Zilebesiran Plus a Background Diuretic in Uncontrolled Hypertension: A KARDIA-3 Phase 2 Post Hoc Analysis

Presenter: N Pagidipati

Despite the availability of oral antihypertensive therapies, most patients with hypertension remain uncontrolled, and combining renin–angiotensin–aldosterone system (RAAS)-targeting agents with a diuretic may enhance blood pressure (BP) lowering through complementary mechanisms. Zilebesiran, an investigational RNA interference therapeutic targeting hepatic angiotensinogen and administered subcutaneously every six months, was evaluated in a post hoc analysis of the Phase 2 KARDIA-3 trial among 110 patients (41%) receiving a background diuretic and with baseline office systolic BP ≥140 mmHg. At Month 3, placebo-adjusted least squares mean office systolic BP fell by 9.2 mmHg (95% CI –17.3, –1.2) with zilebesiran 300 mg and 7.0 mmHg (95% CI –15.3, 1.3) with 600 mg; ambulatory systolic BP reductions were –6.8 and –6.0 mmHg, respectively, and were sustained to Month 6. Adverse event rates were similar to placebo (43.7% vs 43.6%), while eGFR decline and hyperkalaemia were low and largely transient, with no hypotension events. These findings suggest complementary BP-lowering effects when zilebesiran is combined with a diuretic-containing standard-of-care regimen and informed the design of the Phase 3 ZENITH trial.

Blood Pressure Variability With a Novel Low-Dose Triple Combination: Findings From the TRIDENT Trial

Presenter: T Wang

Blood pressure variability (BPV) predicts cardiovascular events and stroke independently of mean blood pressure, yet the effect on BPV of the low-dose triple single-pill combination tested in TRIDENT, previously shown to lower mean BP and reduce stroke in patients with prior intracerebral haemorrhage, remained unclear. This analysis of 1,557 participants (mean age 58 years; 33% female) compared telmisartan 20 mg, amlodipine 2.5 mg and indapamide 1.25 mg against placebo over a mean 3-year follow-up. Versus placebo, the combination significantly reduced systolic BPV by standard deviation (−2.05 mmHg; 95% CI −2.73 to −1.36; p<0.001), coefficient of variation (−0.82%; p<0.001) and average real variability (−2.47 mmHg; p<0.001), with parallel diastolic reductions, but showed no difference in variability independent of the mean (VIM) for either systolic (+0.07; p=0.83) or diastolic BPV. Because VIM adjusts for mean BP, these BPV reductions were predominantly attributable to mean BP lowering rather than an independent effect on variability.

Age and Sex Differences in Global and Regional Hypertension Phenotypes Among Untreated Adults: A May Measurement Month Analysis

Presenter: X Wang

Isolated systolic hypertension (ISH), usually associated with increased arterial stiffness, is more common in older adults, whereas younger adults more often present with isolated diastolic hypertension (IDH); however, large-scale comparisons across age, sex and regions have been limited. This cross-sectional analysis characterised hypertension phenotypes among 246,401 untreated hypertensive adults from 84 countries participating in May Measurement Month campaigns from 2021–2023. Crude proportions were 28.7% ISH, 38.9% combined systolic–diastolic hypertension (SDH) and 32.4% IDH. ISH increased sharply with age, reaching 55.7% in females and 48.5% in males aged ≥70, whereas IDH predominated among younger adults, particularly females. Regional differences were also marked, with ISH ranging from 18.5% in East Asia to 41.0% in Northern Africa and the Middle East. After adjustment, ISH predominated above age 65, while IDH predominated below age 40, more so in females.

Add-On Zilebesiran in Inadequately Controlled Hypertension: Efficacy and Safety Across Background Therapies

Presenter: T Bonafe

Hypertension remains the leading modifiable cardiovascular risk factor, yet control rates are suboptimal, partly reflecting poor adherence to daily oral regimens. Zilebesiran, an investigational RNA interference therapeutic targeting hepatic angiotensinogen, was evaluated as add-on therapy in this PRISMA-guided systematic review and meta-analysis of three randomised controlled trials comprising 1,320 patients inadequately controlled on stable monotherapy. Versus placebo, single-dose subcutaneous zilebesiran significantly reduced 24-hour ambulatory systolic BP at Month 3 across all background therapies, with placebo-adjusted reductions ranging from 4.0 mmHg (95% CI −7.6 to −0.3) in the olmesartan cohort to 12.1 mmHg (95% CI −16.5 to −7.6) in the indapamide cohort, amid high heterogeneity (I²=91.2%). However, it was associated with significantly higher risks of hyperkalaemia (RR 3.24; 95% CI 1.40 to 7.49; p<0.01) and eGFR decline ≥30% (RR 2.80; 95% CI 1.38 to 5.67; p<0.01). The findings support BP-lowering efficacy but underscore the need for renal monitoring and larger trials to establish longer-term safety.

