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Resistant Hypertension New and Emerging Therapies
Resistant Hypertension: Controlling the Uncontrollable With New and Emerging Therapies

Released: August 14, 2025

Keith C. Ferdinand
Keith C. Ferdinand, MD, FAHA, FACC, FASPC, FNLA
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Key Takeaways
  • Resistant hypertension affects up to 20% of patients with hypertension despite treatment with at least 3 maximally tolerated antihypertensive agents, often including a diuretic.
  • Novel aldosterone synthase inhibitors like baxdrostat and lorundrostat are showing promise in reducing blood pressure for patients with resistant hypertension.
  • Aprocitentan, a dual endothelin receptor antagonist, was recently approved by the FDA to treat hypertension in combination with other antihypertensive agents in adults with uncontrolled blood pressure despite adequate treatment.

Resistant hypertension is defined as blood pressure that remains above goal despite adherence to at least 3 antihypertensive agents often including a diuretic at maximally tolerated doses and may affect up to 20% of patients with treated hypertension. These individuals face an elevated risk for cardiovascular events, including myocardial infarction, stroke, and renal dysfunction. Identifying and managing true resistant hypertension is critical, yet many patients are misclassified because of pseudoresistance from poor blood pressure measurement techniques, treatment nonadherence, or interfering substances.

Resistant hypertension is rarely driven by a single factor. Rather, it results from dysregulation across several interconnected systems: the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous system, and endothelin pathway. Comorbidities like chronic kidney disease, obesity, and obstructive sleep apnea further compound these mechanisms. Elevated aldosterone levels promote sodium retention and vascular inflammation whereas endothelin-1 contributes to vasoconstriction and endothelial dysfunction. Sympathetic nervous system overactivity heightens arterial stiffness and vascular resistance, perpetuating elevated pressures.

New and Emerging Therapies Are Closing the Gap
Despite decades of pharmacologic options, many patients’ blood pressure remains poorly controlled because of the current limitations of standard therapy. Adverse events, polypharmacy, and adherence challenges reduce treatment effectiveness, especially among high-risk groups like older adults, Black patients, and those with comorbidities. In some cases, available standard regimens that include a RAAS blocker, calcium channel blocker, and diuretic fail to adequately address the multifactorial pathophysiology of resistant hypertension.

It is fortunate to now have new and emerging therapies that are targeting these important mechanisms more precisely. Aldosterone synthase inhibitors such as baxdrostat and lorundrostat block aldosterone production at the source rather than downstream at the receptor. In the phase II BrigHTN trial, baxdrostat demonstrated significant blood pressure reductions without serious adverse events—paving the way for 4 ongoing phase III trials. Lorundrostat showed promising results in the Target-HTN trial and recently met key endpoints in the large phase III Launch-HTN trial.

The dual endothelin receptor antagonist aprocitentan inhibits both endothelin A and B receptors to reduce vasoconstriction and inflammation. Aprocitentan was recently approved by the FDA following the PRECISION trial, which showed sustained blood pressure reduction in patients with resistant hypertension receiving multiple antihypertensive agents including a diuretic. Its favorable safety profile makes it an attractive add-on for complex treatment regimens.

Meanwhile, a small interfering RNA like zilebesiran offers an upstream approach by silencing the hepatic production of angiotensinogen, the RAAS cascade’s initiating molecule. Early data show durable blood pressure lowering with infrequent subcutaneous dosing, potentially providing an option to improve treatment adherence for certain patients.

Integrating the Evidence Into Practice
As these therapies progress through clinical trials and into our practice, healthcare professionals must stay current on understanding mechanisms of action, evidence, and potential place in treatment. Personalized care that is guided by patients’ characteristics, comorbidities, and biomarker-driven strategies will be essential to effectively harness these therapeutic advances.

Controlling resistant hypertension ultimately requires more than simply adding on medications. It demands a proactive-driven and pathophysiology-driven approach with shared decision-making and continuous patient engagement. With these new tools and deeper understanding, we are poised to improve outcomes for a population once thought untreatable. So join us at the upcoming satellite to explore these advances, review the data, and discuss how to implement these innovations in your clinical practice.

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