Novel approach to hypertension sees single injection of zilebesiran reduce blood pressure

24th July 2023

A single subcutaneous injection of zilebesiran, which inhibits hepatic angiotensinogen synthesis, maintained a reduced 24-hour ambulatory blood pressure for 24 weeks, an international research team has found.

If approved, the drug paves the way for a more convenient means of managing hypertension, which is normally treated with oral antihypertensive agents.

In the study, published in the New England Journal of Medicine, the research team, which included experts from the University of Edinburgh’s Centre for Cardiovascular Science, examined the value of zilebesiran – an investigational RNA interference therapeutic agent which inhibits hepatic angiotensinogen synthesis – as a treatment for hypertension.

The study consisted of five different parts (A to E) but the current analysis focused on only three: Parts A, B and E.

In Part A, patients with hypertension were randomised 2:1 to either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400 or 800 mg) or placebo and followed for 24 weeks. Part B focused on the effect of an 800 mg dose of zilebesiran on blood pressure under conditions of either a low- or high-salt diet. Finally, the team provided the results from Part E, which was an open-label study of a single fixed dose of zilebesiran in combination with daily irbesartan.

Zilebesiran and blood pressure control

Of the 107 patients enrolled, there were no reports of hypotension, hyperkalaemia or worsening of renal function that required medical intervention.

In Part A, patients who received zilebesiran had decreases in serum angiotensinogen levels that correlated with the administered dose after eight weeks (r = –0.56). Single doses of the drug exceeding 200 mg were associated with decreases in both systolic (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) after only eight weeks and which were sustained after 24 weeks.

The findings from part B were consistent with attenuation of the effect on blood pressure by a high-salt diet. Similarly, patients in part E experienced a reduction in blood pressure with zilebesiran co-administration with irbesartan.

Professor David Webb, Christison chair of therapeutics and clinical pharmacology at the University of Edinburgh, who led the Edinburgh study site, said: ‘This is a potentially major development in hypertension. There has not been a new class of drug licensed for the treatment of high blood pressure in the last 17 years. This novel approach leads to a substantial reduction in blood pressure, both by day and night, that lasts for around six months after a single injection. This is attractive because it helps avoid the difficulty with adherence to treatment seen with current medicines. The next stage of clinical trials will focus on developing robust safety data, and broader evidence of efficacy, before zilebesiran can be licensed for use.‘

Baxdrostat effective in treatment-resistant hypertension

24th November 2022

Baxdrostat has been found to provide a significant reduction in systolic blood pressure in patients with treatment-resistant hypertension

Use of baxdrostat in patients with treatment-resistant hypertension, concurrently taking three other anti-hypertensives, led to significant reductions in systolic blood pressure compared to placebo according to the findings of a trial by UK and US researchers.

Hypertension is the leading preventable cause of premature death worldwide with one analysis of 90 countries estimated that globally, in 2010, 31.1% of the world’s adults had hypertension and which equated to 1.39 billion people. Despite the availability of a range of effective anti-hypertensive therapies, treatment-resistant hypertension, defined as above-goal elevated blood pressure in a patient despite the concurrent use of 3 antihypertensive drug classes, can be as high as 10.3%. One therapeutic target in hypertension is aldosterone synthase and a new class of drugs, the aldosterone synthase inhibitors, are currently under development. One such agent is baxdrostat and which has been shown in preclinical studies to completely suppress aldosterone production in humans without affecting cortisol production. Nevertheless, whether reducing aldosterone would also lower blood pressure was unclear and the subject of the current study.

Researchers focused on patients with treatment-resistant hypertension with a mean blood pressure of at least 130/80 mmHg, despite the use of three different anti-hypertensives. Participants were then randomised equally to 0.5, 1 or 2 mg of baxdrostat or matching placebo and were assessed for a period of 12 weeks. The primary efficacy endpoint was the change in the mean seated systolic blood pressure from baseline to the end of the study period. The change in diastolic pressure was then set as the secondary outcome measure.

Baxdrostat and changes in systolic blood pressure

A total of 248 patients with a mean age of 62.3 (55.8% male) were included and randomised to either placebo, 0.5, 1 and 2 mg of baxdrostat. The mean baseline systolic blood pressure ranged from 147.7 to 148.9 mmHg and the mean diastolic from 87.6 to 88.2 mmHg.

The change in systolic blood pressure at 12 weeks was significantly greater than placebo for the 2 mg dose (-20.3) and the mean difference compared to placebo was significant (p < 0.001). Similarly, the 1 mg dose achieved -17.5 reduction in systolic pressure and again the mean difference compared to placebo was significant (p = 0.003). There was no significant difference for the 0.5 mg dose.

The highest reduction in diastolic pressure occurred with the 2 mg dose (-14.3) and the 1 mg dose (-11.8) although no statistical significance data were reported.

The authors that there were reported no serious adverse events attributable to baxdrostat, and no instances of adrenocortical insufficiency.

They concluded that in patients with treatment-resistant hypertension, baxdrostat provided a dose-related reduction in blood pressure.

Citation
Freeman MW et al. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Eng J Med 2022

Study finds paracetamol use increases systolic blood pressure

23rd June 2022

Regular paracetamol use in both normotensive and hypertensive patients has been found to increase systolic but not diastolic blood pressure

Paracetamol use over a period of only two to three weeks seems to be enough to produce a significant increase in systolic blood pressure in normotensive and hypertensive patients according to the findings of a meta-analysis by researchers from New York, US.

