Advanced hypertension therapeutics: angiotensinogen and aldosterone synthase in focus

Why new classes at all

Existing antihypertensive drugs work when they are taken. The gaps they leave are adherence to daily tablets, the compensatory rise in renin that partly offsets downstream blockade of the renin-angiotensin system, and aldosterone-driven, salt-sensitive hypertension that persists on three or more agents. The three classes below each address one of these gaps. This note keeps three questions apart: what is established about the mechanism, what randomised trials show for blood pressure, and what is known about hard clinical outcomes.

1. Mechanism: what is experimentally established

Silencing angiotensinogen

Angiotensinogen is the only precursor of every angiotensin peptide and is made mainly in hepatocytes. Small interfering RNA (zilebesiran) or antisense oligonucleotides (IONIS-AGT-LRx) conjugated to N-acetylgalactosamine are taken up by hepatocytes and suppress angiotensinogen synthesis for weeks to months. The rationale is to act above renin, so that the renin rise that limits ACE inhibitors and angiotensin-receptor blockers has nothing to act on.

In the phase 1 study of zilebesiran in 107 patients, single subcutaneous doses of 200 mg or more lowered serum angiotensinogen in a dose-related way and reduced 24-hour ambulatory systolic pressure by more than 10 mm Hg and diastolic pressure by more than 5 mm Hg by week 8, an effect sustained to week 24. A high-salt diet attenuated the response and co-administration of irbesartan augmented it. No hypotension, hyperkalaemia or deterioration in renal function needing medical intervention was reported. The antisense compound reduced angiotensinogen with a favourable safety profile in phase 1 and 2 studies, with trends rather than powered effects on blood pressure.

Inhibiting aldosterone synthase

Aldosterone synthase (CYP11B2) shares 93 percent sequence identity with the cortisol-synthesising enzyme CYP11B1, which is why selective inhibition took decades to achieve. Baxdrostat showed roughly 100 to 1 selectivity in preclinical and phase 1 work and lowered plasma aldosterone without lowering cortisol; lorundrostat is likewise selective. Unlike receptor antagonists, which leave circulating aldosterone elevated, synthase inhibitors lower the hormone itself.

Blocking endothelin

Endothelin-1 is a potent vasoconstrictor that also promotes inflammation and sodium retention, and no established antihypertensive class targets it. Aprocitentan blocks both endothelin receptor subtypes.

2. Blood pressure in randomised trials

Zilebesiran

KARDIA-1 randomised 394 adults with mild to moderate hypertension after washout of previous treatment. At three months the placebo-corrected change in 24-hour ambulatory systolic pressure was −14.1 mm Hg with 150 mg every six months, −16.7 mm Hg with 300 mg every three or six months and −15.7 mm Hg with 600 mg every six months. Adverse events occurred in 60.9 percent of zilebesiran-treated patients and 50.7 percent of placebo-treated patients; drug-related non-serious events, chiefly injection-site reactions and mild hyperkalaemia, occurred in 16.9 percent versus 8.0 percent.

KARDIA-2 added a single 600 mg dose to a run-in of indapamide, amlodipine or olmesartan in 663 patients whose pressure remained uncontrolled. The placebo-corrected reduction in 24-hour systolic pressure at three months was −12.1 mm Hg on indapamide, −9.7 mm Hg on amlodipine and −4.5 mm Hg on olmesartan. Hyperkalaemia (5.5 versus 1.8 percent), hypotension (4.3 versus 2.1 percent) and acute kidney failure events (4.9 versus 1.5 percent) were more frequent with zilebesiran; most were mild and resolved without intervention.

KARDIA-3 extended testing to patients at high cardiovascular risk on several agents. According to a 2026 review, the trial did not meet its prespecified multiplicity-adjusted threshold for significance at month 3; the primary publication should be consulted once available.

Baxdrostat

BrigHTN, a phase 2 trial in treatment-resistant hypertension on at least three drugs including a diuretic, recorded systolic changes of −20.3, −17.5, −12.1 and −9.4 mm Hg with 2 mg, 1 mg, 0.5 mg and placebo over 12 weeks, a placebo-corrected difference of −11.0 mm Hg for 2 mg and −8.1 mm Hg for 1 mg. Two patients had potassium of 6.0 mmol/L or more; there was no adrenocortical insufficiency. A second phase 2 trial in uncontrolled hypertension, HALO, did not separate from placebo, which reviews attribute to a large placebo response.

