Beyond the Pill: RNA Interference, Aldosterone Synthase Inhibition and Incretins Reshape Hypertension Drug Development
核心洞察
A Nature review highlights RNA interference, aldosterone synthase (搜索) inhibition and incretin-based therapies as the leading breakthrough approaches in hypertension (搜索)-related disease.
Zilebesiran, an siRNA targeting liver angiotensinogen (搜索), lowered blood pressure in the KARDIA-2 and KARDIA-3 trials, including in patients at high cardiovascular risk.
Lorundrostat and baxdrostat, oral aldosterone synthase (搜索) inhibitors, reduced blood pressure in patients with uncontrolled and resistant hypertension (搜索) in recent trials.
Hypertension (搜索) drug development is shifting away from incremental refinements of established drug classes toward mechanisms that intervene earlier in the renin-angiotensin-aldosterone system or exploit metabolic pathways, according to a review published in Hypertension Research on breakthrough drugs for hypertension-related disease.
The review frames the problem in terms of unmet need: despite decades of available antihypertensives, adherence remains a persistent obstacle to blood pressure control, and hypertension (搜索) is increasingly understood as a driver of a wide spectrum of age-related diseases rather than an isolated cardiovascular risk factor. Against that backdrop, three therapeutic directions stand out — RNA interference targeting hepatic angiotensinogen (搜索), aldosterone synthase (搜索) inhibition, and incretin-based therapies already established in diabetes and obesity (搜索).
Silencing Angiotensinogen With siRNA
The most advanced of these approaches targets angiotensinogen (搜索) production in the liver. Zilebesiran, an RNA interference therapeutic, was shown to reduce blood pressure in a phase 1 study published in the New England Journal of Medicine in 2023. The clinical program has since expanded: the KARDIA-2 randomized clinical trial, reported in JAMA in 2025, evaluated zilebesiran as add-on treatment in patients with inadequately controlled hypertension (搜索), and the KARDIA-3 trial examined its blood-pressure-lowering effects in hypertensive patients at high cardiovascular risk, according to a European Society of Cardiology press release from August 2025.
The mechanistic rationale rests on preclinical work showing strong and sustained antihypertensive effects from small interfering RNA directed at liver angiotensinogen (搜索), and on the predictable pharmacokinetic and pharmacodynamic behavior of N-acetylgalactosamine-conjugated siRNA that supports translation to humans. An earlier antisense oligonucleotide against angiotensinogen, IONIS-AGT-LRx, was evaluated in phase 1 and phase 2 studies.
A distinguishing feature of this drug class is reversibility. Preclinical work demonstrated reversal of siRNA-mediated gene silencing in vivo, and subsequent research showed that REVERSIR technology can counteract angiotensinogen (搜索) siRNA-mediated antihypertensive effects — a potential safety valve for a therapy designed to suppress a pathway for months at a time.
Aldosterone Synthase Inhibition and the Mineralocorticoid Receptor
A second front targets aldosterone synthesis directly. Two oral aldosterone synthase (搜索) inhibitors reported positive results in 2025: lorundrostat in patients with uncontrolled hypertension (搜索), published in the New England Journal of Medicine, and baxdrostat in uncontrolled and resistant hypertension, also in the New England Journal of Medicine.
These agents build on a substantial body of evidence implicating aldosterone in hypertensive organ damage. Preclinical studies showed that aldosterone and salt induce renal inflammation and fibrosis, and that mineralocorticoid receptor (搜索) function is modified by Rac1 GTPase with implications for proteinuric kidney disease. Clinically, the aldosterone blocker eplerenone reduced albuminuria (搜索) in non-diabetic hypertensive patients with albuminuria, and mineralocorticoid receptor blockade suppressed dietary salt-induced ACE inhibitor/ARB-resistant albuminuria in non-diabetic hypertension (搜索) in a sub-analysis of the EVALUATE study.
Mineralocorticoid receptor (搜索) antagonism is already firmly established in heart failure (搜索), with spironolactone and eplerenone showing morbidity and mortality benefits in severe heart failure and in left ventricular dysfunction after myocardial infarction, respectively, and an individual patient-level meta-analysis confirming the class effect. Finerenone reduced chronic kidney disease (搜索) outcomes in type 2 diabetes (搜索). More recently, the ACHIEVE trial tested spironolactone versus placebo in patients undergoing maintenance dialysis, and the AMBER trial examined patiromer to enable spironolactone use in patients with resistant hypertension (搜索) and chronic kidney disease.
Incretins and SGLT2 Inhibitors as Blood Pressure Agents
The review also examines therapies whose primary indications lie outside hypertension (搜索) but which produce meaningful blood pressure reductions. Glucagon-like peptide-1 receptor agonists lower 24-hour ambulatory blood pressure, as shown for liraglutide in patients with type 2 diabetes (搜索) and stable coronary artery disease and confirmed in a meta-analysis of the class. Tirzepatide reduced 24-hour ambulatory blood pressure in adults with a body mass index of at least 27 kg/m² in the SURMOUNT-1 ambulatory blood pressure monitoring substudy, with stratified analyses of SURMOUNT-1 also reporting blood pressure reduction. A separate individual patient data meta-analysis examined semaglutide and blood pressure.
Mechanistic work supports these observations: endothelial GLP-1 receptor (搜索) signaling mediates cardiovascular protection by liraglutide in experimental arterial hypertension (搜索), GLP-1 induces natriuresis in healthy and insulin-resistant obese subjects, and central GLP-1 receptor signaling via brainstem catecholamine neurons counteracts hypertension in spontaneously hypertensive rats. Adipocyte-derived leptin has been identified as a direct regulator of aldosterone secretion promoting endothelial dysfunction and cardiac fibrosis, and adipocytes themselves produce aldosterone through calcineurin-dependent pathways — linking obesity (搜索)-related hypertension to aldosterone biology.
Sodium-glucose cotransporter 2 inhibitors represent a parallel case. Beyond their established cardiovascular and renal outcome benefits in type 2 diabetes (搜索) and heart failure (搜索), empagliflozin reduced blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes, and the SACRA study showed 24-hour blood pressure lowering with an SGLT2 (搜索) inhibitor in patients with diabetes and uncontrolled nocturnal hypertension (搜索). Proposed mechanisms include normalization of circadian blood pressure rhythm, sympathoinhibition, and differential volume regulation.
Combination Strategies and Residual Gaps
The review highlights combination approaches that pair these mechanisms. Sacubitril/valsartan, a dual angiotensin receptor and neprilysin inhibitor, lowered blood pressure versus amlodipine in Japanese patients with essential hypertension (搜索) in the PARASOL noninferiority study, and ameliorated renal tubulointerstitial injury in a mouse model of type 2 diabetes (搜索) with aldosterone excess. The non-steroidal mineralocorticoid receptor (搜索) blocker esaxerenone lowered home blood pressure versus trichlormethiazide in uncontrolled hypertension in the EXCITE-HT randomized controlled study, with the ESCORT-HT study designed to further evaluate esaxerenone. A meta-analysis also compared mineralocorticoid receptor antagonist plus SGLT2 (搜索) inhibitor versus SGLT2 inhibitor alone in chronic kidney disease (搜索).
One persistent limitation cuts across the field: antihypertensive treatment frequently fails to control blood pressure during exercise, a gap noted in the review's discussion of blood pressure responses to physical activity. The review also cites evidence that exercise training lowers resting blood pressure and that endurance training affects blood pressure-regulating mechanisms, while work in hypertensive rats treated with losartan showed that physical exercise is essential for increasing ventricular contractility — suggesting that pharmacologic and lifestyle interventions may interact rather than simply add.