Hypertension Management– Unmet Needs
Hypertension, which is commonly known as high blood pressure, is the primary cause of death and years lost to disability. Perhaps something like, “Hypertension, or high blood pressure, relentlessly claims lives and fuels disability worldwide, standing as a leading risk factor for debilitating conditions like heart disease, stroke, and dementia (Redon et al,2024).1
However, despite the wide availability of various classes of medications, the incidence of hypertension continues to increase. (Kanbay et al,2023).2 Also, a significant portion of those with hypertension do not respond or are resistant to these treatment options. Resistant hypertension is a critical form of high blood pressure associated with a higher risk of complications and deaths. The American Heart Association describes resistant hypertension as a state in which blood pressure continues to exceed the target range despite the administration of three or more high blood pressure medications from different classes, including a diuretic, at their highest tolerated doses (Naseralallah et al,2024).3 Thus, there is a renewed interest in new and upcoming innovative therapies for the management of hypertension that can effectively lower blood pressure, some of which are discussed here.
But, before we explore the future of hypertension treatment, it’s essential to understand what hypertension really is and how it affects your body. If you’re new to the topic or want a quick refresher, check out our earlier blog post: Essentials of high blood pressure. This guide breaks down key concepts, including blood pressure readings, risk factors, and the importance of managing high blood pressure.
Newly Approved Therapies
Recently, the U.S. Food and Drug Administration (FDA) has approved a new drug, Aprocitentan, to treat hypertension, specifically in conjunction with other medications, for patients whose blood pressure is not adequately managed by current treatments. Additionally, renal denervation, a procedure, is being recognized as a potential solution for resistant hypertension. We hereby discuss a few key points.
Aprocitentan (ET Receptor Antagonist)
Aprocitentan (TRYVIO™) is an oral medication that acts as a dual antagonist for endothelin A (ETA) and B (ETB) receptors. Idorsia Pharmaceuticals has developed it specifically to treat resistant hypertension. Moreover, this drug is designed to focus on the endothelin (ET) pathway, “a pathway largely untouched by current therapies,” for resistant hypertension.
Approval
- In March 2024, the U.S. Food and Drug Administration (FDA) approved Aprocitentan for the treatment of hypertension in combination with other antihypertensive drugs to lower blood pressure in adults with resistant hypertension (who are not adequately controlled by other drugs).
- It was approved based on the results of the Phase III PRECISION trial.
- Consequently, the PRECISION trial demonstrated that Aprocitentan effectively reduces blood pressure in patients with resistant hypertension, underscoring the need for additional studies to evaluate its long-term safety and broader clinical applications.
Mechanism of action
- Endothelin-1 (ET-1) is a natural chemical made by the body that causes blood vessels to tighten or narrow. When blood vessels become narrow, it increases blood pressure.
- Aprocitentan is a medicine that blocks the effects of ET-1. It does this by preventing ET-1 from attaching to receptors ETA and ETB on blood vessels. As a result, the blood vessels stay more relaxed and open, which helps to lower blood pressure.
(Image generated with AI using ChatGPT and DALL·E by OpenAI.)
Safety Profile
- The most common adverse reactions reported are oedema (swelling) and fluid retention, as well as anaemia.
- Also, Aprocitentan may cause serious birth defects, so it is not allowed to be taken during pregnancy. In addition, you should avoid becoming pregnant during treatment with Aprocitentan and continue using effective contraception for one month after stopping the medication, to prevent potential harm to the fetus
- Aprocitentan has the potential to lead to liver damage or toxicity. Therefore, patients who are at a higher risk should be made aware of the symptoms of liver toxicity and urged to quickly reach out to their healthcare provider if they experience any signs.
Dosage Form and Strength
- It is available as a 12.5 mg tablet for oral use
Dosage and Administration
- The recommended dosage is 12.5 mg orally once daily, with or without food.
(Naseralallah et.al,2024 3; Dhillon et.al.,2024 4 ;Tryvio 5; Riaz et.al.,2025 6)
Renal Denervation (Device-Based Therapy)
In November 2023, the U.S. FDA approved two renal (kidneys) denervation systems for the treatment of hypertension. Additionally, the FDA’s approval of renal denervation represents a significant milestone in hypertension treatment, introducing a novel therapeutic option for individuals with resistant hypertension.
Sources
Mechanism of Action
- Renal denervation involves the selective destruction or interruption of renal nerves of the renal arteries (blood vessels that supply the kidneys).
- These renal nerves are part of the sympathetic nervous system, which plays a major role in regulating blood pressure.
- In patients with hypertension, particularly resistant hypertension, there’s often an overactivity of this renal sympathetic nervous system.
- The aim of renal denervation is to disrupt or destruct these overactive sympathetic nerves.
Procedure
(Image generated with AI using ChatGPT and DALL·E by OpenAI.)
- The procedure is generally performed under local anesthesia and conscious sedation to lessen pain.