BaxHTN, the phase 3 trial, randomised 796 patients with uncontrolled (two drugs) or resistant (three or more) hypertension. At 12 weeks the placebo-corrected change in seated systolic pressure was −8.7 mm Hg with 1 mg and −9.8 mm Hg with 2 mg. Potassium above 6.0 mmol/L occurred in 2.3 and 3.0 percent versus 0.4 percent on placebo. In a 26-week phase 2 trial in chronic kidney disease (mean eGFR 44 mL/min/1.73 m², median albumin-creatinine ratio 714 mg/g), baxdrostat lowered systolic pressure by a placebo-corrected 8.1 mm Hg, and hyperkalaemia was recorded as an adverse event in 41 percent versus 5 percent.

Lorundrostat

Target-HTN, a phase 2 dose-ranging trial in 200 adults on two or more drugs, found placebo-corrected office systolic reductions at eight weeks of −9.6 mm Hg with 50 mg once daily and −7.8 mm Hg with 100 mg in the suppressed-renin cohort; six participants had potassium above 6.0 mmol/L, corrected by dose reduction or discontinuation, and no cortisol insufficiency occurred. Advance-HTN standardised background therapy for three weeks and then randomised 285 participants; at 12 weeks the placebo-adjusted change in 24-hour systolic pressure was −7.9 mm Hg with a stable 50 mg dose and −6.5 mm Hg with dose adjustment to 100 mg. Potassium above 6.0 mmol/L occurred in 5 and 7 percent versus none.

Launch-HTN, the phase 3 trial, enrolled 1083 adults across 13 countries on two to five medications. At week 6 automated office systolic pressure fell by 16.9 mm Hg with 50 mg against 7.9 mm Hg with placebo, a difference of −9.1 mm Hg. Hyponatraemia, hyperkalaemia and reduced kidney function were reported more often with lorundrostat, each leading to discontinuation in fewer than 1 percent of participants.

Aprocitentan

PRECISION randomised 730 patients with resistant hypertension on standardised triple therapy. At four weeks the difference in office systolic pressure versus placebo was −3.8 mm Hg with 12.5 mg and −3.7 mm Hg with 25 mg, and −4.2 and −5.9 mm Hg by 24-hour ambulatory monitoring. After randomised withdrawal, pressure rose by 5.8 mm Hg on placebo. Mild to moderate oedema or fluid retention occurred in 9, 18 and 2 percent of the 12.5 mg, 25 mg and placebo groups. In the 147 participants with chronic kidney disease, systolic pressure fell by 13.5 and 16.6 mm Hg against 4.4 mm Hg with placebo, with reductions in albuminuria of 47 to 60 percent and no change in potassium. Aprocitentan was approved for resistant hypertension by regulators in the United States and Europe in 2024.

Across the classes

A 2026 meta-analysis of fourth-line therapy in resistant hypertension, covering eleven trials and 3931 adults, reported the largest clinic systolic reductions with lorundrostat (−11.7 mm Hg) and baxdrostat 2 mg (−10.1 mm Hg), a reduction with baxdrostat 1 mg (−8.6 mm Hg) similar to spironolactone (−8.0 mm Hg), and −3.8 mm Hg with aprocitentan 12.5 mg. No agent significantly increased serious adverse events. These are indirect comparisons across trials with different endpoints, run-in designs and populations, and should be read as such.

3. Hard outcomes: what exists

None of the four agents has a published randomised trial with cardiovascular or kidney events as its primary endpoint. Every trial above measured blood pressure over 4 to 26 weeks. Blood-pressure lowering is a well-validated surrogate, but each class carries a mechanism-specific question that only outcome trials can answer: for aldosterone synthase inhibitors, the consequences of hyperkalaemia, hyponatraemia and reduced glomerular filtration over years; for zilebesiran, the inability to withdraw a months-long effect quickly during sepsis, surgery, volume depletion or acute heart failure; for aprocitentan, fluid retention in patients prone to heart failure. Reviews describe outcome testing of zilebesiran as under way and aldosterone synthase inhibitors as approaching licensing; the albuminuria reductions seen with aprocitentan and the blood-pressure effect of baxdrostat in kidney disease are surrogate signals, not outcomes.

What to take from this

• The populations differed: KARDIA-1 studied untreated mild to moderate hypertension; BaxHTN, Launch-HTN and PRECISION studied patients uncontrolled on two or more drugs. Effect sizes are not interchangeable.
• Potassium, sodium and kidney function were monitored at initiation and after every dose change in the aldosterone synthase trials; the low discontinuation rates depend on that monitoring.
• Salt intake modified the response to angiotensinogen silencing in phase 1, which matters for how these drugs would be used.
• Nothing here is a treatment recommendation. Prescribing decisions belong to the treating clinician within the labelling and guidance in force.

This note is an expert summary. The sources below carry the full evidence base.