key: cord-0006495-mnkwjplb
authors: Davis, Jared; Oparil, Suzanne
title: Novel Medical Treatments for Hypertension and Related Comorbidities
date: 2018-08-25
journal: Curr Hypertens Rep
DOI: 10.1007/s11906-018-0890-y
sha: 8163c127b818505db88177b205930858405b62da
doc_id: 6495
cord_uid: mnkwjplb

PURPOSE OF REVIEW: The purpose of this review is to summarize the most recent data available on advances in development of novel medical treatments for hypertension and related comorbidities. RECENT FINDINGS: Approximately half of all hypertensive patients have not achieved goal blood pressure with current available antihypertensive medications. Recent landmark studies and new hypertension guidelines have called for stricter blood pressure control, creating a need for better strategies for lowering blood pressure. This has led to a shift in focus, in recent years, to the development of combination pills as a means of achieving improved blood pressure control by increasing adherence to prescribed medications along with further research and development of promising novel drugs based on discovery of new molecular targets such as the counter-regulatory renin-angiotensin system. SUMMARY: Fixed-dose combination pills and novel treatments based on recently discovered pathogenic mechanisms of hypertension that have demonstrated promising results as treatments for hypertension and related comorbidities will be discussed in this review.

Following the death of President Franklin D. Roosevelt in 1945 from a cerebral hemorrhage secondary to longstanding uncontrolled hypertension, the problem of high blood pressure (BP) gained national attention as a health crisis for the first time [1] . Healthcare providers and researchers began to turn their attention to the detection and treatment of hypertension and the development of antihypertensive medications. The earliest medications to be approved by the United States Food and Drug Administration (FDA) for hypertension treatment were the alpha adrenergic receptor antagonist phenoxybenzamine and the vasodilator hydralazine in 1953 (Table 1) . Since then over 130 agents, many of which are available in single-pill combinations, have been approved by the FDA for the treatment of hypertension. Each of these agents uses one or more of the 17 mechanisms of action to lower BP [2] . Antihypertensive drug development and approval began in the early 1950s, peaked in the 1980s and 1990s, and decreased in the twenty-first century. Since 2011, only four antihypertensive drugs and drug combinations have been approved by the FDA, including azilsartan (Edarbi, Arbor Pharmaceuticals), azilsartan/chlorthalidone (Edarbiclor, Arbor Pharmaceuticals), perindopril/amlodipine (Prestalia, Marina Biotech), and most recently nebivolol/ valsartan (Byvalson, Allergan) in 2016 [2] . In this review, we discuss new drugs and drug combinations that have undergone preclinical or clinical testing for the treatment of hypertension and its comorbidities since our previous review of the topic in 2015 [3••] .

Based on the evidence from the landmark SPRINT trial (Systolic Blood Pressure Intervention Trial) that lowering systolic BP (SBP) to < 120 mmHg produced significant reductions in cardiovascular events and all-cause mortality compared to treating to the standard SBP target of < 140 mmHg and from a number of recent meta-analyses and observational studies that demonstrated similar benefits of aggressive BP reduction, the 2017 AHA/ACC Hypertension Guidelines [6] [7] [8] . Achieving these aggressive treatment goals will likely be a daunting task since approximately 50% of hypertensive patients are now uncontrolled to the traditional target of < 140/ 90 mmHg. Failure to achieve BP control is often due to nonadherence to prescribed medication regimens [9] . Of all patients treated for hypertension, 40% stopped their regimen within 2 years of initiation and 61% stopped by 10 years [10] . In 2017, the Center for Disease Control (CDC) reported that one in five prescriptions is never filled and 50% that are filled are not taken properly [11] . Based on these data, it is apparent that a large gap exists between current treatment guidelines and long-term, successful BP control in the majority of patients. For these reasons, much of the ongoing research and development in hypertension treatment is dedicated to developing fixed-dose combination drugs, allowing for better BP control by improving adherence to medications. Recent research has been Table 2 ). Each of these contains at least one FDAapproved antihypertensive medication and four combinations contain three or more agents. The majority of these are combinations of an ACE inhibitor or an ARB with a calcium channel blocker (CCB) and/or thiazide diuretic.

Tripliam contains the angiotensin converting enzyme (ACE) inhibitor perindopril, the dihydropyridine CCB amlodipine, and the indoline diuretic indapamide. Multiple phase III clinical trials of Tripliam have been completed, and it is currently in a phase IV study. The Perindopril-Indapamide plus AmlodipiNe in high rISk hypertensive patients (PIANIST) trial evaluated the BP lowering effect of the perindopril- Ang indicated angiotensin, AT2 angiotensin type 2, ACE2 angiotensin converting enzyme 2, ARB angiotensin type 1 receptor blocker, ACE angiotensin converting enzyme, CCB calcium channel blocker amlodipine-indapamide combination in 4731 patients with difficult to treat hypertension who were high-risk for CVD and were uncontrolled on their current regimen, which included a wide range of antihypertensives [13] . The three-drug combination reduced office BP significantly from a baseline mean of 160/93 mmHg to a treatment mean of 132/80 mmHg and also significantly reduced ambulatory BP (ABP). In another study, similar reductions in 24 h ABP, daytime and nighttime BP, and pulse pressure were shown with the fixeddose triple combination compared to the same three individual "free" anti-hypertensive medications after 1 month of treatment [14] . The Once-daily Fixed combiNation vErsus freEdrug cOmbination of Three aNtihypertensive Agents in arteriaL hYpertension (ONE & ONLY) trial randomized 305 patients to receive either a fixed-dose combination of perindopril-indapamide-amlodipine-atorvastatin or a freedrug combination of perindopril, indapamide, and amlodipine with atorvastatin [15] . The study demonstrated that Tripliam significantly increased adherence and reduced SBP without increasing costs compared to the free-drug group. No significant difference in LDL lowering was found between the groups, though the fixed-dose combination group experienced greater CVD risk reduction overall.

