Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension

Utkarsh Ojha; Sanjay Ruddaraju; Navukkarasu Sabapathy; Varun Ravindran; Pitchaya Worapongsatitaya; Jeesanul Haq; Raihan Mohammed; Vinod Patel

Disclosures

Am J Cardiovasc Drugs. 2022;22(3):271-285.

Abstract and Introduction

Abstract

Cardiovascular disease accounts for more than 17 million deaths globally every year, of which complications of hypertension account for 9.4 million deaths worldwide. Early detection and management of hypertension can prevent costly interventions, including dialysis and cardiac surgery. Non-pharmacological approaches for managing hypertension commonly involve lifestyle modification, including exercise and dietary regulations such as reducing salt and fluid intake; however, a majority of patients will eventually require antihypertensive medications. In 2020, the International Society of Hypertension published worldwide guidelines in its efforts to reduce the global prevalence of raised blood pressure (BP) in adults aged 18 years or over. Currently, several classes of medications are used to control hypertension, either as mono- or combination therapy depending on the disease severity. These drug classes include those that target the renin-angiotensin-aldosterone system (RAAS) and adrenergic receptors, calcium channel blockers, diuretics and vasodilators. While some of these classes of medications have shown significant benefits in controlling BP and reducing cardiovascular mortality, the prevalence of hypertension remains high. Significant efforts have been made in developing new classes of drugs that lower BP; these medications exert their therapeutic benefits through different pathways and mechanism of actions. With several of these emerging classes in phase III clinical trials, it is hoped that the discovery of these novel therapeutic avenues will aid in reducing the global burden of hypertension.

Introduction

Hypertension is a multifactorial, complex disorder estimated to affect one in three adults in the United States (US).^[1] Globally, the prevalence of hypertension is expected to reach 1.6 billion by 2025.^[2] Several factors influencing elevated blood pressure (BP) have been identified. Modifiable risk factors affecting BP include diet, obesity, smoking and physical exercise, while non-modifiable factors include increasing age, sex and genetics. Adequately controlling high BP reduces the risk of stroke, coronary artery disease, peripheral vascular disease, congestive heart failure and end-stage renal failure. The risk of developing these complications can start at a BP level as low as 115/75 mmHg.^[3] In 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) released updated guidelines in which they lowered the traditional BP cut-off value for diagnosing hypertension (Table 1).^[4] Accurately diagnosing hypertension can still pose significant challenges for physicians, as BP readings can fluctuate unexpectedly, a phenomenon referred to as labile hypertension. In 2020, the International Society of Hypertension produced global guidelines to enable physicians to diagnose and manage hypertension as accurately as possible.^[5] These guidelines classified hypertension based on systolic and diastolic cut-offs, taking into account the manner and environment in which the BP measurements were taken.

The exact pathophysiology of hypertension remains largely unknown. It is thought that up to 5% of patients with hypertension have either renal or adrenal system impairment. In the remainder of patients, the cause is not entirely clear and these patients are labelled as having 'essential hypertension'. The regulation of BP relies on cardiac output and systemic vascular resistance. Most patients with essential hypertension have normal cardiac output but raised peripheral resistance. Peripheral resistance is determined by the small arterioles which contain smooth muscle. A rise in intracellular calcium leads to contraction of these smooth muscles, which in turn raises peripheral resistance. The autonomic nervous system is also thought to play an important role in increasing BP. Sympathetic nervous system (SNS) stimulation can lead to an increase in cardiac output and both arteriolar constriction and dilation. The SNS has an important function in short-term changes in BP that occur in response to physical exercise, however there is a lack of evidence suggesting its involvement in the development of chronic hypertension. It has also been suggested that endothelial dysfunction can lead to essential hypertension. Currently available antihypertensive agents exert their therapeutic effect by altering these underlying pathologic processes. These drug classes include those that target the renin-angiotensin-aldosterone system (RAAS), adrenergic receptors, and calcium channel blockers (CCBs), and induce diuresis and vasodilation. The increasing global incidence and burden of hypertension and its associated complications has necessitated the development of novel drugs with greater safety and efficacy than existing treatments.

