Hypertension: A Silent Killer Requiring Novel Therapies

Pharmacists routinely encounter hypertension in diverse clinical settings, highlighting their essential role in its early detection, ongoing management, and patient education. As a multifactorial condition influenced by both genetic predisposition and lifestyle factors, hypertension is a leading risk factor for serious health outcomes including microvascular complications (retinopathy and nephropathy) and macrovascular events (myocardial infarction and stroke).^1,2 Often termed the "silent killer," it typically remains asymptomatic until significant target organ damage has occurred.² Primary (or essential) hypertension, which accounts for approximately 95% of cases, lacks a clearly identifiable or reversible cause and becomes more common with advancing age.³ In contrast, secondary hypertension results from a specific underlying condition; however, even with targeted treatment, it can be challenging to manage effectively.³

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Hypertension, according the most recent US guidelines, is diagnosed when systolic blood pressure (sBP) is ≥130 mm Hg or diastolic blood pressure (dBP) is ≥80 mm Hg, based on the average of 2 or more accurate readings taken on ≥2 separate occasions.¹ This shift from the previous threshold of ≥140/90 mm Hg, reflects a greater emphasis on more intensive intervention to mitigate cardiovascular risk. In contrast, the European Society of Cardiology and the European Society of Hypertension continue to define hypertension at the higher threshold of ≥140/90 mm Hg, illustrating variations in international clinical practice.^2,3

Hypertension remains a major public health challenge both in the United States and globally.⁴ According to the CDC, nearly half of US adults—approximately 48.1%, or about 119.9 million people—either have hypertension or are taking medication to manage it.⁴ Despite its widespread prevalence, only about 1 in 4 US adults and just 20% to 29% of individuals globally have their blood pressure adequately controlled.^4,5 This high burden significantly increases the risk of cardiovascular diseases, particularly heart disease and stroke, which are among the leading causes of death nationwide.⁶ Modifiable lifestyle factors such as unhealthy diet, physical inactivity, and obesity play a central role in the development of hypertension highlighting the critical need for public health initiatives focused on prevention, early detection, and effective long-term management.

The primary goal of antihypertensive therapy is to achieve and maintain a BP <130/80 mmHg. Pharmacologic treatment is not always required for individuals with BP in the range of 130 to 139/80 to 89 mm Hg unless they meet specific high-risk criteria.¹ These include age ≥65 years, established atherosclerotic cardiovascular disease (ASCVD), a 10-year cardiovascular risk exceeding 10%, diabetes, chronic kidney disease, or heart failure.¹ In contrast, patients with a sBP ≥140 mm Hg or dBP ≥90 mm Hg should be initiated on pharmacologic therapy, regardless of other risk factors, to reduce the likelihood of cardiovascular complications.¹

First-Line Antihypertensive Therapies and Combination Strategies

Thiazide or thiazide-like diuretics, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs) are commonly recommended as first-line antihypertensive agents, either as monotherapy or in combination with drugs from different classes.¹ Guideline-based first-line therapy status is based on data from randomized trials demonstrating statistically significant reductions in cardiovascular events with low rates of placebo-subtracted drug discontinuation.^1-3 Combination therapy with 2 agents from different classes is advised when baseline BP exceeds the target by more than 20/10 mm Hg and should be considered for patients with BP ≥140/90 mm Hg.¹ Utilizing lower doses of 2 medications provides greater efficacy and better tolerability compared to higher doses of single agents. Beta blockers and mineralocorticoid receptor antagonists (MRA) are generally not recommended as initial therapy for hypertension but remain appropriate for patients with specific clinical indications (Figure 1).¹ Most adults with hypertension have other comorbidities such as diabetes, obesity, kidney disease, or heart disease which make other specific drug therapy options reasonable.⁶

Figure 1. Antihypertensive drug therapy treatment algorithm based on the American College of Cardiology/the American Heart Association and the European Society of Hypertension’s guidelines.^1-3

The rising prevalence of hypertension, coupled with persistently low rates of control, underscores the need for novel antihypertensive therapies targeting alternative mechanisms of action. Despite a wide array of available drug treatments, a significant proportion of patients fail to achieve adequate BP control. Nearly 20% of appropriately treated individuals are classified as having resistant hypertension, defined as BP above guideline targets (≥130/80 mm Hg) despite adherence to a regimen of 3 or more antihypertensive drugs (including a diuretic) from different classes at maximally tolerated doses using proper dosing schedules.⁷ Newly approved and late-stage investigational drugs aim to meet these challenges by targeting new mechanisms of action. Table 1 lists recently approved and late-stage investigational antihypertensive drugs.

