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Key Points: Question: Does targeting hepatic angiotensinogen synthesis with the RNA interference therapeutic zilebesiran reduce blood pressure in adults with mild to moderate hypertension? Findings: In a phase 2 trial, subcutaneous zilebesiran doses of 150, 300, or 600 mg every 6 months or 300 mg every 3 months significantly decreased systolic blood pressure at 3 and 6 months vs placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients, principally injection site reactions and mild hyperkalemia. Meaning: Single subcutaneous doses of zilebesiran significantly lower blood pressure for up to 6 months, suggesting potential for use as an effective antihypertensive with quarterly or biannual dosing. Importance: Angiotensinogen is the most upstream precursor of the renin–angiotensin–aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. Objective: To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. Design, Setting, and Participants: This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Interventions: Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. Main Outcomes and Measures: The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Results: Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were −7.3 mm Hg (95% CI, −10.3 to −4.4) with zilebesiran, 150 mg, once every 6 months; −10.0 mm Hg (95% CI, −12.0 to −7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; −8.9 mm Hg (95% CI, −11.9 to −6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were −14.1 mm Hg (95% CI, −19.2 to −9.0; P <.001) with zilebesiran, 150 mg, once every 6 months; −16.7 mm Hg (95% CI, −21.2 to −12.3; P <.001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and −15.7 mm Hg (95% CI, −20.8 to −10.6; P <.001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. Conclusions and Relevance: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. Trial Registration: ClinicalTrials.gov Identifier: NCT04936035 This phase 2 randomized trial examines the antihypertensive efficacy and safety of different zilebesiran dosing regimens. [ABSTRACT FROM AUTHOR]

Chronic insulin infusion in Sprague-Dawley rats caused an increase in mean arterial pressure, cardiac output, total peripheral resistance and heart rate. It had no effect on sodium balance even at elevated arterial pressure. It is suggested that insulin hypertension is marked by changes in cardiac output and renal function in rats.

Hypertension is a well-recognized complication of obesity. However, the mechanisms for the development of obesity hypertension are not known. One mechanism proposed is that the hyperinsulinemia present in obese hypertensive patients causes hypertension via sodium retaining and/or sympathetic nervous system stimulatory effects. However, numerous studies in dogs have revealed no evidence for such chronic pressor actions of hyperinsulinemia. This is in close agreement with studies in human insulinoma patients that show marked hyperinsulinemia and normal blood pressure. The appropriateness of the dog as an experimental model is strengthened by reports from our laboratory and others that inducing obesity in dogs reproduces many of the characteristics of obesity in humans, including insulin resistance, hyperinsulinemia, sodium retention, hypertriglyceridemia and hypertension. Recent studies in obese dogs have indicated that significant increases in renal medullary cellularity and intercellular matrix deposition could contribute to the sodium retention and hypertension. Additional evidence suggests that sympathetic nervous system stimulation also may contribute to the elevated blood pressure. However, the mechanisms through which obesity induces these changes and the temporal relationship between these factors and the development of the hypertension remain to be determined. INDEXING KEY WORDS: obesity; hypertension; sympathetic nervous system; insulin; kidney

Available data of event-based clinical outcomes trials show that little evidence supports the guidelines recommendations to lower blood pressure (BP) to <130/80 mmHg in middle-aged and elderly people with type 2 diabetes mellitus and hypertension. We addressed this issue by post-hoc analysing the risk of cardiovascular (CV) events in mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial. Patients (n = 5250) were divided into 4 groups according to the proportion of on-treatment visits before the occurrence of an event (<25% to ≥ 75%) in which BP was reduced to <140/90 or <130/80 mmHg. After adjustment for baseline demographic differences between groups, a reduction in the proportion of visits in which BP achieved <140/90 mmHg accompanied a progressive increase in the risk of CV mortality and morbidity as well as of cause-specific events such as stroke, myocardial infarction and heart failure. A progressive reduction in the proportion of visits in which BP was reduced <130/80 mmHg did not have any effect on CV risks. In mostly elderly high-risk hypertensive patients with type 2 diabetes mellitus participating in the VALUE trial, achieving more frequently BP <140/90 mmHg showed a marked protective effect on overall and all cause-specific cardiovascular outcomes. This was not the case for a more frequent achievement of the more intensive BP target, i.e. <130/80 mmHg. [ABSTRACT FROM AUTHOR]