Micatrio contains the angiotensin II receptor blocker (ARB) telmisartan, the dihydropyridine CCB amlodipine, and the thiazide diuretic hydrocholorothiazide. One of the earliest studies to examine this three-drug combination in 2009 showed that the fixed-dose combination resulted in mean reductions in SBP and diastolic BP (DBP) of 38.5 mmHg and 16 mmHg greater than telmisartan monotherapy [16] . Subsequent studies found that Micatrio is more effective at lowering SBP and DBP compared to telmisartan and amlodipine combined. The Telmisartan/Amlodipine+ Hydrochlorothiazide Versus Telmisartan/Amlodipine Combination Therapy for Essential Hypertension Uncontrolled With Telmisartan/Amlodipine (TAHYTI) trial was a randomized controlled trial of 310 patients that showed that addition of hydrochlorothiazide to telmisartan and amlodipine resulted in a clinically significant 12.3/ 8.4 mmHg reduction in office BP compared to telmisartan/ amlodipine [17] . Another study revealed that the three-drug combination produced a significantly greater reduction in SBP (− 5.3 mmHg difference) when adjusted for baseline BP compared to telmisartan-amlodipine [18] . Micatrio is approved for the treatment of hypertension in Japan.

Fimasartan is an ARB that was approved for the treatment of hypertension in South Korea under the name Kanarb after studies found it to produce DBP reductions greater than losartan and comparable to candesartan after 12 weeks [19, 20] . Fimasartan was combined with amlodipine and approved in South Korea under the name Dukarb after clinical studies revealed greater reduction in sitting DBP for the fixed-dose combination of fimasartan and amlodipine over placebo or either agent as monotherapy [21] . A phase I clinical trial of a fixed-dose combination pill containing fimasratan, amlodipine, and hydrochlorothiazide is currently underway, and a fixed-dose combination of fimasartan, amlodipine, and rosuvastatin, a HMG-CoA reductase inhibitor, is currently in phase III clinical trials. The combination of fimasartan and rosuvastatin has been found to be efficacious in lowering both BP and LDL cholesterol and to be as safe as either agent administered alone [22] . Initial studies of the triple agent fixed-dose combination are expected to be completed in 2019.

Entresto, a fixed-dose combination of sacubitril, a neprilysin inhibitor, and the ARB valsartan was approved by the FDA in 2014 for the treatment of heart failure (HF) and has also been evaluated as a potential treatment for hypertension. Neprilysin is a neutral endopeptidase that degrades endogenous vasodilator peptides such as bradykinin and natriuretic peptides, leading to increased BP and target organ damage ( Fig. 1 )

The Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial is a randomized double-blind study of 8442 patients with HF with reduced left ventricular ejection fraction (HFrEF) that demonstrated a reduction in the composite outcome of death from CV causes or hospitalization for recurrent HF for Entresto compared to enalapril [23•] . Since its approval for the treatment of HF in 2014, Entresto has been evaluated in multiple clinical trials as a treatment for hypertension and its comorbidities, including chronic kidney disease (CKD), HF, diabetes, and obesity [24] [25] [26] [27] .

The Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly (PARAMETER) study is a randomized, double-blind trial that compared the effects of Entresto to olmesartan on central hemodynamics by measuring overall reduction in mean central aortic systolic pressure (CASP) in elderly patients with systolic hypertension [28•] . Entresto produced greater reduction in CASP and central aortic pulse pressure at 12 weeks that was not sustained at 52 weeks. However, the olmesartan group required more addon therapy with either amlodipine or hydrochlorothiazide to achieve the same BP reduction. The Efficacy and Safety of Crystalline Valsartan/Sacubitril (LCZ696) Compared With Placebo and Combinations of Free Valsartan and Sacubitril in Patients With Systolic Hypertension (RATIO) study examined the effectiveness of Entresto in reducing clinic sitting SBP compared to sacubitril and valsartan monotherapy [29] . Entresto produced significantly greater reductions in office BP, pulse pressure, and all secondary end-points (24 h mean BP, pulse pressure, mean daytime and nighttime ABP).