- During the process of renal denervation, a catheter is inserted into the femoral artery, located in the groin, and navigated to the renal arteries.
- Once correctly positioned, the catheter administers radiofrequency energy or ultrasound to ablate/destroy/burn the nerve fibers around the renal arteries.
- The primary objective is to reduce the activity of these nerves, which may be excessively active in individuals with hypertension, leading to increased blood pressure.
(Zhang etal,2025 7; Cluett et.al,2024 8)
Pros (Advantages)
- May lower blood pressure when medicines don’t work well
- One-time procedure (no daily pills required)
- Minimally invasive (done through a small puncture, not surgery)
- Safe and well-tolerated in most studies
- No major recovery time – quick return to daily activities
Cons (Limitations)
- Not suitable for everyone
- Still not widely available in all countries
- Some risk of bleeding or injury at the catheter site
- May not work for all patients
- Long-term effects still being studied
- May need to continue blood pressure medications in some cases
(Generated with AI using ChatGPT and DALL·E by OpenAI.)
Therapies in the Pipeline
Several innovative therapies for hypertension are emerging, such as mineralocorticoid receptor antagonists and aldosterone synthase inhibitors. Moreover, device-based therapies are showing potential, especially for resistant hypertension. Here’s a brief look at a few of the upcoming therapies.
Finerenone
- Finerenone, known by its brand name Kerendia, was granted approval by the US FDA in July 2021 for the management of chronic kidney disease (CKD) in adult patients with type 2 diabetes. Furthermore, it obtained approval from the European Medicines Agency in February 2022.
- In recent research, Finerenone has shown positive results in patients suffering from resistant hypertension.
- Finerenone serves as a nonsteroidal selective mineralocorticoid antagonist. It works by blocking the effects of aldosterone, a mineralocorticoid.
- Aldosterone causes the kidneys to retain sodium and water, resulting in increased blood volume and elevated blood pressure.
- Finerenone, by blocking the action of aldosterone, helps the kidneys excrete more sodium and water, which subsequently lowers blood pressure.
- Although Finerenone is currently not recognized as a first-line treatment for hypertension, its ability to protect organs makes it an important adjunct therapy for specific individuals, especially those with CKD, diabetes, or resistant hypertension.
Lorundrostat
- Lorundrostat is a novel oral medication that acts as a highly selective inhibitor of aldosterone synthase, currently under development by Mineralys Therapeutics for addressing uncontrolled hypertension .
- Aldosterone is a hormone that plays a crucial role in regulating blood pressure and maintaining electrolyte balance. In certain instances, an overproduction of aldosterone can lead to hypertension. Thus , by inhibiting aldosterone synthase Lorundrostat lowers aldosterone levels and helps to control blood pressure
- In Phase 3 clinical trials (Launch-HTN trial ), Lorundrostat has revealed promising findings for cases of uncontrolled or resistant hypertension.
- Lorundrostat 50 mg, dosed once daily, demonstrated clinically meaningful and sustained reductions in systolic blood pressure, with a 16.9 mmHg reduction at Week 6 and a 19.0 mmHg reduction at Week 12.
(Laffin,2023 10 ; Lapoce,202511)
Baxdrostat
- Baxdrostat is another strong aldosterone synthase inhibitor.
- The Phase 2 trial, BrigHTN, demonstrated robust efficacy in managing treatment-resistant hypertension, with a systolic blood pressure decrease of up to 20 mmHg at 2 mg compared to placebo.
- However, in another Phase 2 trial, the HALO Baxdrostat failed to achieve the primary endpoint.
- The ongoing phase 3 BaxHTN trial aims to assess the safety profile of baxdrostat and its influence on blood pressure among patients experiencing uncontrolled or resistant hypertension. The results are projected to be released in late 2025.
(BrigHTN,202212; HALO,2023 13; Shira et.al,2024 14)
Zilebesiran
- Zilebesiran represents a novel RNA interference therapy that is being explored for the management of hypertension.
- Zilebesiran utilizes RNA interference technology to reduce the synthesis of angiotensinogen, a protein essential to the Renin-Angiotensin-Aldosterone System (RAAS), which regulates blood pressure.
- When administered via subcutaneous injection, Zilebesiran exhibited prolonged blood pressure reductions over a 6-month period following a single dose in patients with hypertension who were not on any antihypertensive medications.
- Further, ongoing Phase 3 trials are assessing its effectiveness as an add-on therapy for individuals with uncontrolled hypertension who also carry a high cardiovascular risk .
(Desai et.al.,2023 15; Laffin,2023 10)
Firibastat
- Firibastat, an inhibitor of brain aminopeptidase A, is being developed by Quantum Genomics. Also, It represents a first-in-class medication that acts within the brain to control blood pressure levels. It may provide a new method for treating patients with resistant hypertension.
