordxab obecalp tatsordnurol htiw %8·34− ,gm 05 tatsordnurol obecalp obecalp htiw %2·2 dna ,gm 001 )egap txen no seunitnoc elbaT( Therapeutics 8 www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 ,)3 esahp(⁹⁵NTH−hcnuaL ,)2 esahp( ⁸⁵NTH−ecnavdA 002=n ,)2 esahp( ⁷⁵NTH−tegraT 497=n ,)3 esahp( ⁰⁶NTHxaB 942=n ,)2 esahp( ⁶⁵lairt OLAH 572=n ,)2 esahp( ⁵⁵NTHgirB 3801=n 582=n )egap suoiverp morf deunitnoC( aimealakrepyH ,L/lomm 6≥ aimealakrepyH :)%( n ,L/lomm 6≥ aimealakrepyH ,L/lomm 6≥ aimealakrepyH htiw 0 :)%( n ,aimealakrepyH ,L/lomm 6≥ aimealakrepyH ytefas yeK :)%( n ,L/lomm 6≥ htiw )%0·5( 5 :)%( n ,gm 5·21 tatsordnurol htiw )%0·4( 1 htiw )%3·2( 6 :)%( n htiw )%6·1( 1 ,gm 5·0 tatsordxab tatsordxab htiw 0 :)%( n snoitavresbo htiw )%1·1( ,gm 05 tatsordnurol ,yliad eciwt gm 5·21 tatsordnurol htiw )%0·5( 1 ,gm 1 tatsordxab htiw )%0·5( 3 ,gm 1 tatsordxab htiw )%0·3( 2 ,gm 5·0 ,gm 05 tatsordnurol tatsordnurol htiw )%0·7( ,yliad eciwt gm 52 tatsordnurol htiw )%0·3( 1 tatsordxab htiw )%0·3( dna ,gm 2 tatsordxab ,gm 1 tatsordxab htiw )%5·1( dna ,tnemtsujda esod htiw ,gm 05 tatsordnurol htiw )%0·4( 1 htiw )%4·0( 1 dna ,gm ;obecalp htiw )%6·1( tatsordxab htiw )%0·2( esod htiw tatsordnurol aimealakrepyh ;obecalp htiw htiw 0 dna ,gm 001 tatsordnurol htiw )%0·3( 1 aimealakrepyh ;obecalp htiw 0 :)%( n ,aimeartanopyh ;obecalp htiw 0 dna ,gm dna ,tnemtsujda :)%( n ,L/lomm 9·5–5·5 :)%( n ,L/lomm 9·5–5·5 aimealakrepyh ;obecalp :)%( n ,L/lomm 9·5–5·5 htiw 0 ,gm 5·0 tatsordxab aimealakrepyh ;obecalp htiw )%7·0( tatsordnurol htiw )%0·6( ,gm 5·21 tatsordnurol htiw )%0·31( 3 tatsordxab htiw )%1·6( htiw )%7·1( 1 ,gm 1 tatsordxab :)%( n ,L/lomm 9·5–5·5 aimealakrepyh htiw )%0·11( 01 ,gm ,yliad eciwt gm 5·21 tatsordnurol htiw )%0·9( 2 htiw )%1·11( 92 ,gm htiw 0 dna ,gm 2 tatsordxab tatsordxab htiw )%0·1( :)%( n ,L/lomm 9·5–5·5 esod htiw tatsordnurol ,yliad eciwt gm 52 tatsordnurol htiw )%0·7( 2 dna ,gm 2 tatsordxab aimeartanopyh ;obecalp htiw )%0·3( 2 ,gm 5·0 htiw )%1·7( htiw )%0·3( 3 dna ,tnemtsujda ,gm 05 tatsordnurol htiw )%0·4( 1 ;obecalp htiw )%4·0( ;detroper ton :)%( n ,L/lomm 531< ,gm 1 tatsordxab ,gm 05 tatsordnurol aimeartanopyh ;obecalp dna ,gm 001 tatsordnurol htiw )%0·61( 5 ,L/lomm 531< aimeartanopyh ;detroper ton :ycneicffiusni lanerda tatsordxab htiw )%0·2( htiw )%7·01( :)%( n ,L/lomm 531< ,L/lomm 531< ,aimeartanopyh ;obecalp htiw 0 htiw )%1·91( 94 ;)%( n ,muissatop mures ni egnahc ;obecalp htiw 0 dna ,gm esod htiw tatsordnurol tatsordnurol htiw )%0·9( ;enon :ycneicffiusni lanerda ;detroper ton :)%( n ,gm 1 tatsordxab ni egnahc ;detroper ton :L/lomm deriuqer taht aimeartanopyh dna ,tnemtsujda htiw )%0·11( 01 ,gm htiw 13·0 :L/lomm ,muissatop mures ni egnahc tatsordxab htiw )%8·22( ton :²m 37·1 rep nim/Lm ,RFGe :)%( n ,noitnevretni lacinilc ;obecalp htiw )%1·1( esod htiw tatsordnurol tatsordnurol htiw 23·0 ,gm 5·21 tatsordnurol htiw )%0·7( 81 dna ,gm detroper ,gm 5·0 tatsordxab htiw aimeartanopyh htiw )%0·6( 6 dna ,tnemtsujda tatsordnurol htiw 43·0 ,yliad eciwt gm 5·21 ni esaerced %03≥ ;obecalp tatsordxab htiw )%0·3( :)%( n ,L/lomm 531< ni esaerced %52≥ ;obecalp tatsordnurol htiw 52·0 ,yliad eciwt gm 52 tatsordxab htiw %6·21 :RFGe htiw )%0·2( 1 ,gm htiw )%9·6( rep nim/Lm 03< RFGe ro RFGe dna ,gm 001 tatsordnurol htiw 92·0 ,gm 05 tatsordxab htiw %6·51 ,gm htiw 0 dna ,gm 2 tatsordxab ,gm 05 tatsordnurol htiw )%0·3( 3 :²m 37·1 nim/Lm ,RFGe ni egnahc ;obecalp htiw 30·0 ;obecalp htiw %5·1 dna ,gm :ycneicffiusni lanerda ;obecalp htiw )%4·01( ,gm 05 tatsordnurol ,gm 5·21 tatsordnurol htiw 7·3− :²m 37·1 rep ;enon :ycneicffiusni lanerda mures ni egnahc ;enon esod htiw tatsordnurol tatsordnurol htiw )%0·7( ,yliad eciwt gm 5·21 tatsordnurol htiw 7·6− ,muissatop mures ni egnahc htiw 91·0 :L/lomm ,muissatop dna ,tnemtsujda dna ,tnemtsujda esod htiw ,yliad eciwt gm 52 tatsordnurol htiw 6·5− yletamixorppa :‡L/lomm htiw 63·0 ,gm 5·0 tatsordxab ;obecalp htiw )%3·3( lanerda ;obecalp htiw )%0·3( htiw 8·7− ,gm 05 tatsordnurol htiw 6·4− ,gm 1 tatsordxab htiw 03·0 htiw 92·0 ,gm 1 tatsordxab :ycneicfied diocitrococulg ni egnahc ;enon :ycneicffiusni obecalp htiw 9·0 dna ,gm tatsordnurol htiw 04·0 yletamixorppa dna ,gm 2 tatsordxab tatsordnurol htiw :L/lomm ,muissatop mures dna ,gm 2 tatsordxab ni egnahc ;obecalp htiw 80·0− htiw 0 ,gm ,gm 05 tatsordnurol htiw 95·0 obecalp htiw 0 yletamixorppa :²m 37·1 rep nim/Lm ,RFGe esod htiw tatsordnurol htiw tatsordnurol htiw 75·0 ;)erugfi eht morf detamitse( ,gm 5·0 tatsordxab htiw 6·2− dna ,tnemtsujda dna ,tnemtsujda esod nim/Lm ,RFGe ni egnahc ,gm 1 tatsordxab htiw 9·7− ;obecalp htiw )%1·1( ni egnahc ;obecalp htiw 01·0 htiw 0·7– :²m 37·1 rep ,gm 2 tatsordxab htiw 7·01− mures ni egnahc :²m 37·1 rep nim/Lm ,RFGe htiw 9·6– ,gm 1 tatsordxab obecalp htiw 1·0 dna :‡L/lomm ,muissatop ,gm 05 tatsordnurol htiw 0·8− dna ,gm 2 tatsordxab htiw 34·0 yletamixorppa htiw tatsordnurol htiw 8·11− obecalp htiw 1·0– dna ,gm 05 tatsordnurol dna ,tnemtsujda esod htiw 01·0 yletamixorppa obecalp htiw 8·2− ,RFGe ni egnahc ;obecalp htiw %3·9− :% ,)deloop( tatsordnurol obecalp htiw %4·0 dna stnemerusaem ytefas yrotarobal gnisu detroper esoht era snoitavresbo ytefas yeK .detats esiwrehto sselnu ,)IC %59( naem sa desserpxe era obecalp sv secnereffid dna ,snaem sa desserpxe era RFGe dna ,muissatop mures ,erusserp doolb ni segnahC naeM‡ .tnacfiingis ton era obecalp sv secnereffid eht llA† .ylno noitalupop locotorp-rep eht ni detropeR* .etar noitartlfi raluremolg detamitse=RFGe .rekcolb rotpecer nisnetoigna=BRA .emyzne gnitrevnoc nisnetoigna=ECA .seirotarobal lartnec ta enod .doirep yduts fo dne ot enilesab morf seulav muissatop mures gniwohs shparg morf detamitse eulav noisnetrepyh ni noitibihni esahtnys enoretsodla fo slairt 3 dna 2 esahp morf sgnidnfi yek fo yrammuS :3 elbaT Therapeutics and eplerenone), and non-steroidal MRAs (eg, finerenone Additionally, mild, early decreases in eGFR (<30%) and esaxerenone) which have dierent chemical were observed in the trials of baxdrostat, lorundrostat, structures and exhibit greater receptor selectivity and and vicadrostat at 8–14 weeks (table 3, appendix p 7), but more complete antagonism than steroidal agents.42 were shown to be reversible upon drug discontinuation.54 Esaxerenone has showed eective blood