Polypill is a general term used to describe a fixed-dose combination pill (FDCP) with multiple therapeutic targets. The polypill was first proposed for the primary prevention of CVD in 2003 by Wald and Law as a combination of a statin, thiazide diuretic, beta blocker, ACE inhibitor, folic acid, and aspirin [30] . Since that time, various polypills have been evaluated in multiple clinical trials for safety, efficacy, adherence, and cost and is now approved for use in over 30 countries [31, 32, 33••, 34, 35] . Polypills have been shown to increase patient adherence by reducing a patient's pill burden, thus improving BP control [31] . Most polypill formulations are comprised of a statin and one or two antihypertensives with or without aspirin, though other formulations, such as atorvastatin, aspirin, and clopidogrel, have been proposed for chronic heart disease [36] . Globally, the prevention and treatment of CVD have advanced to the forefront of healthcare policy in recent years, thereby creating a new push for use of polypills [37] . Recently, the Heart Outcomes Prevention Evaluation-3 (HOPE-3) trial showed an overall benefit of a multi-target FDCP consisting of rosuvastatin, candesartan, and hydrochlorothiazide compared to placebo in primary prevention for those at intermediate risk of CVD [38] . This FDCP has also been suggested as a primary and secondary prevention strategy for cerebrovascular disease [39] . Multiple studies have assessed the potential cost-effectiveness of polypills and have found them to be more cost-effective than the simultaneous use of each individual agent [32, 40] . There are many ongoing clinical trials of polypills worldwide, indicating continued interest and acknowledgement of their potential for improved public health globally. However, to date, polypills have struggled to gain widespread use because of low pharmaceutical interest, clinician concern, and a lack of advocacy for multitarget FDCPs [41•, 42] .

Mineralocorticoid receptors (MR) are expressed in high concentrations in the renal cortex where they line the collecting ducts and are activated by aldosterone, promoting sodium and water reabsorption and causing an increase in intravascular volume (Fig. 2) . These changes over time can lead to hypertension. Further, extrarenal MRs in cardiac and vascular tissue stimulate NADPH oxidase, leading to endothelial damage through release of oxidative stressors [43] . MRs, starting with spironolactone, have long been a target for antihypertensive and vasoprotective therapy. Spironolactone is used in the treatment of HF and resistant hypertension, where it is considered the fourth drug of choice, after thiazide diuretics, CCBs, and RAS blockers [44, 45•] . Spironolactone is structurally similar Fig. 1 Mechanism of Entresto (LCZ696). The ARB-neprilysin inhibitor, Entresto (LCZ696), is a single molecule comprising the ARB valsartan and the neprilysin inhibitor, sacubitril. Entresto has been shown to lower BP, and to prevent death from cardiovascular events and hospitalizations for HF in patients with HF with a reduced EF. (Reprinted with permission from Circulation Research 116: 6, 2015) to progesterone and binds non-selectively to MRs and sex hormone receptors such as progesterone and estrogen receptors, causing adverse effects such as gynecomastia and erectile dysfunction in men and irregular menses in women. This unfavorable risk profile led to the development of eplerenone, a more selective MR antagonist (MRA) that causes fewer sex hormone-related adverse effects than spironolactone. However, eplerenone requires twice daily dosing and has less antihypertensive efficacy than spironolactone [46] .

Finerenone, the newest MRA, is being evaluated in clinical trials for the treatment of hypertension, HF, and diabetic nephropathy. Finerenone has less structural similarity to steroid hormones than the other MRAs and thus does not produce the adverse effects seen with spironolactone [47] . The Mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) was the first to evaluate the effect of finerenone in humans with CVD [48] . ARTS compared finerenone to placebo and spironolactone in patients with HFrEF and CKD. Finerenone use resulted in significantly lower serum potassium concentrations and preserved glomerular filtration rates compared with spironolactone. However, finerenone did not lower SBP (a secondary outcome) when compared to placebo. The ARTS results redirected the developmental profile of finerenone toward the treatment of some well-known complications of hypertension, HF, and CKD, rather than hypertension per se.

The Mineralocorticoid Receptor Antagonist Study-Heart Failure (ARTS-HF) was a randomized, double-blind, multicenter study of 1286 patients that compared finerenone to eplerenone in patients with worsening HF and diabetes and/ or CKD [49•] . ARTS-HF found that all-cause mortality, hospitalizations for CVD, and emergency department presentations for HF were significantly lower in the finerenone group compared to eplerenone.

A recent preclinical study demonstrated the efficacy of finerenone in prerenal acute kidney injury (AKI) and its progression to CKD in a rodent model [50] . Normotensive Wistar rats were randomized to either AKI or chronic kidney injury groups. The AKI group was further randomized to receive sham surgery or 25 min of bilateral renal ischemia with or without finerenone dosed at 48, 24, and 1 h prior to induction of ischemia. The chronic kidney injury groups were randomized to the same treatments but received 45 min of bilateral renal ischemia and were followed for 4 months following reperfusion. In the AKI group, finerenone treatment attenuated renal tubular injury and preserved normal renal function after 24 h of reperfusion. Expression of markers of tubular injury, including kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin-2 (NGAL-2) was reduced in finerenone-treated rats. In the chronic kidney injury group, untreated rats developed CKD characterized by increased proteinuria and renal vascular resistance, tubular dilation, extensive tubule-interstitial fibrosis, and an increase in kidney transforming growth factor-ß and collagen-I mRNA after 4 months of follow-up. The transition from acute kidney injury to CKD was fully prevented by finerenone.

