New Drugs in the Treatment of Uncontrolled or Resistant Hypertension

Arterial hypertension remains one of the leading modifiable risk factors for cardiovascular and renal morbidity and mortality worldwide, while resistant hypertension continues to represent a major therapeutic challenge despite the widespread use of conventional antihypertensive agents. Recent advances in the understanding of hypertension pathophysiology have enabled the development of novel pharmacological strategies targeting previously unexplored mechanisms. This review summarizes recently approved and emerging drugs for hypertension, with particular emphasis on agents acting on the renin–angiotensin–aldosterone system (RAAS), endothelin pathway, aldosterone synthesis, and RNA interference technology. Novel approaches include modulation of the ACE2/angiotensin-(1–7)/Mas receptor axis, inhibition of aminopeptidase A, and targeting tissue-specific RAAS activity, aiming to counteract the deleterious effects of classical RAAS activation. Dual endothelin receptor antagonists, particularly aprocitentan, have demonstrated significant and sustained blood pressure reduction in resistant hypertension with improved tolerability compared with earlier endothelin receptor antagonists. Highly selective aldosterone synthase inhibitors, including baxdrostat, lorundrostat, vicadrostat, and dexfadrostat, provide effective blood pressure lowering while minimizing cortisol suppression associated with previous agents, although hyperkalemia remains an important adverse effect. Small interfering RNA (siRNA)-based therapies represent an innovative therapeutic class, with zilebesiran producing prolonged suppression of angiotensinogen synthesis and sustained antihypertensive effects after infrequent subcutaneous administration. Collectively, these therapies offer promising alternatives for patients with uncontrolled or resistant hypertension and may provide additional cardiovascular and renal protection beyond blood pressure reduction. Nevertheless, many of these agents remain under clinical investigation, and further large-scale, long-term studies are required to establish their safety, cost-effectiveness, and impact on cardiovascular outcomes before their routine incorporation into clinical practice.