pressure Similarly, in trials of both esaxerenone and finerenone, reduction across a broad range of patients with untreated decreases in eGFR have been observed, although in the hypertension, primary aldosteronism, and chronic kidney context of ultimate improvement in kidney outcomes.64 disease, but is currently available only in Japan (appendix Consequently, monitoring of serum potassium and p 11).63 creatinine, especially within the first 2 weeks of initiating Finerenone has been evaluated primarily for chronic therapy, will be necessary when ASIs will become kidney disease and cardiovascular indications. In phase 2 commercially available, as is currently recommended for and 3 trials in patients with chronic kidney disease or MRAs. Of note, in patients with chronic kidney disease, heart failure, finerenone produced modest systolic blood the combined use of SGLT2 inhibitors might partly pressure decreases in the range of 2–5 mm Hg with doses mitigate the risk of hyperkalaemia.59,71 between 10 mg and 20 mg daily, compared with placebo Finally, a legitimate initial concern for the ASI class is when added to background renin–angiotensin system in relation to potential risks of both hypocortisolism and inhibitor therapy.64–68 Compared with other MRAs, hypercortisolism—the former resulting from direct finerenone appears to lower blood pressure less than inhibition of cortisol synthesis and the latter due to spironolactone, albeit to a similar extent as eplerenone, shunting precursor metabolites toward cortisol but finerenone is not licensed for the treatment of synthesis.48 Importantly, however, these adverse eects hypertension.69,70 have not yet been reported with these highly selective Finally, as for ASIs, ongoing studies are evaluating the ASIs at the doses tested for clinical use. combination of finerenone and other steroidal MRAs The development of highly selective ASIs has shown with SGLT2 inhibitors to assess their long-term benefits that this treatment approach is feasible in various clinical on cardiovascular and kidney outcomes (appendix p 10). settings without excess risk, paving the way to further In patients with chronic kidney disease and type 2 investigate their ecacy and safety in patients with a diabetes receiving a renin–angiotensin system inhibitor, wide spectrum of hypertension that might relate to 6 months of treatment with a combination of finerenone aldosterone dysregulation, primary aldosteronism, and empagliflozin resulted in a clinically significantly chronic kidney disease, or heart failure (table 2). How greater reduction in UACR and systolic blood pressure ASIs compare with MRAs in terms of ecacy, tolerability, than either agent alone, and was associated with a slightly and safety is unknown due to the absence of head-to- lower incidence of serum potassium concentrations head trials across various clinical conditions.74 greater than 5·0 mmol/L.71 Endothelin-targeted therapy Clinical considerations for ASIs and MRAs for Endothelin-1 is one of the most potent vasoconstrictors hypertension implicated in the pathogenesis of both hypertension and Because both ASIs and MRAs (steroidal and non-steroidal) chronic kidney disease.75,76 Endothelin-1 exerts its eects inhibit the aldosterone pathway (although at two dierent through two G protein-coupled receptors widely steps), similar safety concerns arise with their use. An distributed across multiple organ systems: the increased risk of hyperkalaemia, in particular, could be endothelin receptor type A, primarily expressed on underestimated because patients with higher serum vascular smooth muscle cells, which mediates potassium concentrations and lower eGFR have been vasoconstriction and fibrosis; and the endothelin excluded from most ASI and MRA trials to date. The rate receptor type B, located on endothelial cells (where it of hyperkalaemia might be higher in clinical practice, promotes vasodilation via nitric oxide release) and on depending on residual aldosterone production, basal kidney tubular epithelial cells and vascular smooth eGFR, comor bidities, and concomitant medications.72 A muscle.75,76 In the setting of hypertension and chronic pooled analysis of the 18 991 participants across the kidney disease, endothelin-1 expression is upregulated, three phase 3 finerenone trials in patients with type 2 which provides a strong rationale for blockade of diabetes and chronic kidney disease or heart failure endothelin-1 signalling to reduce blood pressure and showed that finerenone was associated with an slow chronic kidney disease progression.75,76 Endothelin approximately doubled risk of hyperkalaemia compared receptor antagonists (ERAs) can be either selective to the with placebo, with 16·5% of patients having a potassium endothelin receptor type A, or act as antagonists to both concentration greater than 5·5 mmol/L and 3·3% with the endothelin receptor type A and the endothelin greater than 6·0 mmol/L.73 Hyperkalaemia rates were also receptor type B (dual ERAs). higher in patients with chronic kidney disease who Even though the first dual ERAs (ie, bosentan and received baxdrostat compared with placebo in a phase 2a darusentan) showed significant blood pressure study (table 3).55 reductions in patients with hypertension, their www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 9 Therapeutics development was discontinued due to adverse events, contraindicated during pregnancy. Caution is warranted including fluid overload, peripheral oedema, and in individuals with a history of heart failure. hepatotoxicity.77,78 Dose-related fluid retention (eg, peripheral oedema, Aprocitentan, another dual ERA, was later developed weight gain, and heart failure) remains a key treatment- for treatment of hypertension. After an 8-week, phase 2, limiting adverse eect of ERAs, particularly in patients dose-finding trial (table 4),79 aprocitentan was evaluated in with chronic kidney disease or pre-existing cardiovascular a large phase 3 study conducted in patients with resistant disease.76 Fluid retention, peripheral oedema, or both were hypertension, all of whom were maintained on a triple the most frequently reported adverse events with fixed-dose combination