The Mineralocorticoid Receptor Antagonist Study-Diabetic Nephropathy (ARTS-DN) compared finerenone to placebo as add-on therapy in patients with diabetic kidney disease and a high level of albuminuria already treated with an ACE inhibitor or an ARB [51•] . Compared with placebo, finerenone treatment was associated with reduction (up to 38% at the highest dose) in urine albumin/creatine ratio, a surrogate marker for progression of diabetic nephropathy, and did not cause a significant decrease in GFR. Together, these studies have not shown robust evidence that finerenone lowers BP but have shown that finerenone may be an effective treatment for diabetic and non-diabetic CKD and HF, common comorbidities of hypertension. Two phase III clinical trials examining the effects of finerenone in patients with diabetic kidney disease, FIGARO-DKD and FIDELIO-DKD, are ongoing and expected to be completed by 2020 [12] .

The classical RAS pathway and its effect on BP have been well studied over the past several decades, and the ACE inhibitors and ARBs have become pivotal treatments for hypertension and its complications [52••, 53••] (Figs. 1 and 3) . Two new ARBs, fimasartan and allisartan, have recently been approved for the treatment of hypertension in South Korea and China, respectively. Fimasartan has been shown to have a superior trough-to-peak ratio and a larger reduction in sitting SBP and DBP compared to valsartan, and a larger in-office BP reduction compared to losartan [19, 54, 55] . Allisartan has been studied in multiple clinical trials in China. A randomized, double-blind, placebo controlled trial in 2015 showed that allisartan was more effective than placebo in reducing BP in patients with essential hypertension [56] .

The discovery of the counter-regulatory RAS pathway has provided researchers with novel targets for the development of new treatments for hypertension [57] (fig. 3 ). Emphasis has been placed on development of medications with the ability to upregulate and activate multiple mediators in the counterregulatory RAS pathway. Several activators are under preclinical and clinical investigation as novel treatments for hypertension. While the classical RAS pathway works through a cascade of mediators to cause vasoconstriction, oxidative stress, and volume expansion, resulting in increased BP and target organ damage, the counter-regulatory RAS pathway blocks this cascade at several major points, causing vasodilation, decreased oxidative stress, and diuresis, thus reducing BP (Fig. 3) . The counter-regulatory RAS system has thus become a target for development of treatments designed to lower BP and prevent related target organ damage [3••, 58] . None of these novel treatments has reached FDA approval, but many have advanced in clinical trials since 2015.

A major component of the counter-regulatory pathway is the ACE2/Ang (1-7)/MAS receptor axis (Fig. 3) . ACE 2 is a carboxypeptidase that cleaves the C-terminal phenylalanine of Ang II to form the Ang (1-7) heptapeptide [59••] . ACE2 also cleaves the C-terminal leucine of Ang I to form the Ang (1-9) nonapeptide, but the affinity of ACE2 for Ang II is 400-fold stronger than for Ang I, making Ang (1-7) the major product of ACE2 activity. Ang (1-7) then activates the G protein coupled Mas receptor, which is found in mammalian testis, brain, and, most importantly for BP control, in the kidney and heart. Activation of the Mas receptor by Ang (1-7) antagonizes the actions of Ang II on the AT 1 receptor and promotes activation of NO synthase, triggering release of NO to cause vasodilation and decreased oxidative stress. This leads to decreased BP and reductions in vascular endothelial injury and target organ damage.

Recombinant human ACE2 (rhACE2) was developed as a method of upregulating the generation of Ang (1-7) from Ang II, taking advantage of the antihypertensive and vasoprotective counter-regulatory RAS pathway. An initial study administered intravenous rhACE2 to 27 healthy human subjects in a dose escalating randomized, placebo controlled, double blind fashion [60] . Administration of rhACE2 resulted in significant reduction in serum levels of Ang II and elevation in Ang (1-7) compared to placebo. The terminal half-life of rhACE2 was 10 h. However, no effect on BP was seen with elevations of Ang (1-7) . Therefore, further studies of rhACE2 have focused on its potential as treatment for a variety of other conditions that are associated with Ang II-induced vasoconstriction, fibrosis, and inflammation, including acute respiratory distress syndrome (ARDS) and HF.

A phase II clinical trial of rhACE2 administered at intervals to 46 patients with ARDS admitted to an Intensive Care Unit demonstrated increases in Ang (1-7) and decreases in Ang II levels in serum following rhACE2 administration [61] . However, rhACE2 did not improve lung mechanics and may have worsened lung compliance. The authors suggested that a better understanding of RAS effects in ARDS and of rhACE2 effects in pulmonary mechanics is needed if rhACE2 is to be further developed for this indication. Given the promising results from preclinical studies, it has been suggested that rhACE2 may be a reasonable candidate for the future treatment of HF due to its ability to decrease Ang II levels and protect against cardiac hypertrophy, remodeling, and fibrosis [62] . While multiple studies have demonstrated that ACE2 and rhACE2 reduce circulating Ang II levels, further studies are needed to test whether the reduction in Ang II results in the desired outcomes of improved hypertension control, treatment of ARDS, and/or cardiac protection in HF.

