New Kids on the Hypertension Block: Novel Agents With New Mechanisms of Action

Over the last 30 years, there have not been any really new molecules introduced for the treatment of hypertension. The exception was the combination of the angiotensin receptor blocker valsartan with the neutral endopeptidase (neprilysin) inhibitor sacubitril. It was developed after the failure of omapatrilat, an angiotensin converting enzyme inhibitor/neprilysin inhibitor, which induced angioedema in some patients. Valsartan/sacubitril demonstrated significant blood pressure (BP) lowering action and offered important cardiovascular protection in spontaneously hypertensive rats.1 However, the combined drug marketed as Entresto® has been approved only for heart failure, condition in which it was shown to be highly effective, and has been used as an antihypertensive agent only in some countries in Asia. Now, for the first time in many years, there are a number of new agents that target novel BP regulating mechanisms. These include endothelin receptor antagonists (ETRA), non-steroidal mineralocorticoid receptor antagonists (nsMRA), aldosterone synthase inhibitors (ASI), small interfering ribonucleic acid (siRNA) to inhibit the production of angiotensinogen (Aogen), and M natriuretic peptide. We recently published a detailed review of these novel agents for the treatment of resistant hypertension.2 Endothelin antagonists were initially approved only for the treatment of primary pulmonary hypertension. Endothelins (ET) are powerful 21-amino acid vasoconstrictor peptides, discovered in 19883 and found in most tissues.4 Among ETs, ET-1 is the most abundant. It induces vasoconstriction, inflammation, and growth via ETA and ETB receptors (ETAR and ETBR) on smooth muscle cells in the vascular wall.5,6 Acting on ETB receptors on endothelial cells, endothelin antagonists stimulate the release of NO and prostacyclin thereby inducing vasodilation in normotensive humans.7 Preclinical data has suggested that endothelin-1 elevates BP by its action on ETAR.8–12 In patients with difficult-to-control hypertension the endothelin system is activated in the vasculature,13 suggesting that its blockade could be effective in the treatment of hypertensive patients. It has been only with the development of aprocitentan, a dual ETAR/ETBR antagonist, with few adverse side effects and a positive phase II trial demonstrating significant BP reduction in hypertensive volunteers, that endothelin antagonism became a contender for the treatment of hypertension.14 Subsequently, the PRECISION trial demonstrated the efficacy of aprocitentan in resistant hypertension.15 Volume retention induced by aprocitentan may require the addition of a diuretic. In contrast to mineralocorticoid receptor antagonists (MRA), aprocitentan does not induce hyperkalemia, allowing its use in patients with advanced chronic kidney disease (CKD). In fact, in the PRECISION trial, an enhanced effect of aprocitentan was found in patients with CKD. Non-steroidal mineralocorticoid receptor antagonists (nsMRAs) are a new class of agents with high affinity and specificity for the MR.16 In contrast to the steroidal MRA spironolactone and eplerenone that function as partial agonists, nsMRAs are bulky inverse agonists that inhibit co-regulator recruitment even in the absence of aldosterone. Finerenone, the best studied, inhibits fibrosis more effectively than steroidal MRAs,17,18 and exerts protective effects on target organs, but is a relatively weak antihypertensive drug.18 Phase III randomized clinical trials in patients with diabetic kidney disease have demonstrated that finerenone reduces major renal [FIDELIO-DKD]17 and cardiovascular events [FIGARO-DKD] added to renin–angiotensin system (RAS) inhibitors.19,20 Another nsMRA is esaxerenone, which has been approved for the treatment of hypertension in Japan and is as effective on BP as eplerenone.21 Other nsMRAs under investigation include apararenone22 and ocedurenone.22,23 The recognition that primary aldosteronism is much more prevalent than previously thought has raised interest in blocking the production of aldosterone as part of hypertension treatment, as a potentially more effective approach than blocking mineralocorticoid receptors. Furthermore, aldosterone may act through membrane receptors such as GPR30, which would not