in a single pill of guideline- aprocitentan (table 4),80 which is also a concern especially directed therapy.80 At 4 weeks, systolic blood pressure was in the context of resistant hypertension, which is clinically significantly reduced with aprocitentan at often a sodium-retaining state. The underlying mech- 12·5 mg and 25 mg versus placebo, and the reduction anisms of fluid retention are multifactorial and was sustained through 48 weeks at the 25 mg dose incompletely understood. Management strategies include (table 4). co-administration or increase in dose of diuretics as part of the background antihypertensive medications.80 In patients Clinical implications for ERAs for hypertension with chronic kidney disease, the lowest available dose of Aprocitentan is approved in the USA, Europe, and aprocitentan should be considered. Combining ERAs with the UK for the treatment of hypertension inadequately SGLT2 inhibitors could oer additional benefit, mitigating controlled by at least three antihypertensive fluid retention while enhancing reductions in albuminuria medications.81–83 Patients with resistant hypertension who and blood pressure.76,84 When initiated, ERAs also induce a are either intolerant of MRAs or for whom MRAs are modest, reversible decline in eGFR (attributable to eerent contraindicated could be candidates for this therapy arteriolar vasodilation).76 Monitoring for anaemia is (table 2).7 Given its teratogenic potential, aprocitentan is recommended, as mild reductions in haemoglobin are PRECISION study⁸⁵ (phase 3), n=730 Dose-response study⁸⁴ (phase 2), n=490 Patient Patients with resistant hypertension despite three or more antihypertensive Patients with grade 1 to 2 hypertension; unattended seated diastolic blood pressure of population medications; unattended seated systolic blood pressure of ≥140 mm Hg ≥90 mm Hg to <110 mm Hg after 4–6 weeks placebo run-in period despite at least 4 weeks of treatment with a triple combination in a single pill continued throughout the trial* Intervention Aprocitentan 12·5 mg and 25 mg once daily vs placebo Aprocitentan 5 mg, 10 mg, 25 mg, or 50 mg once daily vs placebo and vs active comparator (lisinopril 20 mg once daily) Trial duration 48 weeks including 4-week double-blind phase, 32-week single-blind active 8 weeks treatment phase, and 12-week randomised withdrawal phase Primary Unattended office systolic blood pressure decrease at 4 weeks: −15·3 mm Hg Unattended office diastolic blood pressure decrease at 8 weeks: −6·3 mm Hg with aprocitentan endpoint with aprocitentan 12·5 mg, −15·2 mm Hg with aprocitentan 25 mg, and 5 mg, −9·9 mm Hg with aprocitentan 10 mg, −12·0 mm Hg with aprocitentan 25 mg, −11·5 mm Hg with placebo; difference vs placebo: −3·8 mm Hg (97·5% CI −10·0 mm Hg with aprocitentan 50 mg, −8·4 mm Hg with lisinopril 20 mg, and −4·9 mm Hg −6·8 to −0·8) with aprocitentan 12·5 mg, and −3·7 mm Hg (97·5% CI with placebo; difference vs placebo: –1·31 mm Hg (–5·10 to 2·49) with aprocitentan 5 mg, −6·2 to −2·1) with aprocitentan 25 mg −4·93 mm Hg (–8·68 to –1·17) with aprocitentan 10 mg, −6·99 mm Hg (–10·80 to –3·19) with aprocitentan 25 mg, −4·95 mm Hg (–8·75 to –1·15) with aprocitentan 50 mg, and −3·81 mm Hg (–7·26 to –0·37) with lisinopril 20 mg Additional Change in 24 h ambulatory systolic blood pressure at 4 weeks (difference Unattended office systolic blood pressure decrease at 8 weeks: –10·3 mm Hg with aprocitentan endpoints† vs placebo): –4·2 mm Hg (–6·2 to –2·1) with aprocitentan 12·5 mg, and 5 mg, –15·0 mm Hg with aprocitentan 10 mg, –18·5 mm Hg with aprocitentan 25 mg, –5·9 mm Hg (–7·9 to –3·8) with aprocitentan 25 mg; changes in office –15·1 mm Hg with aprocitentan 50 mg, –12·8 mm Hg with lisinopril 20 mg, and –7·7 mm Hg systolic blood pressure after 4 weeks in the placebo-controlled randomised with placebo; difference vs placebo: –2·45 mm Hg (–8·44 to 3·54) with aprocitentan 5 mg, withdrawal phase: 5·8 mm Hg (3·7 to 7·9) for placebo vs aprocitentan 25 mg –7·05 mm Hg (–12·98 to –1·12) with aprocitentan 10 mg, –9·90 mm Hg (–15·92 to –3·88) with aprocitentan 25 mg, –7·58 mm Hg (–13·58 to –1·59) with aprocitentan 50 mg, and –4·84 mm Hg (–10·49 to 0·82) with lisinopril 20 mg; change in 24 h ambulatory systolic blood pressure at 8 weeks‡ (difference vs placebo): 0·87 mm Hg (–3·58 to 5·32) with aprocitentan 5 mg, –3·99 mm Hg (–8·49 to 0·52) with aprocitentan 10 mg, –4·83 mm Hg (–9·33 to –0·33) with aprocitentan 25 mg, –3·67 mm Hg (–8·08 to 0·73) with aprocitentan 50 mg, and –3·43 mm Hg (–8·30 to 1·44) with lisinopril 20 mg Key safety Peripheral oedema: 9% of patients who received aprocitentan 12·5 mg and Mild-to-moderate peripheral oedema in four patients (mainly at higher doses); dose-related observations 18% in those who received aprocitentan 25 mg vs 2% in those who received decreases in haemoglobin, and increase in estimated plasma volume; eGFR changes: not placebo; hospitalisation for heart failure: ten patients who received reported; no significant weight changes; no hepatotoxicity aprocitentan and one who received placebo; eGFR changes at week 4: approximately −1·0 mL/min per 1·73 m² with aprocitentan 12·5 mg, approximately −2·0–3·0 mL/min per 1·73 m² with aprocitentan 25 mg, and approximately −0·5 mL/min per 1·73 m² with placebo; no hepatotoxicity Changes in blood pressure and eGFR are expressed as means, and differences vs placebo are expressed as mean (95% CI), unless otherwise stated. eGFR=estimated glomerular 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 10 www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 Therapeutics also common, reflecting a combination of haemodilution, given alone.90,91 Despite the ecacy of sacubitril–valsartan diminished endothelin-1-mediated erythropoiesis, and at lowering blood pressure, subsequent development and possibly increased hepcidin levels.76 Hepatotoxicity, licensing of this drug primarily focused on patients with prominent with first-generation agents, is uncommon heart failure.92 A recent systematic review showed that with newer ERAs, although liver function monitoring sacubitril–valsartan (200 mg or 400 mg orally) is more remains advisable. eective than a conventional ARB or ACE inhibitor at lowering