Ang (1-7) has been the subject of intense interest in hypertension research because of its dominant role in the counter-regulatory RAS pathway. Early studies in animal models revealed favorable effects on BP in hypertensive subjects and on components of the metabolic syndrome such as glycemic control and lipid profiles by increasing insulin sensitivity and decreasing oxidative stress [63, 64•] . Later studies suggested a beneficial effect of Ang (1-7) in rodent models of hypertension, cardiac remodeling, HF, and kidney disease via inhibition of oxidative stress, inflammation, and fibrosis/pathologic remodeling [65] [66] [67] [68] [69] . Ang (1-7) has especially promising effects in preventing progression of HF, a highly prevalent complication of hypertension [67, [70] [71] [72] . Due to the short halflife in vivo, conducting clinical studies with Ang (1-7) has been difficult. Only recently have multiple phase I clinical trials begun to evaluate the effects of Ang (1-7) on BP, the metabolic syndrome, and other CV parameters. Completion of these studies is expected by 2018 year-end [12].

With the success of Ang (1-7) in reducing BP in animal models, Ang (1-7) mimetics, including AVE 0991 and CGEN 856S, have been studied as potential targets for future treatment of hypertension [73] [74] [75] . These compounds are selective Mas receptor agonists and elicit similar BP lowering and cardioprotective effects as Ang (1) (2) (3) (4) (5) (6) (7) . AVE 0991 has been shown to decrease BP in DOCA-salt hypertensive rats and potentiate the effect of aliskiren in combination therapy [75] . A more recent study demonstrated the cardioprotective effects Fig. 3 Classical and counter-regulatory RAS pathways and drug targets. Activation of the classical RAS pathway increases BP and target organ damage, and this pathway is the target for many currently available antihypertensive drugs, including ACE inhibitors and ARBS. Novel approaches to RAS inhibition, including vaccines targeting Ang II and the AT1 receptor, are being evaluated in preclinical and clinical trials. In contrast, activation of the more recently described counter-regulatory RAS pathway decreases BP and target organ damage, and drugs that activate this pathway are being developed as antihypertensive agents. (Reprinted with permission from Circulation Research 116: 6, 2015) of AVE 0991 in C57BL/6J mice that were subjected to pressure overload. The AVE 0991-treated mice had decreased left ventricular (LV) weight, LV end diastolic diameter, and increased ejection fraction (EF) compared to controls [76] . Neither of these novel Mas receptor agonists has been tested in humans.

Alamandine is nearly identical in structure to Ang (1-7) with the exception of decarboxylation of the N-terminal aspartate radical to form alanine [77] . Alamandine is a selective agonist of the Mas-related G protein coupled receptor, member D (MrgD) that lowers BP and provides cardiovascular protection similar to that seen with Ang (1-7)-induced Mas receptor activation. Studies in hypertensive rat models suggest that alamandine decreases BP [77] [78] [79] .

Activation of the AT2 receptor in the counter-regulatory RAS pathway causes vasodilation and inhibition of arterial and myocardial hypertrophy/hyperplasia and fibrosis (Fig.  3) . According to the hypothesis that activation of the AT 2 R would lower BP, compound 21 (C21) was developed as the first nonpeptide AT 2 R agonist. Although studies of C21 in hypertensive rat models have failed to produce conclusive evidence of a BP lowering effect, C21 has been shown to have beneficial effects on hypertension-induced target organ damage, including reducing vascular stiffness and myocardial fibrosis in hypertensive rats [80-82, 83•, 84] . Most recently, C21 has been found to be effective in preventing progression of CKD in type 1 and type 2 diabetic animal models [85] .

The classical RAS pathway is expressed in brain tissue, where it plays an important role in hypertension development. Aminopeptidase A (APA) converts Ang II to Ang III in brain by removing the N-terminal aspartic acid residue. Ang III in brain increases sympathetic nervous system activity and causes release of arginine vasopressin, thereby raising BP. Thus, APA has gained interest as a potential target for antihypertensive therapy. The APA dimer RB150 has been developed as an orally active APA inhibitor that crosses the blood brain barrier to inhibit APA in hypertensive rats. RB150 given orally to spontaneously hypertensive rats (SHR) has been shown to inhibit formation of Ang III in brain and lower BP in a dose dependent fashion by decreasing sympathetic tone and vascular resistance [86, 87] . RB150 was found to work synergistically with enalapril to reduce BP in that study. Chronic treatment with RB150 has also been shown to reduce BP and plasma arginine vasopressin levels in DOCA-salt hypertensive rats [88] . RB150 was patented by Quantum Genomics and was renamed QGC001. QGC001 was well tolerated in phase I studies evaluating its efficacy and tolerability as a potential hypertension treatment [89] . The QUID-HF study is an ongoing multinational phase II trial comparing QGC001 to placebo in patients with NYHA class II-III HF. The primary outcomes are changes in NT-proBNP and BP, and results are expected later this year. QGC001 has recently been renamed FIRIBASTAT and is currently being investigated as a treatment for hypertension in a larger phase IIa trial, NEW-HOPE [12].