be blocked by MRA, to induce its genomic effects, which may explain the advantage of unilateral adrenalectomy over MRA therapy in primary aldosteronism associated with an aldosteronoma. Aldosterone synthase (CYP11B2) has 93% sequence similarity with 11β-hydroxylase (CYP11B1) that participates in the synthesis of cortisol. Thus, it has been critical to develop highly selective inhibitors of CYP11B2: baxdrostat, lorundrostat, and dexfadrostat. In the BrigHTN phase 2 trial, baxdrostat effectively lowered BP in patients with resistant hypertension without serious adverse events, and with no evidence of hypocortisolism.24 A phase 3 baxdrostat trial is being carried out (clinicaltrials.gov ID NCT06034743). Dexfadrostat phosphate has reduced the aldosterone/renin ratio without reduction of cortisol levels,25 and lorundrostat lowered BP in a small study of patients with uncontrolled hypertension without evidence of adrenal insufficiency.26 Angiotensinogen (Aogen) is the precursor of all angiotensin peptides, and the first and rate-limiting step of the RAS. Thus, reducing its concentration would ultimately lower circulating angiotensin II and BP.27 Aogen production by the liver has been reduced with antisense oligonucleotides (ASOs) that inhibit RNA translation, and with siRNAs, both of which lead to degradation of Aogen mRNA and reduced Aogen synthesis. In a phase 1 study, the siRNA zilebesiran lowered Aogen for up to 24 weeks without hypotension, hyperkalemia, or worsening of renal function.28 The phase 2 study KARDIA-1 induced sustained dose-dependent reductions in Aogen and BP lowering for up to 6 months.29 The ASO targeting AGT (Ionis-AGT-LRx) has also been studied but so far in only two small studies.30 Additional medications are being developed or repurposed for hypertension from other indications. The association of the angiotensin receptor blocker valsartan with the neprilysin inhibitor sacubitril was shown in preclinical studies to be a powerful antihypertensive agent and to significantly protect the heart from fibrosis in the spontaneously hypertensive rat.1 It has been approved for heart failure as Entresto® in the United States but also approved in some Asian countries for the treatment of difficul-to-control hypertension and has been shown to effectively lower BP in resistant hypertension in patients with heart failure and preserved ejection fraction.31 M-atrial natriuretic peptide (MANP) represents the first agent of its class to be developed for the treatment of hypertension. To date, only one open-label, single-dose small trial has been reported, that showed a lowering of BP and dose-dependent natriuresis.32 Another new target for antihypertensive therapy is aminopeptidase A, which converts angiotensin II to the pressor angiotensin III (AngIII). In preclinical studies, EC33 was identified.33 This is an inhibitory molecule that reduces systemic vasopressin and sympathetic tone and stimulates the baroreflex.34 Firibastat is a prodrug metabolized to release EC33 that lowered BP in a phase 2b study of hypertensive patients.35 However, the phase 3 FRESH trial was not effective in lowering BP in difficult-to-treat and resistant hypertensive patients,36 and its development has been discontinued. Finally, sildenafil or similar phosphodiesterase 5 inhibitors, developed for erectile dysfunction, are being repurposed in some countries for the treatment of hypertension. As well, a potentially novel idea may be to combine antihypertensive agents with sodium-glucose transporter 2 (SGLT2) inhibitors rather than diuretics, to combat sodium and fluid retention or edema, and enhance BP lowering. With these discoveries, the field of hypertension has moved from boring and “been there, done that,” to an exciting terrain of novel options. Now we can wander “where the gods don’t dare to tread,” and we can look forward to more advances over the next several years. The research reported from the work of ELS and the present work was supported by Canadian Institutes of Health Research (CIHR) grants 37917, First Pilot Foundation Grant 143348, and Project Grant PJT 186248, a Canada Research Chair (CRC) on Hypertension and Vascular Research by the CRC Government of Canada/CIHR Program, by the Canada Fund for Innovation, and a Distinguished James McGill Professorship. The author declared no conflict of interest.