New Pharmacologic Therapies for Hypertension on the Horizon

Almost half of adults in the United States have a diagnosis of hypertension, with declining blood pressure control rates that lead to increased morbidity and mortality (1). A recent flurry of research into novel agents with unique mechanisms to manage hypertension bears promise for better blood pressure control, particularly in the subset of patients with resistant hypertension, summarized in the Table.

Table

Summary and status of novel pharmacologic agents undergoing research to manage hypertension

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Of these, aprocitentan—a dual endothelin receptor antagonist—is approved by the US Food and Drug Administration (FDA) for treatment of resistant hypertension. Unlike other agents studied for systemic hypertension (e.g., bosentan and darusentan), aprocitentan appears to have a better safety profile. A phase 3 trial showed modest but consistent blood pressure reduction in patients with resistant hypertension, with a secondary outcome of albuminuria reduction by −21% and −38%, with 12.5 mg and 25 mg doses, respectively (2). Edema was a concern, particularly with the higher 25-mg dose. The FDA-approved dose is 12.5 mg once daily in patients with an estimated glomerular filtration rate (eGFR) of 15 or greater. Aprocitentan prescribers need to be enrolled in a Risk Evaluation and Mitigation Strategy safety program due to risk of major birth defects.

An increasing recognition of autonomous aldosterone production as a contributor to hypertension has prompted evaluation of agents beyond steroidal mineralocorticoid receptor antagonists (MRAs), like spironolactone. Although the non-steroidal MRA (ns-MRA) finerenone is the most recognizable in this class and has proven cardiorenal benefits in type 2 diabetes, its effect on blood pressure reduction has been more limited (although data suggest more potent effects at a systolic blood pressure >140 mm Hg). It should be noted that the randomized controlled trials examining kidney outcomes for finerenone (FIDELIO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease] and FIGARO-DKD [Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease]) were not blood pressure studies but were cardiovascular and kidney outcome studies (3, 4). Ocedurenone is a third-generation ns-MRA, with a small phase 2 trial showing significant blood pressure reduction compared with placebo in patients with uncontrolled hypertension and chronic kidney disease (CKD) stages 3b and 4, with no reported cases of severe hyperkalemia (≥6 mmol/L) (5).

Distinct from ns-MRAs, which block aldosterone binding to MRs, aldosterone synthase inhibitors prevent adrenal aldosterone synthesis by inhibiting the CYP11B2 isoenzyme. The challenge is to specifically inhibit CYP11B2 without inhibiting CYP11B1, which is involved in cortisol production. Osilodrostat, which was the first aldosterone synthase inhibitor in clinical development, inhibited cortisol synthesis and was repurposed to treat hypercortisolism (6). Newer aldosterone synthase inhibitors have more selectivity for CYP11B2, and agents currently under study include baxdrostat and lorundrostat for hypertension, dexfadrostat for primary aldosteronism, and BI 690517 for CKD and albuminuria. Phase 2 trials of baxdrostat in resistant hypertension (7) and lorundrostat in uncontrolled hypertension (8) showed significant blood pressure differences compared with placebo. Both trials showed lower serum aldosterone and an increase in plasma renin activity, with no cortisol insufficiency. Although the incidence of severe hyperkalemia (≥6 mmol/L) was low, it should be noted that these trials were of short duration, and the mean eGFR in these trials was 80–83; the real-world incidence of hyperkalemia could be higher, particularly in those with lower eGFR.

Hepatic angiotensinogen attenuators are one of the more intriguing innovative therapies, which include small interfering RNA (siRNA) targeting hepatic angiotensinogen and antisense oligonucleotide for hepatic angiotensinogen mRNA knockdown. Zilebesiran is a first-in-class siRNA that binds to an hepatic asialoglycoprotein receptor leading to reduction in angiotensinogen mRNA and decreased hepatic angiotensinogen. The phase 2 KARDIA-1 (A Study to Evaluate Efficacy and Safety of ALN-AGT01 in Patients With Mild-to-Moderate Hypertension) study showed blood pressure reduction at 300 mg doses and higher, when injected subcutaneously with dosing schedules of once every 3 months or once every 6 months (approximately a 14-mm Hg blood pressure difference from placebo) and sustained angiotensinogen and blood pressure reduction at 6 months (9). The phase 2 KARDIA-2 (Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication) study evaluated zilebesiran 600 mg vs placebo on background of olmesartan, indapamide, or amlodipine (10). Interestingly, blood pressure reduction was more pronounced in the indapamide and amlodipine groups at 3 months and sustained to 6 months in these groups but not in the olmesartan group. Although the potential for improved adherence with a once-every-6-month dosing schedule is appealing, several questions remain, including concern for refractory hypotension, particularly in states like shock. No severe adverse events of hypotension or orthostasis were noted in studies, but these were of relatively short follow-up, and longer-term safety data are needed.

In addition to pharmacologic agents, device-based therapy, in particular, renal denervation, has emerged as a possible adjunctive option and now has FDA approval for clinical use, with newer catheter designs and more recent studies showing modest but significant blood pressure reductions.

Overall, this is an exciting era for antihypertensive therapy. Although continued development and research into newer therapies are essential to advance the field, it is also critical to remember the basic paradigms of management, including proper blood pressure measurement and continued emphasis on lifestyle modifications. The availability of newer therapies also brings the challenge of access, and effective ways of implementation need to be examined. The exact place of these newer therapies in the armamentarium remains to be determined in future studies and with clinical use, particularly in comparison with older, inexpensive agents like spironolactone.