Vasoactive intestinal peptide (VIP) activates two G protein coupled receptors (VPAC 1 and VPAC 2) to produce positive inotropic, chronotropic, and vasodilator effects [90] . These properties have stimulated interest in VIP as a potential treatment for systemic and pulmonary hypertension and HF. PB1046 (Vasomera) is a synthetic analogue of VIP that is selective for VPAC 2 receptors and thus has minimal intestinal side effects. PB1046 also has a longer half-life than native VIP, making it more optimal for therapy. PB1046 was studied in a rodent model of diastolic dysfunction induced by renoprival hypertension (hypertension induced by bilateral nephrectomy) and was found to improve arterial elastance and inotropy and reduce filling pressures [91] . Two phase I randomized, double-blind, placebo controlled studies of PB1046 to evaluate its safety and tolerability in patients with essential hypertension (NCT 01873885, NCT 01523067) have been completed, but the results have not been published. A phase IIa randomized, double-blind, placebo controlled study of PB1046 in patients with stable HFrEF and patients with cardiac dysfunction due to Duchenne muscular dystrophy has recently completed enrollment, but results are not yet published (NCT 02808585) [12] . Most recently, a phase I trial to assess safety and tolerability of PB1046 in patients with pulmonary arterial hypertension (PAH) has begun. PhaseBio, the patent holders of Vasomera, plan to begin a phase II trial for PAH treatment in 2018.

The intestinal Na + /H + Exchanger 3 (NHE3) expressed on enterocytes throughout the intestinal lumen plays a major role in intestinal sodium absorption [92] . NHE3 controls the majority of sodium absorption, and since sodium balance plays an important role in volume status and hypertension, inhibiting NHE3 has been seen as a potential target for the control of hypertension and its complications [93, 94] . Tenapanor is a NHE3 inhibitor that is effective in inhibiting sodium absorption from the gut when administered orally but is not, itself, absorbed from the gut [95] . Tenapanor has been shown to lower BP, reduce albuminuria, and prevent LV hypertrophy in salt-fed 5/6th nephrectomized rat models and to have an additional BP lowering effect when combined with enalapril [94] . Further studies have focused on the ability of tenapanor to reduce phosphorous absorption and protect against vascular calcification in CKD patients [96] . A phase II randomized, double-blind, placebo controlled efficacy and safety trial of tenapanor in the treatment of constipationpredominant irritable bowel syndrome is ongoing [97] .

Entry of calcium into vascular smooth muscle cells via L-type calcium channels is a major determinant of vascular tone and BP. Blockade of the L-type calcium channel with calcium channel blockers effectively lowers BP in hypertensive subjects. Endothelin-1 (ET-1) is a potent vasoconstrictor and mediator of inflammation when activating its type A and type B 2 receptors. In contrast, ET-1 has vasodilator and antiinflammatory effects mediated by its B 1 receptor. Recently, a dual L-type calcium channel blocker/ET A/B 2 antagonist, sargachromenol-D, was isolated from Sargassum siliquastrum, a marine brown alga [98] . Sargachromenol-D was shown to reduce ET-1 and K + depolarization-induced vasoconstriction in basilar arteries of rabbits and to reduce BP in rodent models of hypertension. Further studies are needed to assess the potential role of sargachromenol-D in the treatment of human hypertension.

Ouabain binds to and activates Na + /K + ATPase, initiating a signaling cascade that leads to inhibition of Na + and K + flux and activation of the cytoplasmic tyrosine kinase (cSRC), resulting in inflammation and reactive oxygen species formation in the vasculature [99] . Activation of cSRC over time can cause hypertension and HF, and ouabain has been shown to increase vascular resistance, leading to hypertension in rodent models [100] . Thus, ouabain inhibitors have been considered as potential therapies for hypertension and CVD. Rostafuroxin, which was developed to antagonize the action of ouabain on Na + /K + ATPase, has been shown to lower SBP, facilitate endothelium-mediated vascular relaxation, increase nitric oxide production, and reduce oxidative stress in resistance arteries from DOCA-salt hypertensive rats [101] . Further investigation is needed to explore the role of rostafuroxin as a potential treatment for hypertension in humans.

Over the last three decades, attempts have been made to develop vaccines for the treatment of hypertension, with mixed results [102•, 103] . Most recently, two vaccines, ATRQß-001 and ATR12181, have revived the possibility of vaccine treatments for hypertension. Both contain peptides isolated from the AT 1 R attached to a virus-like particle in order to stimulate production of antibodies to the AT 1 R [104, 105] . Both vaccines reduced BP and resulted in favorable vascular remodeling and regression of CV complications when compared to controls in rodent models of hypertension [104] . ATRQß-001 also lowered BP and prevented streptozotocininduced diabetic nephropathy in a rodent model [106] . These newer antihypertensive vaccines have yet to be evaluated in clinical trials, but offer the potential advantage of not requiring daily dosing to effectively lower BP in hypertensive patients, thus improving treatment adherence and BP control rates in the population.

Recent evidence for the beneficial effects of targeting lower BP goals in hypertensive patients has created a paradigm shift in CVD treatment development. Prior to these recent revelations in hypertension management, development of antihypertensive medications had reached a low point over the last decades. But now, FDCPs, polypills, and novel therapeutic agents offer promising solutions as treatments for hypertension. Although few hypertensive treatments have been approved for clinical use in recent years, the drugs and vaccines discussed in this review remain viable options for treatments in the near future and represent a means to close the gap between new stricter BP goals and the current suboptimal rates of goal BP achievement.

