Zilebesiran is an arni targeting the hepatic synthesis of angiotensinogen (precursor of angiotensin, involved in high blood pressure). In 2023, a phase 1 trial carried out with a hundred patients with uncontrolled blood pressure (HTA) confirmed the capacity of a single subcutaneous injection of Zilebésiran to cause prolonged decrease in circulating angiotensinogenic levels and blood pressure (1).
Results that made the launch of the Kardia-2 clinical trial, in 1,491 hypertensive adults despite antihypertensive monotherapy-by thiazide, ARA2 or antagonist of calcium channels (2).
A new long -lasting drug candidate: Zilebesiran
Patients first received 2.5 mg of Indapamide, 5 mg of amlodipine, or 40 mg of Olmesartan for four weeks. Those who were members of the treatment, and whose tension stood between 130 and 160 mmHg at the end of this phase (n = 130 in the Indapamide group, n = 240 in the amlodipine group, n = 293 in the olmessartan group) were then randomized in 1: 1 to receive a subcutaneous injection of 600 mg of zilebesiran, or a placebo.
At three months, patients who received Zilebésiran had better control than on placebo, regardless of the classic antihypertensive used -even if the most notable effects were noted in combination with Indapamide: -12,1 [-16,5 à -7,6] mmHg (p <0.001) Average ambulatory blood pressure voltage over 24 hours compared to the initial value for Indapamide; -9.7 [−12,9 à −6,6] mmHg (p <0.001) for amlodipine; -4.5 [-8,2 à -0,8] mmHg (p = 0.02) for Olmésartan.
The undesirable effects, most often light, proved more frequent in participants who received zilebesiran than in the control arm: hyperkalemia (recorded in 5.5 % of patients in the interventional arm, but only in less than 2 % of patients in the placebo arm), hypotension (twice as frequent in the event of zilebis), acute renal insufficiency (identified in 5 % of patients Under Zilebesiran, but only in 1.5 % of patients in the placebo group).
Amiloride, alternative to spironolactone in resistant hypertension
But new experimental antihypertensors are not the only ones to be the subject of research.
For the first time, a well-conducted clinical trial compared two diuretics directly, Spironolactone and Amiloride, in resistant HTA, that is to say uncontrolled despite a tritherapy already including a thiazidic diuretic, an ARA2 and an antagonist of calcium channels (3).
118 patients (70 % of men, 55 years of median age) still with systolic blood pressure greater than 130 mmHg after 4 weeks of treatment with tritherapy were included in this Korean trial. They were randomized to receive either spironolactone or amilorid, initially at daily doses of 12.5 mg and 5 mg respectively, with the possibility of doubling the dosages after four weeks, in the event of blood pressure still greater than 130 mmHg and serum potassium levels less than 5.0 mmol/l.
The study concludes that the amiloride of the spironolactone is not inferred. While initially, patients in the two groups presented on average a systolic blood pressure greater than 140 mmHg, at 12 weeks, participants in the amilorid arm saw this lowered parameter of -13.6 mmHg, a figure close to -14.7 mmHg observed in the Spironolactone arm.
Only a case of treatment arrest linked to hyperkalemia was registered in the Aminoride group.
Quid you moment of administration of treatments?
Should you advise a catch in the morning when you wake up, or rather in bed at bedtime? Over the past twenty years, several works such as the Mapec Investigation, the Hygia study or the Time test have looked at this issue. But their results appeared contradictory, or difficult to interpret due to methodological limits.
Hence a new trial conducted in Canada with 3,357 adults on antihypertensors, randomized in 1: 1 to receive their medication either at bedtime or at raising (4). These patients, 67 years of median age, half under antihypertensive monotherapy, were followed for a median period of 4.6 years. The composite main judgment criterion concerned all causes and hospitalizations for stroke, infarction or heart failure.
In total, no difference was released between the two methods of taking, whether in view of efficiency (the moment of administration was without effect on cardiovascular risk), or the safety of treatment: despite hypothetical fears concerning an increased risk of adverse effects (glaucoma, hypotension, in particular) in the event of administration in the evening, the study finds in the two groups an equivalent prevalence of cases of falling, fracture, glaucoma and cognitive decline.
(1) Akshay S. Desai, David J. Webb, Jorg Taubel, et al. Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension. N Engl J Med. Published July 19, 2023 N Engl J Med 2023;389:228-238
(2) Akshay S. Desai, Adam D. Karns, Jolita Badariene, et al. Add-On Treatment With Zilebesiran for Inadequately Controlled HypertensionThe KARDIA-2 Randomized Clinical Trial. JAMA. Published online May 28, 2025
(3) Chan Joo Lee, Sang-Hyun Ihm, Dong-Ho Shin, et al. Spironolactone vs Amiloride for Resistant Hypertension. A Randomized Clinical Trial. JAMA. Published online May 14, 202(4) Scott R. Garrison, Jeffrey A. Bakal, Michael R. Kolber, et al. Antihypertensive Medication Timing and Cardiovascular Events and DeathThe BedMed Randomized Clinical Trial. JAMA. Published online May 12, 2025