Table 1.^{10,11,14,15,17,18,20,21,22} Summary of Novel Therapies

Aprocitentan: A New Option for Resistant Hypertension

Aprocitentan (Tryvio; Idorsia Pharmaceuticals) is a dual endothelin receptor antagonist approved by the FDA in March 2024 for the treatment of resistant hypertension.⁸ Aprocitentan works by blocking both endothelin-1a and -1b receptors, key mediators of vasoconstriction and sodium retention.⁸ The clinical trial which led to the approval of aprocitentan included a 4 week randomized placebo-controlled, double-blind comparison of aprocitentan 12.5 mg/d, 25 mg/d, or placebo in 730 patients.⁹ Both doses of aprocitentan produced a statistically significant placebo-subtracted 3.8/4.0 mmHg reduction in BP at 4 weeks (p = 0.004). However, there was no meaningful difference in BP reduction between the 12.5 or 25 mg doses of aprocitentan. A longer follow-up using aprocitentan 25 mg/d found that this drug maintained BP reduction for 44 weeks. Edema or volume overload was the most common adverse event occurring in 2%, 9%, and 18% with aprocitentan 12.5 mg, aprocitentan 25 mg, and placebo, respectively. Edema was rated as mild to moderate with roughly half of the patients developing edema requiring additional diuretic therapy. No patient on aprocitentan 12.5 mg per day had drug discontinued due to volume overload.⁸

The approved dose of aprocitentan is 12.5 mg taken once daily with or without food.¹⁰ It is intended for use in resistant hypertension in combination with other antihypertensive drugs.Aprocitentan may cause fetal harm if used in pregnancy. It is contraindicated in pregnancy with a black box warning restricting it use through a Risk Evaluation and Mitigation Strategy program.¹⁰ Patients who can become pregnant must use acceptable contraception prior to initiation of treatment, during treatment, and for 1 month after stopping the drug. The drug is not recommended in severe hepatic or renal dysfunction (glomerular filtration rate <30 ml/min).¹⁵ The risk of volume overload suggests this drug be used cautiously in patients with heart failure. Class warnings with other endothelin receptor antagonists include a risk of hepatotoxicity and decreases in hemoglobin and sperm counts. While the BP reduction observed in the clinical trial with aprocitentan was statistically significant compared to placebo, the approximate 4 mmHg greater reduction in both sBP and dBP is small. It is also not known how many patients can achieve BP control or if this drug reduces the risk of vascular events.

The First Triple-Combination Antihypertensive: Telmisartan, Amlodipine, and Indapamide

The FDA recently approved a triple-combination antihypertensive agent formulated to include different doses of telmisartan (an ARB),amlodipine (a CCB), and indapamide (a thiazide-like diuretic).¹¹ This fixed-dose combination is currently the only triple combination drug approved as first line therapy for hypertension.The standard or full-dose combination includes telmisartan 40 mg, amlodipine 5 mg, and indapamide 2.5 mg. A one-half dose (20/2.5/1.25) anda one-quarter (10/1.25/0.625) fixed dose version of this product is also available. These dose levels afford a reasonable opportunity for dose titration based on BP response.¹¹

The approval of this agent was based on 2 phase 3 trials (GMRx2 PCT and GMRx2 ACT).^12,13 GMRx2 PCT was a randomized, double-blind, placebo-controlled comparison of the triple drug combination given once daily at the one-quarter and one-half dose levels in 295 low risk patients with mild-to-moderate hypertension.¹² The placebo-subtracted reductions in clinic BP were 8.0/4/0 mmHg and 9.5/4.9 mmHg for the 2 dose levels. Clinic BP control (≤135/85 mmHg) was achieved in 37%, 65%, and 70% for placebo, quarter dose, and half dose triple therapy, respectively (p < 0.001 for both doses vs placebo).¹²

Serious adverse events occurred in 0%, 1.7%, and 3.2% of patients on the quarter dose, half dose triple therapy, and placebo, respectively. In the GMRx2 active control study, half dose triple drug therapy reduced mean BP by an additional 4.3/3.5 mm Hg, 5.6/3.7 mm Hg, and 6.3/4.5 mm Hg (all p<0·001) compared to 3 different 2-drug combinations of telmisartan, amlodipine, and indapamide.¹³The triple combination drug was not associated with a significant increase inadverse events compared to dual drug combinations.^25,26 This product is expected to be commercially available as Widaplik (Georges Medicine) in the fourth quarter of 2025. Given that all 3 drugs in this combination have been available for many years, the prescribing information includes the usual adverse effects and warnings associated with these drugs.¹¹ This single pill combination is a reasonable option for patients expected to require multiple antihypertensive drugs who have a history of concerns for adherence.