Conflict of Interest The authors declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Timeline of history of hypertension treatment

Approved drug products with therapeutic equivalence evaluations (orange book)

New approaches in the treatment of hypertension

This comprehensive review of novel hypertension treatments published in 2015 serves as the basis for our paper outlining updates of these novel treatments

The SPRINT trial has provided important new evidence to inform the most recent hypertension guidelines

NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Hypertension Canada's 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children

Guideline for the diagnosis and management of hypertension in adults -2016

New European HTN Guidelines hit hard with initial therapy, keep 'normal high' label

Medication adherence and blood pressure control among hypertensive patients with coexisting long-term conditions in primary care settings: a cross-sectional analysis

Executive summary: heart disease and stroke statistics-2014 update: a report from the

CDC Grand Rounds: Improving Medication Adherence for Chronic Disease Management -Innovations and Opportunities

Antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients)

Fixed-dose triple combination of antihypertensive drugs improves blood pressure control: from clinical trials to clinical practice

Greater cardiovascular risk reduction with oncedaily fixed combination of three antihypertensive agents and statin versus free-drug combination: the ALL-IN-ONE trial

Treatment of hypertension: postmarketing surveillance study results of telmisartan monotherapy, fixed dose combination of telmisartan + hydrochlorothiazide/ amlodipine

Efficacy and tolerability of telmisartan/amlodipine + hydrochlorothiazide versus telmisartan/amlodipine combination therapy for essential hypertension uncontrolled with telmisartan/amlodipine: the phase III, multicenter, randomized, Double-blind TAHYTI Study

Effect of hydrochlorothiazide in addition to telmisartan/ amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study

Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallelgroup, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension

A randomized, double-blind, candesartan-controlled, parallel group comparison clinical trial to evaluate the antihypertensive efficacy and safety of fimasartan in patients with mild to moderate essential hypertension

A randomized, multicenter, double-blind, placebo-controlled, 3 x 3 factorial design, phase II study to evaluate the efficacy and safety of the combination of fimasartan/amlodipine in patients with essential hypertension

The efficacy and safety of co-administration of fimasartan and rosuvastatin to patients with hypertension and dyslipidemia

Angiotensin-neprilysin inhibition versus enalapril in heart failure

Potential beneficial effects of sacubitrilvalsartan in renal disease: a new field for a new drug

Pharmacokinetic, pharmacodynamic, and antihypertensive effects of the neprilysin inhibitor LCZ-696: sacubitril/ valsartan

Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial

Effect of sacubitril/valsartan on exercise-induced lipid metabolism in patients with obesity and hypertension. Hypertension. 2 0 1 8

Effects of sacubitril/valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension: the PARAMETER study

Efficacy and safety of crystalline valsartan/sacubitril (LCZ696) compared with placebo and combinations of free valsartan and sacubitril in patients with systolic hypertension: the RATIO study

A strategy to reduce cardiovascular disease by more than 80%

Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial

Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: within-trial cost-effectiveness analysis of the UMPIRE trial

Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover

The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, doubleblind, placebo-controlled, 8-week factorial efficacy and safety study

Fixeddose combinations improve medication compliance: a meta-analysis

Development of compressed coated polypill with mucoadhesive core comprising of atorvastatin/clopidogrel/aspirin using compression coating technique

Combination pharmacotherapy to prevent cardiovascular disease: present status and challenges

Blood-pressure and cholesterol lowering in persons without cardiovascular disease

Future of polypill use for the prevention of cardiovascular disease and strokes

Generalized cost-effectiveness analysis of pharmaceutical interventions for primary prevention of cardiovascular disease in Thailand. Value Health Reg Issues

Putting polypills into pract ice: cha llenge s and le ssons lea rned

Fixed-dose combination therapy to reduce the growing burden of cardiovascular disease in low-and middle-income countries: feasibility and challenges

Emerging roles of the mineralocorticoid receptor in pathology: toward new paradigms in clinical pharmacology

The effect of spironolactone on morbidity and mortality in patients with severe heart failure. randomized aldactone evaluation study investigators

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial

This article showed a benefit of adding spironolactone over bisoprolol and doxazosin as fourth-line agent in resistant hypertension

Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics

A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule

Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial

A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease

Nonsteroidal mineralocorticoid receptor antagonist finerenone protects against acute kidney injurymediated chronic kidney disease: role of oxidative stress

This RCT showed a beneficial effect of finerenone on renal protection indexed by albuminuria in diabetic nephropathy

The renin-angiotensin system (first of two parts)

The renin-angiotensin system (second of two parts)

Ambulatory blood pressure response to once-daily fimasartan: an 8-week, multicenter, randomized, double-blind, active-comparator, parallel-group study in Korean patients with mild to moderate essential hypertension

Efficacy and safety of 30-mg fimasartan for the treatment of patients with mild to moderate hypertension: an 8-week, multicenter, randomized, double-blind, phase III clinical study

A randomized, double blind, placebo-controlled, multicenter phase II trial of allisartan isoproxil in essential hypertensive population at low-medium risk

Therapeutic targeting of the angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas cascade in the renin-angiotensin system: a patent review

Regulation of cardiovascular remodeling by the counterregulatory axis of the renin-angiotensin system