blood pressure when combined with a thiazide Natriuretic peptide system and cyclic guanosine and a calcium channel blocker in patients with resistant monophosphate signalling-targeted therapies hypertension;93 this superiority was also confirmed in The natriuretic peptides—atrial natriuretic peptide and patients of Black African ancestry.94 Furthermore, after B-type natriuretic peptide—are released from the atria 52 weeks of treatment, one trial95 found that sacubitril– and ventricles, respectively, in response to wall stretch due valsartan reduced diuse interstitial fibrosis and to volume, pressure overload, or both. Their biological favourably decreased left ventricular mass in hypertensive action to promote natriuresis, diuresis, vasodilation, patients with left ventricular hypertrophy, compared with suppression of renin, aldosterone, and the sympathetic valsartan alone, when both regimens were titrated and nervous system, as well as antifibrotic, anti-inflammatory, combined with other antihypertensives to reach a systolic and antihypertrophic eects, are principally mediated via blood pressure target of less than 140 mm Hg. Sacubitril– binding to the atrial natriuretic peptide receptor 1.85 valsartan is not approved for the treatment of The challenge is that natriuretic peptides have a short hypertension in Europe and the USA. half-life of only minutes in the systemic circulation, due to rapid degradation by enzymes such as neprilysin and Direct natriuretic peptide system activators clearance by the natriuretic peptide clearance receptor. Intravenous recombinant natriuretic peptides are Upon binding to the atrial natriuretic peptide receptor 1, approved for decompensated heart failure, but their atrial natriuretic peptide and B-type natriuretic peptide short half-life and route of administration limits broader activate cyclic guanosine monophosphate signalling, use.85 Modified forms of the atrial natriuretic peptide, which mediates the aforementioned action of the designed as ANP mimetics, are engineered to be more natriuretic peptides.86 Strategies have been developed to resistant to enzymatic degradation and renal clearance. A exploit the potential of the natriuretic peptide system to proof-of-concept study96 confirmed that a single treat hypertension, such as augmenting the natural subcutaneous injection lowered blood pressure, natriuretic peptide system by inhibiting the degradation increased cyclic guanosine monop hosphate of atrial natriuretic peptide and B-type natriuretic concentrations, and was not associated with serious peptide, or by direct activation of the atrial natriuretic adverse events, but the plasma half-life of ANP was only peptide receptor 1. extended to around 1 h and the blood pressure eect waned substantially by 24 h.96,97 The short duration of Augmenting the natriuretic peptide system: neprilysin action and the need for daily subcutaneous injection inhibitors would be challenging for its adoption as a long-term Inhibition of neprilysin to augment the circulating levels treatment. of atrial natriuretic peptide and B-type natriuretic peptide, and prolong their half-life, has the potential to Conclusions substantially lower blood pressure, especially when There has been renewed interest in the development of combined with renin–angiotensin system inhibition. new antihypertensive medications; however, how these The blood pressure-lowering potential of dual inhibition treatments will be integrated with established, low-cost of both ACE and neprilysin was originally confirmed generic antihypertensive drugs remains uncertain. with omapatrilat, but its developm ent was discontinued Moreover, combining these novel agents into single-pill because it was associated with a higher risk of angio- combination products would also be challenging given oedema than ACE inhibition alone,87 probably due to regulatory requirements for outcomes-based trials and the concomitant inhibition of neprilysin, ACE, and poor uptake of existing single-pill products, despite their aminopeptidase P, all of which participate in the increasing endorsement in clinical guidelines worldwide. breakdown of bradykinin.88 Subsequently, a sacubitril– Furthermore, in low-income and middle-income countries, valsartan combination was developed, which combined where the availability, accessibility, and aordability of care the neprilysin inhibitor sacubitril with the ARB valsartan and therapies remain constrained, demonstration of cost- in a single oral tablet.89 When used at higher doses than eectiveness will be essential to establish the feasibility in heart failure (ie, 400 mg/day), this dual-acting and the potential global eect of these new therapeutic combination therapy was shown to be eective at approaches. Thus, it could be argued that the focus should lowering blood pressure in patients with mild-to- be on developing more eective systems of care to enhance moderate hypertension when compared with each of its adherence to existing low-cost treatments. However, this components given alone89 and versus the ARB olmesartan approach has proved challenging, and despite multiple www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 11 Therapeutics iterations of guidelines and various models of care, overall and revision of the manuscript, and had final responsibility for the global blood pressure control rates have not improved decision to submit for publication. substantially. Moreover, recent advances in other medical Declaration of interests fields challenge the assumption that we already have all of MA reports institutional grants from Novartis, Recor Medical, the treatments we need. The advent of SGLT2 inhibitors AstraZeneca, and Sonivie; consulting fees from Novartis, Recor Medical, AstraZeneca, Alnylam, Medtronic, and Sonivie; honoraria for lectures and GLP-1 receptor agonists has transformed the from Servier, NovoNordisk, Boehringer Ingelheim, and Alnylam; and management of patients with high cardiovascular risk, travel support from Novartis. KRT reports investigator-initiated grant chronic kidney disease, diabetes, obesity, and heart support from Travere, Bayer, Benaroya Research Institute, and the Doris Duke Charitable