Persistent Carotid Mechanical Impairment in Non-Dipping Hypertension Despite Blood Pressure Control

Presenter: CS Park

Non-dipping and morning blood pressure surge are associated with poorer prognosis and higher cardiovascular event rates. Never-treated patients newly diagnosed with hypertension underwent 24-hour ambulatory blood pressure monitoring and carotid ultrasound to assess whether altered carotid mechanics persisted after adequate office blood pressure control. Among 147 participants, 79 (53.7%) were dippers and 68 (46.3%) were non-dippers; carotid ultrasound was repeated after one year in those achieving adequate office blood pressure control. Circumferential strain and strain rate differed significantly between dippers and non-dippers at baseline and remained lower in non-dippers after blood pressure control. When patients were stratified by morning blood pressure surge quartiles, only circumferential strain differed significantly after one year. Persistent deterioration in carotid circumferential strain from the early stage of hypertension, despite office blood pressure control in patients with lost diurnal blood pressure variation, may help explain their poorer outcomes.

Sex-Specific Associations Between Systolic BP Control and Clinical Outcomes in Working-Age Hypertension

Presenter: K Takegawa

Current guidelines recommend a systolic blood pressure (SBP) target <130 mmHg, but whether achieving this target is similarly associated with outcomes in working-age men and women remains unclear. Health check-up data from 55,830 adults (mean age 52±9 years; baseline SBP 155±14 mmHg) who initiated antihypertensive therapy between April 2015 and March 2022 were analysed according to achievement of SBP <130 mmHg at follow-up. The primary outcome comprised all-cause death, acute myocardial infarction, stroke and heart failure hospitalisation. After inverse probability of treatment weighting, achieving SBP <130 mmHg was associated with lower risk of the composite outcome in men (HR 0.85; 95% CI 0.78–0.93), but not women (HR 0.94; 95% CI 0.79–1.12). The findings suggest that the association between achieving SBP <130 mmHg and clinical outcomes may differ by sex, supporting consideration of sex-specific BP targets in working-age adults.

Subfornical Organ AT1a Receptors, Splenic Sympathetic Activity and Blood Pressure During Angiotensin II Exposure

Presenter: M Perrotta

Circumventricular organs (CVOs) respond to circulating angiotensin II (AngII) and influence peripheral autonomic activity. In mice, fluorescent AngII localised to the subfornical organ (SFO) and brainstem, demonstrating that circulating AngII reaches these regions. SFO neurons were activated within 3 days of AngII exposure, coinciding with the early increase in splenic sympathetic nerve activity (SSNA), while angiotensin II type 1a receptor (AT1aR)-expressing SFO neurons remained activated during chronic exposure. Selective deletion of AT1aR in the SFO significantly reduced SSNA and protected against the AngII-induced rise in blood pressure (BP). Activity-dependent neuronal labelling showed early SFO activation, while neuronal activity was reassessed after 28 days of AngII exposure, when BP remained chronically elevated. These findings identify AT1aR-expressing SFO neurons as an important pathway linking circulating AngII to splenic sympathetic activation and BP elevation during AngII-induced hypertension, and provide mechanistic insight into how circulating AngII influences autonomic control of BP.

Sex Differences in Hypertension Prevalence, Treatment and Blood Pressure Control: 11-Year Trends in the ELSA-Brasil Cohort

Presenter: M Feital Nunes

Hypertension contributes substantially to cardiovascular risk, with men reported to carry a higher burden. Prospective data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) were analysed across three visits spanning 2008–2010, 2012–2014 and 2017–2019, including 15,088, 13,949 and 12,289 participants, respectively. Hypertension was defined as blood pressure (BP) ≥140/90 mmHg or antihypertensive medication use, with control assessed at <140/90 and <130/80 mmHg. Across all visits, men had higher hypertension prevalence, lower pharmacological treatment rates and poorer BP control than women. At the final visit, the prevalence ratio for hypertension in men versus women was 1.17, while the proportion receiving pharmacological treatment was 0.93 and BP control at <130/80 mmHg was 0.71. Although sex differences progressively narrowed over 11 years, men continued to experience a greater burden of hypertension and remained less likely to receive treatment or achieve BP control than women.

ESC Congress 2026, 28 - 31 Aug, Munich, Germany