Opportunities for targeting the angiotensin-converting enzyme 2/angiotensin-(1-7)/ mas receptor pathway in hypertension

Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects

A pilot clinical trial of recombinant human angiotensinconverting enzyme 2 in acute respiratory distress syndrome

Angiotensin-converting enzyme 2-angiotensin 1-7/1-9 system: novel promising targets for heart failure treatment

Beneficial effects of long-term administration of an oral formulation of angiotensin-(1-7) in infarcted rats

Angiotensin 1-7: a peptide for preventing and treating metabolic syndrome

Angiotensin-(1-7) enhances the effects of angiotensin II on the cardiac sympathetic afferent reflex and sympathetic activity in rostral ventrolateral medulla in renovascular hypertensive rats

An orally active angiotensin-(1-7) inclusion compound and exercise training produce similar cardiovascular effects in spontaneously hypertensive rats

Mas receptor mediates cardioprotection of angiotensin-(1-7) against angiotensin II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress

Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis

Angiotensin-(1-7) prevents systemic hypertension, attenuates oxidative stress and tubulointerstitial fibrosis, and normalizes renal angiotensin-converting enzyme 2 and Mas receptor expression in diabetic mice

The potential role of atrial natriuretic peptide in the effects of angiotensin-(1-7) in a chronic atrial tachycardia canine model

Lifetime overproduction of circulating angiotensin-(1-7) attenuates deoxycorticosterone acetate-salt hypertension-induced cardiac dysfunction and remodeling

Long-term administration of angiotensin (1-7) prevents heart and lung dysfunction in a mouse model of type 2 diabetes (db/db) by reducing oxidative stress, inflammation and pathological remodeling

Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor

The novel Mas agonist, CGEN-856S, attenuates isoproterenol-induced cardiac remodeling and myocardial infarction injury in rats

Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA-salt-induced hypertension in rats

AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress

Discovery and characterization of alamandine: a novel component of the renin-angiotensin system

Differences in cardiovascular responses to alamandine in two-kidney, one clip hypertensive and normotensive rats

Hypotensive effect induced by microinjection of alamandine, a derivative of angiotensin-(1-7), into caudal ventrolateral medulla of 2K1C hypertensive rats

Stimulation of angiotensin AT2 receptors by the nonpeptide agonist, compound 21, evokes vasodepressor effects in conscious spontaneously hypertensive rats

Effects of angiotensin metabolites in the coronary vascular bed of the spontaneously hypertensive rat: loss of angiotensin II type 2 receptor-mediated vasodilation

AT2 receptor signaling and sympathetic regulation

Impact of the AT(2) receptor agonist C21 on blood pressure and beyond

Angiotensin type 2 receptor agonist compound 21 reduces vascular injury and myocardial fibrosis in stroke-prone spontaneously hypertensive rats

AT2 receptor agonist compound 21: a silver lining for diabetic nephropathy

Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats

A new strategy for treating hypertension by blocking the activity of the brain renin-angiotensin system with aminopeptidase A inhibitors

Central antihypertensive effects of chronic treatment with RB150

Randomised, double-blind, placebo-controlled, doseescalating phase I study of QGC001, a centrally acting aminopeptidase a inhibitor prodrug

VPAC receptors: structure, molecular pharmacology and interaction with accessory proteins

Vasomera, a novel VPAC2-selective vasoactive intestinal peptide agonist, improves arterial elastance and ventriculo-arterial coupling in rats with induced diastolic dysfunction via renoprival hypertension

Novel developments in differentiating the role of renal and intestinal sodium hydrogen exchanger 3

Antihypertensive and laxative effects by pharmacological inhibition of sodium-proton-exchanger subtype 3-mediated sodium absorption in the gut

Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans

Pharmacologic inhibition of intestinal sodium uptake: a gut centric approach to sodium management

Gastrointestinal inhibition of sodiumhydrogen exchanger 3 reduces phosphorus absorption and protects against vascular calcification in CKD

Tenapanor treatment of patients with constipation-predominant irritable bowel syndrome: a phase 2, randomized, placebo-controlled efficacy and safety trial

A novel antihypertension agent, sargachromenol D from marine brown algae, Sargassum siliquastrum, exerts dual action as an L-type Ca(2+) channel blocker and endothelin A/B2 receptor antagonist

The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na. K-ATPase

Novel role of ouabain as a cystogenic factor in autosomal dominant polycystic kidney disease

Rostafuroxin ameliorates endothelial dysfunction and oxidative stress in resistance arteries from deoxycorticosterone acetate-salt hypertensive rats: the role of Na+K+-ATPase/cSRC pathway

Effectiveness and safety of a therapeutic vaccine against angiotensin II receptor type 1 in hypertensive animals

Decrease in blood pressure and regression of cardiovascular complications by angiotensin II vaccine in mice

Effect of active immunization against angiotensin II type 1 (AT1) receptor on hypertension & arterial remodelling in spontaneously hypertensive rats (SHR)

Construction, expression and immunogenicity of a novel anti-hypertension angiotensin II vaccine based on hepatitis A virus-like particle

Vaccination against type 1 angiotensin receptor prevents streptozotocininduced diabetic nephropathy