Foundation; consultancy fees from Boehringer failure—conditions once considered adequately treated Ingelheim, Eli Lilly, Novo Nordisk, Roche–Genentech, AstraZeneca, and with existing therapies. These developments highlight the ProKidney; speaker fees from Novo Nordisk, Bayer, and Boehringer potential for innovative antihypertensive drugs to improve Ingelheim; travel support from Bayer and Novo Nordisk; is chair of data standards of care and address residual disease risk, even in safety monitoring boards for the National Institute of Diabetes and Digestive and Kidney Disease and for the George Clinical Institute; is a a therapeutic landscape dominated by inexpensive generic member of the data safety monitoring board for AstraZeneca; is chair for drugs. the Diabetic Kidney Disease Collaborative for the American Society of Unlike many drug developments in medicine, the new Nephrology and for the Kidney Week 2025 Program Committee; and is a antihypertensive therapies we have discussed have the member of the American Heart Association/American College of Cardiology Cardiovascular–Kidney–Metabolic Guideline Committee. potential to transform hypertension management. RNA JMB reports consulting fees from AstraZeneca, Bayer, and Recordati silencing therapies oer the potential to deliver the first Rare Diseases; and funding from the American Heart Association always-on blood pressure-lowering treatment, lasting for (grant 21CDA852429) and US National Institutes of Health/National at least 6 months after a single subcutaneous injection, Heart, Lung, and Blood Institute (grant K23HL159279). DLP reports consulting fees, honoraria, participation on an advisory board, and travel overcoming the substantial problem of low treatment support from Novo Nordisk. KK reports research grants from Otsuka adherence. How this therapy would aect patient Pharmaceutical, Daiichi Sankyo, Sumitomo Pharma, and Nippon outcomes is unknown but, at a population level, even a Boehringer Ingelheim; consulting fees from Sanwa Kagaku Kenkyusho; modest sustained blood pressure reduction could prevent honoraria from Otsuka Pharmaceuticals, Daiichi Sankyo, Novartis Pharma, and Viatris; and participation on advisory boards for Daiichi thousands of cardiovascular events per year.98 Furthermore, Sankyo and Novartis Pharma. BW is Chief Scientific and Medical Ocer better targeting of disease pathophysiology with novel of the British Heart Foundation; reports consulting fees from Novartis, treatments such as ASIs has the potential to transform the AstraZeneca, Alnylam, and Antlia; and reports honoraria from treatment of blood pressure in the many millions of Medtronic. people with (often unrecognised) aldosterone References 1 Collaboration NCDRF, and the NCD Risk Factor Collaboration dysregulation as the underlying cause of their so-called (NCD-RisC). Worldwide trends in hypertension prevalence and essential hypertension.99 Together with the re-emergence progress in treatment and control from 1990 to 2019: a pooled of interest in the natriuretic peptide system as a target for analysis of 1201 population-representative studies with 104 million participants. Lancet 2021; 398: 957–80. novel therapies, these treatments could deliver the first 2 Global Cardiovascular Risk Consortium, Magnussen C, new generation of targeted diuretic therapies for Alegre-Diaz J, et al. Global Eect of Cardiovascular Risk Factors on hypertension for over 70 years. As newer therapies target Lifetime Estimates. N Engl J Med 2025; 393: 125–28. the underlying pathophysiology of hypertension more 3 Bennett A, Chow CK, Chou M, et al. Ecacy and safety of quarter- dose blood pressure-lowering agents: a systematic review and meta- precisely, blood pressure control rates could improve, analysis of randomized controlled trials. Hypertension 2017; 70: 85–93. potentially reducing the number of medications required 4 Parati G, Kjeldsen S, Coca A, Cushman WC, Wang J. Adherence to per patient, and with some of those treatments delivered single-pill versus free-equivalent combination therapy in hypertension: a systematic review and meta-analysis. Hypertension as injectables in the future. 2021; 77: 692–705. Many of these treatments will be approved for the 5 Chow CK, Atkins ER, Hillis GS, et al, and the QUARTET treatment of hypertension simply on the basis of their Investigators. Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure ecacy in lowering blood pressure, once their ecacy and medicines versus standard dose monotherapy in patients with safety are adequately confirmed. However, to move beyond hypertension (QUARTET): a phase 3, randomised, double-blind, use in niche cohorts—in countries and for patients with active-controlled trial. Lancet 2021; 398: 1043–52. 6 Rodgers A, Salam A, Schutte AE, et al, and the GMRx2 the resources to deploy them—and to provide a compelling Investigators. Ecacy and safety of a novel low-dose triple single- case for more widespread use, evidence from pill combination of telmisartan, amlodipine and indapamide, cardiovascular outcome trials would likely also be needed compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical to justify their cost relative to widely available evidence- trial. Lancet 2024; 404: 1536–46. based generic therapies. Such trials would establish 7 Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for whether these novel therapies can improve outcomes for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of the hundreds of millions of patients with uncontrolled Hypertension: endorsed by the International Society of hypertension, and in so doing, close the treatment gap that Hypertension (ISH) and the European Renal Association (ERA). has frustrated existing treatment strategies. J Hypertens 2023; 41: 1874–2071. 8 McEvoy JW, McCarthy CP, Bruno RM, et al, and the ESC Scientific Contributors Document Group. 2024 ESC Guidelines for the management of MA and BW were responsible for conceptualisation, literature search, elevated blood pressure and hypertension. Eur Heart J 2024; and supervision. All authors contributed to creation of the figure, writing 45: 3912–4018. 12 www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 Therapeutics 9 Brouwers S, Sudano I, Kokubo Y, Sulaica EM. Arterial hypertension. 