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Abstract and Introduction
Current Pharmacological Classes of Antihypertensive Agents
Conclusion
References
Sidebar

Table 1. Stages of hypertension as defined by the ACC/AHA [4]
Stage	Blood pressure (mmHg)
Normal	< 120/< 80
Elevated	120–129/<80
Stage 1	130–139/80–89
Stage 2	≥ 140/≥ 90
Hypertensive crisis	> 180/> 120

ACC American College of Cardiology, AHA American Heart Association

Table 2. Emerging agents for the pharmacological management of hypertension
Agent and developer	Mechanism of action	Trial details	Comments
Esaxerenone (CS-3150) Daiichi Sankyo Co.	Non-steroidal inhibitor of the mineralocorticoid receptor [63] Inhibits aldosterone-dependent sodium retention, causing decreased fluid reabsorption Reduces proteinuria in CKD patients	Phase III [98] 368 patients with essential hypertension administered either esaxerenone 2.5 or 5 mg for 52 weeks Completed but findings not yet reported Phase III [99] 1001 patients with essential hypertension received either esaxerenone 2.5 or 5 mg or eplerenone 50 mg for 12 weeks Esaxerenone 5 mg reduced SBP by 4.8 mmHg, compared with 2.3 mmHg in the eplerenone group, with significant decrease in 24-h BP	Esaxerenone has a longer (18.6 h) half-life than eplerenone (5 h), and thus causes less fluctuations in 24 h BP reduction. It also does not have the unwanted effect of hyperkalemia seen with eplerenone No difference in the incidences of adverse effects in any groups Also shown to be well tolerated and effective in lowering SBP in patients with primary aldosteronism [100] Currently approved in Japan for the treatment of hypertension
Firibastat (RB 150) [68] Quantum Genomics SA	Inhibits aminopeptidase A, which converts angiotensin II into brain angiotensin III [67] Decreased vasopressin release, increasing diuresis Reduction in sympathetic tone and hence vascular resistance Inhibition of the baroreflex response	Phase IIb [101] 256 overweight or obese hypertensive patients (54% Black or Hispanic) received firibastat 250 mg bid for 8 weeks. No placebo arm Significant reduction in SBP by 10.5 mmHg in Black patients and 8.9 mmHg in non-Black patients Phase III [102]—expected completion December 2021 502 patients will receive firibastat 250 mg bid for 12 weeks or placebo in addition to current antihypertensives	Adverse effects were headache (4%) and skin reactions (3%). 7.5% recipients stopped the drug due to adverse effects (one serious) Potential alternative therapy for Black populations, with an 18% greater SBP decrease compared with non-African Americans
Bexagliflozin (EGT0001442) Theracos [103]	Inhibits sodium-glucose co-transporter-2. Several hypothesized mechanisms [79, 81] Glycosuria-accompanied osmotic diuresis Inhibits sodium reuptake in the proximal tubule Upregulation of angiotensin 1–7 Reduction of serum uric acid	Phase III [104] 1700 patients with T2DM across 10 countries received either bexagliflozin 20 mg or placebo over 30 months Modest reduction in SBP by 9.8 mmHg in the treatment arm, compared with 6.9 mmHg in the placebo arm Phase III [105] 680 hypertensive patients received either bexagliflozin 20 mg or placebo over 24 weeks	Incidence of adverse effects in the treatment group (36.7%) were similar to placebo (33%) The BEST trial was not specifically powered or designed to evaluate BP effects and the results of trials evaluating this are pending
Nesiritide Oslo University Hospital	Recombinant B-type natriuretic peptide [74] Leads to vasodilation, natriuretic and diuretic effects	Phase I and II (TENSE1) [106] 15 patients will receive gradually increasing doses of either nesiritide or placebo bid Estimated completion in 2030	Degraded quickly by tissue proteases and therefore needs to be administered by continuous IV infusion
Vitamin D3 and Omega-3 fatty acids (antioxidants) Brigham and Women's Hospital	Vitamin D [107] Negative regulator of the RAS by suppressing renin gene expression Regulates vascular smooth muscle intracellular calcium concentrations Omega-3 fatty acids [108] Vasorelaxant effects on vascular endothelial and smooth muscle cells through nitrous oxide Inhibit inflammatory processes in arteries	Phase NA [109] 25,875 men and women with no prior history of hypertension will receive vitamin D3 2000 IU or omega-3 fatty acid 1 g	Ongoing trial investigating whether supplementation prevents the development of hypertension in people with normal BP
RLD2001-1 and HCP1904-1 Hanmi Pharma	NA	Phase III [110] 116 participants with hypertension will take either HCP1904-1 or RLD2001-1 once daily for 8 weeks	Estimated completion September 2021
Amlodipine/candesartan cilexetil (CKD-330) and D086 Chong Kun Dang Pharmaceutical	NA	Phase III [111] 154 patients with hypertension will either receive amlodipine/candesartan cilexetil and D086 combination therapy or placebo	Completed, no results posted. Also targeting dyslipidemias and T2DM

bid twice daily, BP blood pressure, CKD chronic kidney disease, IU international units, IV intravenous, NA not available, RAS renin-angiotensin system, SBP systolic blood pressure, T2DM type 2 diabetes mellitus