Lorundrostat: Advancing Aldosterone Synthase Inhibition

Lorundrostat is an investigational aldosterone synthase inhibitor currently in phase 3 trials for the treatment of hypertension.¹⁴ It selectively inhibits aldosterone synthase, the enzyme responsible for aldosterone production.The Target-HTN trial was a placebo-controlled dose ranging study evaluating lorundrostat doses of 12.5 mg, 50 mg, and 100 mg once daily and 12.5 mg and 25 mg twice daily over 8 weeks of treatment in patients with suppressed or normal plasma renin activity.¹⁴ A dose-related decrease in sBP ranged from 7 mmHg to 14 mmHg with lorundrostat compared to a 4 mmHg decrease with placebo. The 50 mg/d and 100 mg/d doses resulted in placebo-adjusted reductions of 9.6 mmHg and 7.8 mm Hg, respectively. The BP response was not different when stratified by baseline plasma renin activity.¹⁴

Two large phase 3 studies with lorundrostat have been conducted. The Advance-HTN study was a randomized, double-blind, placebo-controlled study evaluating lorundrostat on 24-hour ambulatory BP in resistant hypertension.¹⁵ Patients with an average BP ≥130/80 mmHg despite treatment with 2 or 3 drug standardized treatment regimen during a 3 week baseline period received lorundrostat 50 mg/d for 12 weeks or lorundrostat 50 mg/d titrated to 100 mg/d at 4 weeks if the sBP was >130 mmHg. The 50 mg dose achieved a 7.9 mmHg reduction in 24-hour average sBP (p=0.001) while the 50 to 100 mg dose achieved a 6.5 mmHg sBP reduction (p=0.006).

The Launch-HTN trial randomized 1083 patients with uncontrolled hypertension to lorundrostat 50 mg/d, 50 mg/d titrated to 100 mg/d if necessary, or placebo.¹⁶ At 12 weeks of treatment, placebo-subtracted reductions in sBP were -11.7 mmHg (p<0.0001) for the 50 mg/d dose group and -8.4 mmHg (p=0.0016) for the dose titration group. These data indicate that lorundrostat is associated with meaningful BP reductions in uncontrolled hypertension as well as treatment-resistant hypertension. The most frequent dose limiting adverse effect is hyperkalemia which is dose-related with an incidence of 5% to 7%. A new drug application for lorundrostat is expected to be filed with the FDA in 2025.

Baxdrostat: Another Approach to Aldosterone Synthesis Blockade

Baxdrostat is also an aldosterone synthase inhibitor in development for the treatment of treatment-resistant hypertension.¹⁷ In the phase 2 BrigHTN trial, 248 patients with hypertension resistant to 3 or more baseline antihypertensive agents were randomized to baxdrostat 0.5 mg/d, 1 mg/d, 2 mg/d, and placebo for 12 weeks.¹⁷ The placebo-subtracted reductions in sBP were 8.1 mmHg (p = 0.003) and 11.0 mmHg (p < 0.001) with the baxdrostat 1 mg/d and 2 mg/d doses, respectively. In a second phase 2 trial using the same dose regimens of baxdrostat in resistant hypertension, placebo-subtracted reductions were not statistically significant.¹⁸ An average reduction in sBP of 16 mmHg to 20 mmHg was observed across the doses of baxdrostat while placebo reduced sBP by almost 17 mmHg. While the results of this study were presented at the American College of Cardiology meeting in 2023, the completed study results have yet to be published. Surprised by these negative results, investigators are evaluating potential reasons for the greater than expected BP response to placebo.¹⁷ A phase 3 trial with baxdrostat (BaxHTN) in resistant hypertension was started in November 2023 with an unknown completion date.