The effects of race and age on 24-hour mean ambulatory systolic blood pressure (maSBP) responses to sequential 4-week periods of angiotensin receptor blocker therapy (valsartan [VAL] 160 mg/d then 320 mg/d and combination VAL/hydrochlorothiazide [HCTZ] 320/12.5 mg/d) were compared in 304 patients with stage 1 or 2 hypertension. There were lesser blood pressure (BP) responses from baseline with VAL monotherapy in black than Caucasian patients (-2.9 and -4.0 mm Hg vs -8.2 and -9.3 mm Hg, respectively; P<.001 each) but VAL/HCTZ BP responses were similar in both groups (-12 vs -15 mm Hg). Participants 65 years and older had lower BP responses with VAL 160 mg/d and 320 mg/d than those younger than 65 years (-2.8 and -4.5 mm Hg vs -6.5 and -7.5 mm Hg, respectively; P<.001) but similar responses to VAL/HCTZ (-14 vs -17 mm Hg). No BP response differences were found between those older than and those younger than 55 years. The authors conclude that: (1) adding low-dose HCTZ (12.5 mg daily) to VAL is more effective than VAL titration, irrespective of age or race, (2) VAL BP efficacy is lower in blacks than Caucasians, and (3) ARB responses are diminished in patients older than 65 years. Guidelines for stage 1 or 2 hypertension that suggest age 55 should determine initial monotherapy choice (eg, ARB vs thiazide diuretic) or that fail to recommend initial ARB-thiazide combination therapy should be reconsidered. [ABSTRACT FROM AUTHOR]

Previous studies have debated the notion that low blood pressure (BP) during treatment, particularly diastolic (DBP), is associated with increased risk of cardiovascular disease. We evaluated the impact of low BP on cardiovascular outcomes in a high-risk population of 15,244 hypertensive patients, almost half of whom had a history of coronary artery disease (CAD). In the prospective Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, patients were randomized to valsartan or amlodipine regimens and followed for 4.2 years (mean) with no difference in the primary cardiovascular endpoint. A Cox proportional hazards model was used to evaluate the relationship between average on-treatment BP and clinical outcomes. The relationship between BP and cardiovascular events was adjusted for age, gender and body mass index, and baseline qualifying risk factors and diseases (smoking, high total cholesterol, diabetes mellitus, proteinuria, CAD, previous stroke and left ventricular hypertrophy). DBP ≥ 90 mmHg, compared with < 90 mmHg, was associated with increased incidence of the primary cardiovascular endpoint (all cardiac events); however, DBP < 70 mmHg, compared with ≥ 70 mmHg, was not associated with increased incidence after covariate adjustment (no J-shaped curve). Similar results were observed for death, myocardial infarction (MI), heart failure and stroke, considered separately. Nadir for MI was at DBP of 76 mmHg and for stroke 60 mmHg. The ratio of MI to stroke increased with lower DBP. In CAD patients the MI to stroke ratio was more pronounced than in patients without CAD but there was no significant J-curve in either group. Systolic BP ≥ 150 but not < 130 mmHg, compared with 130–149 mmHg, similarly was associated with increased risk for primary outcome. In conclusion, patients in BP strata ≥ 150/90 mmHg, but not patients in BP strata < 130/70 mmHg, were at increased risk for adverse outcomes in this hypertensive, high-risk population. Although benefit in preventing MI in relation to preventing stroke levels off for the lowest BPs, these data provide no support for a J-curve in the treatment of high-risk hypertensive patients . The increase in the ratio of MI to stroke with lower DBP indicates target organ heterogeneity in that the optimal on-treatment DBP for cerebroprotection is below that for cardioprotection. [ABSTRACT FROM AUTHOR]