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.‘

Inspiratory muscle strength training lowers blood pressure

29th September 2022

Inspiratory muscle strength training significantly reduced both systolic and diastolic blood pressure according to a review of 5 studies

Inspiratory muscle strength training (IMST) for a period of six weeks results in a significant reduction in both systolic and diastolic blood pressure compared to sham strength training according to a review of studies by US researchers.

Elevated systolic blood pressure is a leading cause of global deaths, accounting for 10·4 million deaths and 218 million disability-adjusted life-years. Lifestyle interventions to lower blood pressure include increased physical activity, weight loss and adoption of a healthy (lower salt) diet.

Another intervention which has gained interest in recent years is inspiratory muscle strength training which has been previously used to help wean patients off mechanical ventilation in hospital. Moreover, IMST has also been shown to be of some value by increasing peak power in recreational cyclists. Nevertheless, IMST has also been shown to reduce blood pressure and autonomic cardiovascular control in hypertensive patients.

In recent years, high-resistance low volume inspiratory muscle strength training which involves 30 daily inspiratory efforts against a resistance equal to 75% of an individual’s maximal inspiratory pressure, has emerged as a time-efficient lifestyle intervention (requiring only 5 minutes) to lower blood pressure. The technique has already been shown to lower blood pressure and may potentially improves vascular endothelial function.

Nevertheless, to date, most blood pressure lowering studies have only included a small number of participants. Consequently, for the present study, the US researchers pooled data from 5 randomised trials to provide a better estimate of the blood pressure lowering effect of IMST.

The trials included young adults, some of whom were taking blood pressure lowering medication but who overall had a low-to-moderate cardiovascular disease risk. Individuals were randomised to either high-resistance IMST or low-resistance (or sham) IMST and each of the trials lasted 6 weeks.

Participants performed 30 inspiratory efforts every day as a single bout, comprising 5 sets of 6 inspiratory efforts.

Inspiratory muscle strength training and blood pressure changes

Data from 128 adults were included of whom 67 with a mean age of 50 years (43.2% female) were assigned to high-resistance IMST and the remainder a sham procedure.

After 6 weeks, systolic blood pressure remained unchanged in the sham group but decreased from a mean of 127 mmHg to 118 mmHg in the high resistance IMST group and this difference was statistically significant (p < 0.01). In addition, systolic blood pressure was observed to decline by an average of 1.5 mmHg per week.

After 6 weeks, the mean diastolic pressure was also significantly lower in the high resistance IMST group (72 vs 76 mmHg, p < 0.01) and significantly lower than for the sham procedure which also reduced by a mean of 1 mmHg (p = 0.03).

The maximal inspiratory pressure (which is a measure of the strength of the inspiratory muscles, in particular the diaphragm) improved in both groups, but to a significantly higher level for the high resistance group (20 cmH₂O vs 6 cmH₂O, p < 0.01).

The authors noted that reductions in both systolic and diastolic pressures also occurred for those taking antihypertensive medication but that the effect was smaller.

They concluded that high resistance IMST induced clinically meaningful reductions in blood pressure and provide support for this technique as a time-efficient lifestyle intervention to lower blood pressure.

Citation
Craighead DH et al. A multi-trial, retrospective analysis of the antihypertensive effects of high-resistance, low-volume inspiratory muscle strength training J Appl Physiol (1985) 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