Zilebesiran: Gene Silencing for Long-Lasting BP Control

Zilebesiran is a small interfering RNA (siRNA) that increases degradation of mRNA associated with the expression of the gene responsible for the synthesis of angiotensinogen (AGT). AGT is a key precursor in the renin-angiotensin-aldosterone system. The upstream inhibition of AGT leads to lower levels of angiotensin I and II resulting in BP reduction. After uptake in the hepatocyte, zilebesiran binds to a multiprotein complex referred to as RNA-induced silencing complex (RISC) which combines with mRNA specific to AGT which induces activation of an enzyme that promotes degradation of the mRNA-RISC complex.¹⁹ The mRNA is degraded, but the siRNA within the RISC remains active producing a long-lasting silencing of mRNA targeting AGT for a prolonged period of time. Due to its novel mechanism, a single subcutaneous injection of zilebesiran can provide durable BP control for several months.

A phase 1 study assigned 107 hypertensive patients to a single subcutaneous (SC) dose of zilebesiran (10 mg up to 800 mg) or placebo.²⁰ Zilebesiran doses of 400 mg and 800 mg produced BP reductions at 24 weeks of 9/5 mmHg and 22/11 mmHg, respectively. Serum AGT levels were also markedly suppressed by doses ≥200 mg for the 24 weeks of follow-up.

Two phase 2 studies with zilebesiran have been completed. In the KARDIA-1 trial, 394 patients with mild-to-moderate hypertension were randomized to zilebesiran 150 mg, 300 mg, or 600 mg subcutaneously (SC) every 6 months, zilebesiran 300 mg SC every 3 months, or placebo.²¹ Placebo-subtracted reductions in sBP measured in the office at 6 months were 7.5 mmHg, 10.5 mmHg, and 12.1 mmHg for the 150 mg, 300 mg, and 600 mg SC doses given every 6 months, respectively. The placebo-subtracted reduction in sBP in the office at 6 months with the 300 mg SC dose given every 3 months was 10.2 mmHg. Serious adverse events occurred in 3.6% of zilebesiran patients and 6.7% of placebo patients. Nonserious drug-related events occurred in 17% of zilebesiran patients and 8% of placebo patients. Injection site reactions (6%) and hyperkalemia (5%) were the most common side effects. Injection site reactions were more common with the every-3-month injection.

The KARDIA-2 trial included 663 patients treated during a 4-week run-in period with indapamide (n = 130), amlodipine (n = 240), or olmesartan (n = 240) who had a mean 24-hour ambulatory sBP of 130 to 160 mmHg.²² These patients were then randomized to zilebesiran 600 mg SC every 6 months (n =332) or placebo (n = 331). The placebo-subtracted reduction in 24-hour mean ambulatory sBP with zilebesiran added to baseline therapy was 12.1 mmHg with indapamide, 9.7 mmHg with amlodipine, and 4.5 mmHg with olmesartan (all comparisons p < 0.05). Compared to placebo, more zilebesiran patients experienced hyperkalemia (5.5% vs 1.8%), hypotension (4.3% vs 2.1%), and acute kidney failure (4.9% vs 1.5%). Acute kidney failure was defined as ≥30% decline in eGFR. After repeat assessment at a 2- to 3-week follow-up, the incidence of acute kidney failure was 2.4% with zilebesiran and 0.9% with placebo. This study suggests that the addition of zilebesiran may produce a more pronounced BP reduction with drugs with mechanisms of action other than RAAS modulation. Larger and longer-term studies with zilebesiran are in progress. While the long duration of action of zilebesiran may be advantageous, it may also be potentially problematic should adverse effects occur. Acquisition cost of this drug will also be barrier to widespread adoption if it becomes available for commercial use.

Conclusion

Hypertension remains a major risk factor for morbidity and mortality worldwide. Guidelines differ between the American College of Cardiology/American Heart Association and the European Society of Hypertension regarding treatment goals and when treatment should be initiated. Current drug therapies emphasize a dual medication approach for first line treatment. These typically include an ACEI or ARB, a CCB, or a thiazide-like diuretic. The addition of beta blockers or other drug classes are indicated when BP goals are not achieved or if concomitant comorbidities are present. The increase in prevalence of resistant hypertension has prompted the development of new medications targeting different drug pathways. These novel drug therapies may afford patients with uncontrolled hypertension opportunities for reductions in adverse clinical outcomes.

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