Paracetamol (acetaminophen) is a widely for its analgesic and anti-pyretic properties and is considered to be generally safe unless taken in large quantities at which point, liver toxicity can occur. Though it is well established that non-steroidal anti-inflammatory drugs (NSAIDs), increase blood pressure in patients with controlled-hypertension, much less is known about the effect of paracetamol use on blood pressure.

Currently, some evidence suggests that paracetamol use, particularly, the effervescent form, is responsible for a significant daytime and overall increase in ambulatory 24 hour systolic blood pressure. However, in contrast, a review of the use of intravenous paracetamol, it was concluded that the drug actually has a hypotensive effect.

Moreover, this hypotensive effect has been shown in a study of 160 patients, to necessitate a therapeutic intervention in 34.9% of participants. While in a study of over 2,000 nursing home residents, paracetamol use was found to be safe for most, this was not the case for all residents.

With conflicting results, for the present analysis, the US team performed a systematic review and meta-analysis to investigate the effect of paracetamol use compared to placebo on systolic and diastolic ambulatory blood pressure.

They undertook a search of three major databases (PubMed, EMBASE and the Cochrane Library records) for randomised, controlled trials that included patients with or without cardiovascular disease and where changes in both systolic and diastolic pressure changes were reported.

Paracetamol use and changes in blood pressure

The search revealed only 3 relevant studies that included a total of 172 patients with a mean age of 59.9 years (73% male) and in which paracetamol was given daily over the course of two to three weeks.

Overall, paracetamol use resulted in a significantly higher systolic blood pressure compared to placebo (standardised mean difference, SMD = 0.35, 95% CI 0.08 – 0.63, p = 0.01). In a subgroup analysis of hypertensive patients, this difference was also significant (SMD = 0.38, 95% CI 0.05 – 0.71, p = 0.02).

Interestingly, there was no significant effect on diastolic blood pressure either overall (SMD = 0.18, 95% CI – 0.09 to 0.45, p = 0.19) or in the subgroup of hypertensive patients(SMD = 0.09, 95% CI -0.34 to 0.52, p = 0.68).

The authors suggested that while there is an underlying assumption that paracetamol use is generally safe, these findings challenge that assumption.

They concluded that there was a significant correlation between the use of paracetamol and systolic blood pressure in both normotensive and hypertensive patients.

Citation
Gupta R et al. Effect of acetaminophen on blood pressure: a systematic review and meta-analysis of randomized controlled trials Eur J Prev Cardiol 2022

No effect of systolic BP on cardiovascular outcomes in heart failure treated with empagliflozin

4th October 2021

Systolic BP has been shown not to effect the reduction in cardiovascular outcomes for heart failure patients treated with empagliflozin.

As a drug class, the sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown in a systematic review to have a moderate effect on major adverse cardiovascular events in patients with established atherosclerotic cardiovascular disease. Moreover, the same review identified how SGLT2is can also reduce hospitalisation for heart failure (HF) and progression of renal disease regardless of existing atherosclerotic cardiovascular disease. In addition to these positive effects on cardiovascular outcomes, SGLT2is have been shown to reduce 24-hour blood pressure (BP) in diabetic patients. Nevertheless, this blood pressure-lowering effect is of concern in those with HF, especially as between 15 and 20% of HF patients have low systolic BP and therefore at a higher risk of in-hospital and post-discharge mortality.

In an effort to evaluate whether the baseline systolic BP affected outcomes associated with the use of empagliflozin, an international team, led by researchers from Saarland University, Germany, enrolled patients in the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial. Patients with class II, III, or IV heart failure and an ejection fraction of less than 40% were randomised in a 1:1 fashion to either empagliflozin (10mg daily) or placebo in addition to their usual therapy for heart failure. For the study, patients were grouped according to their baseline systolic BP, as <110mmHg, 110–130mmHg or > 130mmHg and the primary outcome in the EMPEROR-Reduced trial was a composite of adjudicated cardiovascular death or hospitalisation for heart failure. For the present study, the researchers focused on whether the baseline systolic BP influenced the outcomes of cardiovascular death and hospitalisations for HF in patients given empagliflozin compared to placebo.

Findings

A total of 3730 patients were randomised to either empagliflozin (1863) or placebo and all patients had a left ventricular ejection fraction of less than 30%. Over a median of 16 months, the event rate per 100 patients years (pys) of follow-up, the primary outcome increased from 16.5 among the high SBP group to 20.8 for the intermediate group, and to 26.3 per 100 among the patients with low SBP (p=0.0015). Compared with placebo, treatment with empagliflozin significantly decreased the risk of cardiovascular death among the low systolic BP (hazard ratio, HR = 0.78, 95% CI 0.61–1.00), intermediate (HR = 0.71, 95% CI 0.58–0.87) and high (HR = 0.82. 95% CI 0.62–1.09) groups. However, while there were reductions in rates of HF hospitalisation with empagliflozin compared with placebo, this was only significant for patients with intermediate (110–130mmHg) systolic BP (HR = 0.66, 95% CI 0.50–0.88).

The authors concluded that empagliflozin reduced the risk of cardiovascular death and the number of HF hospitalisations and that this effect occurred independently of the baseline systolic BP.

Citation

Bohm M et al. Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure. J Am Coll Cardiol 2021.