30 Palmer BF. Renal dysfunction complicating the treatment of Lancet 2021; 398: 249–61. hypertension. N Engl J Med 2002; 347: 1256–61. 10 Barbato E, Azizi M, Schmieder RE, et al. Renal denervation in the 31 Heerspink HJL, Eddington D, Chaudhari J, et al. A meta-analysis of management of hypertension in adults. A clinical consensus randomized controlled clinical trials for implications of acute statement of the ESC Council on Hypertension and the European treatment eects on glomerular filtration rate for long-term kidney Association of Percutaneous Cardiovascular Interventions (EAPCI). protection. Kidney Int 2024; 106: 688–98. Eur Heart J 2023; 44: 1313–30. 32 Azizi M, Ménard J. Combined blockade of the renin-angiotensin 11 Ye D, Cruz-López EO, Tu HC, Zlatev I, Danser AHJ. Targeting system with angiotensin-converting enzyme inhibitors and angiotensinogen with N-acetylgalactosamine-conjugated small angiotensin II type 1 receptor antagonists. Circulation 2004; interfering RNA to reduce blood pressure. 109: 2492–99. Arterioscler Thromb Vasc Biol 2023; 43: 2256–64. 33 Ye D, Cruz-López EO, Veghel RV, et al. Counteracting 12 Webb DJ. Zilebesiran, a ribonucleic acid interference agent angiotensinogen small-interfering RNA-mediated antihypertensive targeting angiotensinogen, proves a promising approach in eects with REVERSIR. Hypertension 2024; 81: 1491–99. hypertension. Cardiovasc Res 2024; 120: e41–43. 34 Malha L, Sison CP, Helseth G, Sealey JE, August P. Renin- 13 Daugherty A, Sawada H, Sheppard MB, Lu HS. Angiotensinogen as angiotensin-aldosterone profiles in pregnant women with chronic a therapeutic target for cardiovascular and metabolic diseases. hypertension. Hypertension 2018; 72: 417–24. Arterioscler Thromb Vasc Biol 2024; 44: 1021–30. 35 Parksook WW, Williams GH. Aldosterone and cardiovascular 14 Addison ML, Ranasinghe P, Webb DJ. Novel pharmacological diseases. Cardiovasc Res 2023; 119: 28–44. approaches in the treatment of hypertension: a focus on RNA-based 36 Epstein M, Kovesdy CP, Clase CM, Sood MM, Pecoits-Filho R. therapeutics. Hypertension 2023; 80: 2243–54. Aldosterone, mineralocorticoid receptor activation, and CKD: a review 15 Cruz-López EO, Ye D, Wu C, et al. Angiotensinogen suppression: of evolving treatment paradigms. Am J Kidney Dis 2022; 80: 658–66. a new tool to treat cardiovascular and renal disease. Hypertension 37 Namsolleck P, Unger T. Aldosterone synthase inhibitors in 2022; 79: 2115–26. cardiovascular and renal diseases. Nephrol Dial Transplant 2014; 16 Morgan ES, Tami Y, Hu K, et al. Antisense inhibition of 29 (suppl 1): i62–68. angiotensinogen with IONIS-AGT-L Rx : results of phase 1 and 38 Williams B, MacDonald TM, Morant S, et al, and the British phase 2 studies. JACC Basic Transl Sci 2021; 6: 485–96. Hypertension Society’s PATHWAY Studies Group. Spironolactone 17 Desai AS, Webb DJ, Taubel J, et al. Zilebesiran, an RNA interference versus placebo, bisoprolol, and doxazosin to determine the optimal therapeutic agent for hypertension. N Engl J Med 2023; 389: 228–38. treatment for drug-resistant hypertension (PATHWAY-2): 18 Bakris GL, Saxena M, Gupta A, et al, and the KARDIA-1 Study Group. a randomised, double-blind, crossover trial. Lancet 2015; RNA interference with zilebesiran for mild to moderate hypertension: 386: 2059–68. the KARDIA-1 randomized clinical trial. JAMA 2024; 331: 740–49. 39 Pitt B, Zannad F, Remme WJ, et al, and the Randomized Aldactone 19 Desai AS, Karns AD, Badariene J, et al, and the KARDIA-2 Study Evaluation Study Investigators. The eect of spironolactone on Group. Add-on treatment with zilebesiran for inadequately morbidity and mortality in patients with severe heart failure. controlled hypertension: the KARDIA-2 randomized clinical trial. N Engl J Med 1999; 341: 709–17. JAMA 2025; 334: 46–55. 40 Pitt B, Remme W, Zannad F, et al, and the Eplerenone Post-Acute 20 Pagidipati N, Weber M, Saxena M, et al. KARDIA-3 trial examines Myocardial Infarction Heart Failure Ecacy and Survival Study blood-pressure lowering eects of zilebesiran in hypertensive Investigators. Eplerenone, a selective aldosterone blocker, in patients at high cardiovascular risk. European Society of Cardiology patients with left ventricular dysfunction after myocardial Congress 2025; Aug 30, 2025. https://www.escardio.org/The-ESC/ infarction. N Engl J Med 2003; 348: 1309–21. Press-Oce/Press-releases/KARDIA-3-trial-examines-blood- 41 Chung EY, Ruospo M, Natale P, et al. Aldosterone antagonists in pressure-lowering-eects-of-zilebesiran-in-hypertensive-patients-at- addition to renin angiotensin system antagonists for preventing the high-cardiovascular-risk# (accessed Sept 10, 2025). progression of chronic kidney disease. Cochrane Database Syst Rev 21 Roche. Roche and Alnylam advance zilebesiran into global phase III 2020; 10: CD007004. cardiovascular outcomes trial for people with uncontrolled 42 Kolkhof P, Bärfacker L. 30 years of the mineralocorticoid receptor: hypertension. Aug 30, 2025. https://www.roche.com/media/ mineralocorticoid receptor antagonists: 60 years of research and releases/med-cor-2025-08-30 (accessed Sept 6, 2025). development. J Endocrinol 2017; 234: T125–40. 22 Ménard J, Guyene TT, Chatellier G, Kleinbloesem CH, Bernadet P. 43 Parthasarathy HK, Ménard J, White WB, et al. A double-blind, Renin release regulation during acute renin inhibition in normal randomized study comparing the antihypertensive eect of volunteers. Hypertension 1991; 18: 257–65. eplerenone and spironolactone in patients with hypertension and 23 Uijl E, Mirabito Colafella KM, Sun Y, et al. Strong and sustained evidence of primary aldosteronism. J Hypertens 2011; 29: 980–90. antihypertensive eect of small interfering RNA targeting liver 44 Vaidya A, Hundemer GL, Nanba K, Parksook WW, Brown JM. angiotensinogen. Hypertension 2019; 73: 1249–57. Primary aldosteronism: state-of-the-art review. Am J Hypertens 2022; 24 Israili ZH, Hall WD. Cough and angioneurotic edema associated 35: 967–88. with angiotensin-converting enzyme inhibitor therapy. A review of 45 Parksook WW, Brown JM, Omata K, et al. The spectrum of the literature and pathophysiology. Ann Intern Med 1992; dysregulated aldosterone production: an international human 117: 234–42. physiology study. J Clin Endocrinol Metab 2024; 109: 2220–32. 