- Nonetheless, two recent phase 3 open-label multicenter studies assessing the efficacy and safety of Firibastat in patients with difficult-to-treat hypertension (FRESH and REFRESH) have not succeeded in lowering blood pressure in cases of resistant hypertension .
(Alomar et.al,2021 16; Redon et.al,2024 1)
Takeaway
The range of therapies available for managing high blood pressure has evolved significantly, marked by the introduction of medications that can affect the primary mechanisms contributing to the onset and maintenance of hypertension. Although lifestyle changes are fundamental, these innovations hold the potential for more individualized and effective care, particularly for patients who struggle with standard treatments.
Further Reading
Hypertension – Unmet Needs
1. Redon J, Carmena R. Present and future of drug therapy in hypertension: an overview. Blood Press. 2024 Dec;33(1):2320401. https://www.tandfonline.com/doi/full/10.1080/08037051.2024.2320401?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org#d1e347
2. Kanbay M, Copur S, Tanriover C, Ucku D, Laffin L. Future treatments in hypertension: Can we meet the unmet needs of patients? Eur J Intern Med. 2023 Sep;115:18-28. https://pubmed.ncbi.nlm.nih.gov/37330317/
3. Naseralallah L, Koraysh S. Aprocitentan: a new emerging prospect in the pharmacotherapy of hypertension. Blood Press. 2024 Dec;33(1):2424824. https://www.tandfonline.com/doi/full/10.1080/08037051.2024.2424824?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
New Approved Therapies
4. Dhillon S. Aprocitentan: First Approval. Drugs. 2024 Jul;84(7):841-847. https://pubmed.ncbi.nlm.nih.gov/38833193/
6. Riaz R, Ahmed U, Naqi U, Afaq L, Shaukat A, Khan Y, Akilimali A. Aprocitentan in hypertension management: clinical efficacy, safety, and future prospects. Ann Med Surg (Lond). 2025 Feb 7;87(3):1472-1478. https://pmc.ncbi.nlm.nih.gov/articles/PMC11981381/#sec14
7. Zhang J, Belford PM, Stouffer GA. Renal Denervation After USA FDA Approval: An Update from an Interventional Cardiologist’s Perspective. J Clin Med. 2025 May 19;14(10):3554. https://pmc.ncbi.nlm.nih.gov/articles/PMC12112698/#sec6-jcm-14-03554
8. Cluett JL, Blazek O, Brown AL, East C, Ferdinand KC, Fisher NDL, Ford CD, Griffin KA, Mena-Hurtado CI, Sarathy H, Vongpatanasin W, Townsend RR; American Heart Association Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on the Kidney in Cardiovascular Disease; and Council on Peripheral Vascular Disease. Renal Denervation for the Treatment of Hypertension: A Scientific Statement From the American Heart Association. Hypertension. 2024 Oct;81(10):e135-e148. https://pubmed.ncbi.nlm.nih.gov/39101202/
Therapies in the Pipeline
9. Nyamagoud SB, Viswanatha Swamy AH, Hiremath J, BJ Abhishek A, Raj S, Hegde M, et al. Finerenone as a New Potent Resistant Hypertension Agent: A Review. International Journal of Pharmaceutical Investigation [Internet]. 2023 Dec 27;14(1):10–5.https://jpionline.org/article/32580/
10. Laffin LJ. Future of Antihypertensive Therapies. Circulation. 2024 Dec 17;150(25):1987-1989. https://pubmed.ncbi.nlm.nih.gov/39680660/.
14. Perl, Shira; Azizi, Michel, Bakris, George, Brown, Jenifer M, Flack, John M, Jones, Erika, Shibata, Hirotaka, Wittes, Janet Wilderäng, Ulrica Olsson, Daniel S.; Williams, Bryan. RATIONALE AND DESIGN OF PHASE 3 TRIAL FOR BAXDROSTAT, A NOVEL HIGHLY SELECTIVE ALDOSTERONE SYNTHETASE INHIBITOR. Journal of Hypertension 42(Suppl 1):p e259-e260, May 2024.https://journals.lww.com/jhypertension/abstract/2024/05001/rationale_and_design_of_phase_3_trial_for.708.aspx
15. Desai AS, Webb DJ, Taubel J, Casey S, Cheng Y, Robbie GJ, Foster D, Huang SA, Rhyee S, Sweetser MT, Bakris GL. Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension. N Engl J Med. 2023 Jul 20;389(3):228-238. https://pubmed.ncbi.nlm.nih.gov/37467498/
16. Alomar SA, Alghabban SA, Alharbi HA, Almoqati MF, Alduraibi Y, Abu-Zaid A. Firibastat, the first-in-class brain aminopeptidase a inhibitor, in the management of hypertension: A review of clinical trials. Avicenna J Med. 2021 Jan 5;11(1):1-7. https://pmc.ncbi.nlm.nih.gov/articles/PMC7839263/#sec1-5
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