25 Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, 46 Brown JM, Honzel B, Tsai LC, et al. Characterizing the origins of Agostoni A. Plasma bradykinin in angio-oedema. Lancet 1998; primary aldosteronism. Hypertension 2025; 82: 306–18. 351: 1693–97. 47 Mogi M. Aldosterone breakthrough from a pharmacological 26 Belachew EA, Peterson GM, Bezabhe WM. Comparative eects of perspective. Hypertens Res 2022; 45: 967–75. angiotensin II stimulating and inhibiting antihypertensives on 48 Azizi M, Riancho J, Amar L. Aldosterone synthase inhibitors: dementia risk: a systematic review and meta-analysis. Geroscience a revival for treatment of renal and cardiovascular diseases. 2025; 47: 5525–41. J Clin Endocrinol Metab 2025; 110: e557–65. 27 Zhou Z, Orchard SG, Nelson MR, Fravel MA, Ernst ME. 49 Freeman MW, Halvorsen YD, Marshall W, et al, and the BrigHTN Angiotensin receptor blockers and cognition: a scoping review. Investigators. Phase 2 trial of baxdrostat for treatment-resistant Curr Hypertens Rep 2024; 26: 1–19. hypertension. N Engl J Med 2023; 388: 395–405. 28 Palmer BF. Angiotensin-converting enzyme inhibitors and 50 Bhatt DL. Ecacy and safety of baxdrostat in patients with angiotensin receptor blockers: what to do if the serum creatinine uncontrolled hypertension—HALO. March 4, 2023. https://www. and/or serum potassium concentration rises. Nephrol Dial acc.org/Latest-in-Cardiology/Clinical-Trials/2023/03/01/23/34/halo Transplant 2003; 18: 1973–75. (accessed Dec 18, 2025). 29 Neuen BL, Tighiouart H, Heerspink HJL, et al, and the CKD-EPI 51 Lan LJ, Rodman D, Luther JM, et al, and the Target-HTN Clinical Trials. Acute treatment eects on GFR in randomized Investigators. Aldosterone synthase inhibition with lorundrostat for clinical trials of kidney disease progression. J Am Soc Nephrol 2022; uncontrolled hypertension: the Target-HTN randomized clinical 33: 291–303. trial. JAMA 2023; 330: 1140–50. www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 13 Therapeutics 52 Lan LJ, Kopjar B, Melgaard C, et al, and the Advance-HTN 71 Agarwal R, Green JB, Heerspink HJL, et al, and the CONFIDENCE Investigators. Lorundrostat ecacy and safety in patients with Investigators. Finerenone with empagliflozin in chronic kidney uncontrolled hypertension. N Engl J Med 2025; 392: 1813–23. disease and type 2 diabetes. N Engl J Med 2025; 393: 533–43. 53 Saxena M, Lan L, Borghi C, et al, and the Launch-HTN 72 McDonald TJ, Oram RA, Vaidya B. Investigating hyperkalaemia in Investigators. Lorundrostat in participants with uncontrolled adults. BMJ 2015; 351: h4762. hypertension and treatment-resistant hypertension: the Launch- 73 Vaduganathan M, Filippatos G, Claggett BL, et al. Finerenone in HTN randomized clinical trial. JAMA 2025; 334: 409–18. heart failure and chronic kidney disease with type 2 diabetes: FINE- 54 Flack JM, Azizi M, Brown JM, et al, and the BaxHTN Investigators. HEART pooled analysis of cardiovascular, kidney and mortality Ecacy and safety of baxdrostat in uncontrolled and resistant outcomes. Nat Med 2024; 30: 3758–64. hypertension. N Engl J Med 2025; 393: 1363–74. 74 Azizi M. Decreasing the eects of aldosterone in resistant 55 Dwyer JP, Maklad N, Vedin O, et al. Ecacy and safety of baxdrostat hypertension—a success story. N Engl J Med 2023; 388: 461–63. in participants with CKD and uncontrolled hypertension: 75 Schirin EL, Pollock DM. Endothelin system in hypertension and a randomized, double-blind, placebo-controlled trial. J Am Soc Nephrol chronic kidney disease. Hypertension 2024; 81: 691–701. 2025; published online Sept 6. https://doi.org/10.1681/ 76 Smeijer JD, Kohan DE, Dhaun N, Noronha IL, Liew A, ASN.0000000849. Heerspink HJL. Endothelin receptor antagonists in chronic kidney 56 ClinicalTrials.gov. A study of CIN-107 in patients with uncontrolled disease. Nat Rev Nephrol 2025; 21: 175–88. hypertension (HALO). https://clinicaltrials.gov/study/NCT05137002 77 Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V, and the (accessed Sept 10, 2025). Bosentan Hypertension Investigators. The eect of an endothelin- 57 Turcu AF, Freeman MW, Bancos I, et al, and the SPARK receptor antagonist, bosentan, on blood pressure in patients with Investigator Group. Phase 2a study of baxdrostat in primary essential hypertension. N Engl J Med 1998; 338: 784–90. aldosteronism. N Engl J Med 2025; 393: 515–18. 78 Bakris GL, Lindholm LH, Black HR, et al. Divergent results using 58 Mulatero P, Wuerzner G, Groessl M, et al. Safety and ecacy of clinic and ambulatory blood pressures: report of a darusentan- once-daily dexfadrostat phosphate in patients with primary resistant hypertension trial. Hypertension 2010; 56: 824–30. aldosteronism: a randomised, parallel group, multicentre, phase 2 79 Verweij P, Danaietash P, Flamion B, Ménard J, Bellet M. trial. EClinicalMedicine 2024; 71: 102576. Randomized dose-response study of the new dual endothelin 59 Tuttle KR, Hauske SJ, Canziani ME, et al, and the ASi in CKD receptor antagonist aprocitentan in hypertension. Hypertension group. Ecacy and safety of aldosterone synthase inhibition with 2020; 75: 956–65. and without empagliflozin for chronic kidney disease: 80 Schlaich MP, Bellet M, Weber MA, et al, and the PRECISION a randomised, controlled, phase 2 trial. Lancet 2024; 403: 379–90. investigators. Dual endothelin antagonist aprocitentan for resistant 60 Sloan-Lancaster J, Raddad E, Flynt A, Jin Y, Voelker J, Miller JW. hypertension (PRECISION): a multicentre, blinded, randomised, LY3045697: results from two randomized clinical trials of a novel parallel-group, phase 3 trial. Lancet 2022; 400: 1927–37. inhibitor of aldosterone synthase. J Renin Angiotensin Aldosterone Syst 81 US Food and Drug Administration. TRYVIO (aprocitentan) tablets, 2017; 18: 1470320317717883. for oral use. March, 2024. https://www.accessdata.fda.gov/ 61 Bornstein SR, de Zeeuw D, Heerspink HJL, et al. Aldosterone drugsatfda_docs/label/2024/217686s000lbl.pdf (accessed synthase inhibitor (BI 690517) therapy for people with diabetes and Dec 18, 2025). albuminuric chronic kidney disease: a multicentre, randomized, 82 European Medicines Agency. Jeraygo: aprocitentan. Aug 29, 2025. double-blind, placebo-controlled, phase I trial. Diabetes Obes Metab https://www.ema.europa.eu/en/medicines/human/EPAR/jeraygo 2024; 26: 2128–38. (accessed Dec 18, 2025). 62 Judge PK, Tuttle KR, Staplin N, et al. The potential for improving 83 GOV.UK. Aprocitentan approved to treat adults with hypertension cardio-renal outcomes in chronic kidney disease with the aldosterone whose blood pressure cannot be controlled by other medications. synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi- https://www.gov.uk/government/news/aprocitentan-approved-to- KIDNEY trial. Nephrol Dial Transplant 2025; 40: 1175–86. treat-adults-with-hypertension-whose-blood-pressure-cannot-be- 63 Satoh F, Ito S, Itoh H, et al. Ecacy and safety of esaxerenone controlled-by-other-medications (accessed Dec 18, 2025). (CS-3150), a newly available nonsteroidal mineralocorticoid receptor 84 Heerspink HJL, Kiyosue A, Wheeler DC, et al. Zibotentan in blocker, in hypertensive patients with primary aldosteronism. combination with dapagliflozin compared with dapagliflozin in Hypertens Res 2021; 44: 464–72. patients with chronic kidney disease (ZENITH-CKD): a multicentre, 64 Bakris GL, Agarwal R, Anker SD, et al, and the FIDELIO-DKD randomised, active-controlled, phase 2b, clinical trial. Lancet 2023; Investigators. Eect of finerenone on chronic kidney disease 402: 2004–17. outcomes in type 2 diabetes. N Engl J Med 2020; 383: 2219–29. 85 Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol 65 Bakris GL, Agarwal R, Chan JC, et al, and the Mineralocorticoid 2014; 176: 630–39. Receptor Antagonist Tolerability Study–Diabetic Nephropathy 86 Sandner P. From molecules to patients: exploring the therapeutic (ARTS-DN) Study Group. Eect of finerenone on albuminuria in role of soluble guanylate cyclase stimulators. Biol Chem 2018; patients with diabetic nephropathy: a randomized clinical trial. 399: 679–90. JAMA 2015; 314: 884–94. 87 Pickering TG. Eects of stress and behavioral interventions in 66 Pitt B, Filippatos G, Agarwal R, et al, and the FIGARO-DKD hypertension: the rise and fall of omapatrilat. Investigators. Cardiovascular events with finerenone in kidney J Clin Hypertens (Greenwich) 2002; 4: 371–73. disease and type 2 diabetes. N Engl J Med 2021; 385: 2252–63. 88 Fryer RM, Segreti J, Banfor PN, et al. Eect of bradykinin 67 Agarwal R, Ruilope LM, Ruiz-Hurtado G, et al. Eect of finerenone metabolism inhibitors on evoked hypotension in rats: rank ecacy on ambulatory blood pressure in chronic kidney disease in type 2 of enzymes associated with bradykinin-mediated angioedema. diabetes. J Hypertens 2023; 41: 295–302. Br J Pharmacol 2008; 153: 947–55. 68 Solomon SD, McMurray JJV, Vaduganathan M, et al, and the 89 Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, FINEARTS-HF Committees and Investigators. Finerenone in heart Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual- failure with mildly reduced or preserved ejection fraction. acting inhibitor of the angiotensin II receptor and neprilysin: N Engl J Med 2024; 391: 1475–85. a randomised, double-blind, placebo-controlled, active comparator 69 Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the study. Lancet 2010; 375: 1255–66. novel non-steroidal mineralocorticoid receptor antagonist BAY 94- 90 Williams B, Cockcroft JR, Kario K, et al. Eects of sacubitril/ 8862 in patients with chronic heart failure and mild or moderate valsartan versus olmesartan on central hemodynamics in the elderly chronic kidney disease: a randomized, double-blind trial. with systolic hypertension: the PARAMETER study. Hypertension Eur Heart J 2013; 34: 2453–63. 2017; 69: 411–20. 70 Filippatos G, Anker SD, Böhm M, et al. A randomized controlled 91 Sun Y, Yang H. Comparison of sacubitril/valsartan with olmesartan study of finerenone vs eplerenone in patients with worsening for hypertension: a meta-analysis of randomized controlled trials. chronic heart failure and diabetes mellitus and/or chronic kidney Medicine (Baltimore) 2024; 103: e37501. disease. Eur Heart J 2016; 37: 2105–14. 14 www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 Therapeutics 92 McMurray JJ, Packer M, Desai AS, et al, and the PARADIGM-HF 97 Ma X, McKie PM, Iyer SR, et al. MANP in hypertension with Investigators and Committees. Angiotensin-neprilysin inhibition metabolic syndrome: proof-of-concept study of natriuretic peptide- versus enalapril in heart failure. N Engl J Med 2014; based therapy for cardiometabolic disease. JACC Basic Transl Sci 371: 993–1004. 2023; 9: 18–29. 93 Lim H, Agustian H, Febriana V, Supit AI. Sacubitril/valsartan role 98 Rahimi K, Bidel Z, Nazarzadeh M, et al, and the Blood Pressure in patients with resistant hypertension: a systematic review. Lowering Treatment Trialists’ Collaboration. Pharmacological blood Hell J Cardiol 2025; published online Jan 27. https://doi.org/10.1016/ pressure lowering for primary and secondary prevention of j.hjc.2025.01.004. cardiovascular disease across dierent levels of blood pressure: 94 Bitar YSL, Durães AR, de Macedo CRB, et al. Ecacy and safety of an individual participant-level data meta-analysis. Lancet 2021; sacubitril/valsartan in Afro-descendant patients with resistant 397: 1625–36. hypertension: a randomized controlled trial. J Hypertens 2025; 99 Brown JM, Siddiqui M, Calhoun DA, et al. The unrecognized 43: 1485–91. prevalence of primary aldosteronism: a cross-sectional study. 95 Lee V, Dalakoti M, Zheng Q, et al. Eects of sacubitril/valsartan on Ann Intern Med 2020; 173: 10–20. hypertensive heart disease: the REVERSE-LVH randomized phase 2 trial. Nat Commun 2025; 16: 6981. Copyright © 2026 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. 96 Chen HH, Wan SH, Iyer SR, et al. First-in-human study of MANP: a novel ANP (atrial natriuretic peptide) analog in human hypertension. Hypertension 2021; 78: 1859–67. www.thelancet.com Published online February 10, 2025 https://doi.org/10.1016/S0140-6736(25)02064-1 15 --- [PDF原文](https://sci-net.xyz/storage/7052102/033802f29beaba61621fd2316267c3cbdb411d40e0341e63335e8d6dba5abb4c/New-drug-therapies-for-hypertension.pdf) DOI: 10.1016/S0140-6736(25)02064-1