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Abstract

Hypertension is the most important cardiovascular risk factor. We have witnessed a significant improvement in hypertension treatment and control and an impressive growth in the pharmacologic options available to clinicians and hypertension specialists. With up to a third of patients with hypertension not at the recommended goal blood pressures, it is critically important to develop novel therapeutic approaches to better treat hypertension. This review will explore the ever-expanding horizon of antihypertensive treatment and will focus on 2 major areas of drug development. First, we will review novel targets for pharmacologic treatment and novel molecules and classes of drugs in various phases of development and recognize the limitations we face in their transition from research and development to clinical practice. Then, we will discuss an expanding array of combination strategies to better treat hypertension with the goal of minimizing the burden of cardiovascular and renal complications of hypertension.

Keywords

hypertension vasopeptidase inhibitors renin–angiotensin–aldosterone system fixed low-dose combination drugs endothelin-converting enzyme

Hypertension is the single most important contributor to the global burden of mortality and morbidity in the world and the most important cardiovascular risk factor.¹ Despite significant improvement in hypertension control over the last 3 decades² and the availability of over 100 commercially available antihypertensive drugs and drug combinations, 5% to 30% of all patients with hypertension are not at the recommended goal blood pressure (BP) as recently recommended in the 2014 Evidence based guideline for the Management of High Blood Pressure in Adults Report form the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). Specifically, JNC 8 first published online on December 18, 2013,³ albeit controversial⁴ recommends treating patients with hypertension to a goal BP of either ≤150/90 mm Hg in the general population ≥60 years or 140/90 mm Hg (for patients ≤60 years or those with chronic kidney disease or diabetes mellitus).

Thus, it is increasingly important to consider novel therapeutic approaches to better treat hypertension. This review will focus on novel targets for pharmacologic treatment of hypertension and novel pharmacologic approaches to hypertension management.

Novel Targets for Pharmacologic Treatment of Hypertension

Neutral Endopeptidase and Endothelin-Converting Enzymes as Novel Targets and the Role of Dual Vasopeptidase Inhibitors

Neprilysin (also called as neutral endopeptidase [NEP]) and endothelin-converting enzyme (ECE) are 2 novel targets for pharmacologic treatment of hypertension that have undergone the most intense research investigation in the last 2 decades. The rationale for targeting neprilysin and endothelin lies in the importance of these as mediators for key pathophysiological steps in vascular biology (Table 1).

Table 1.

Novel Drugs in Different Stages of Development for Treatment of Hypertension.^a

Compound (Trade Name)	Company (Location)	Mechanism of Action	Phase of Development
Ilepatril (AVE7688)	Sanofi-Aventis (Paris, France)	Dual neprilysin–ACE inhibitor	Phase 3
LCZ696	Novartis (Basel, Switzerland)	Dual angiotensin receptor—neprolysin inhibitor	Phase 3
Daglutril (SLV306)	Solvay Pharmaceuticals (Brussels, Belgium)	Dual neprilysin—ECE inhibitor	Phase 2
VNP489	Novartis (Basel, Switzerland)	Dual angiotensin receptor—neprolysin inhibitor	Phase 1
PMD3117	Protherics Inc (London, England)	Angiotensin 1 vaccine	Phase 2
Cyt006-AngQb	Cytos Biotechnology AG (Schlieren, Switzerland)	Angiotensin 2 vaccine	Phase 2
Angiotensin vaccine (ATV) with CoVaccine HT adjuvant	Protherics Inc (London, England)	Angiotensin 1 vaccine with adjuvant for improved immune response	Phase 2
Compound 21	Vicore (Goteberg, Sweden)	AT2R agonist	Preclinical
LCI699	Novartis (Basel, Switzerland)	Aldosterone synthase inhibitor	Phase III
FAD286	Novartis (Basel, Switzerland)	Aldosterone synthase inhibitor	Preclinical
SPP635	Speedel Pharmaceuticals (Warren, New Jersey)	Renin inhibitor	Phase II
SPP676	Speedel Pharmaceuticals	Renin inhibitor	Phase I
SPP1148	Speedel Pharmaceuticals	Renin inhibitor	Phase I
SPP1234	Speedel Pharmaceuticals	Renin inhibitor	Phase I
VTP2799	Vitae Pharmaceuticals (Fort Washington, Pennsylvania)	Renin inhibitor	Phase I
Bosentan	Actelion Pharmaceuticals (Allschwil near Basel)	Endothelin A and B receptor antagonist	Phase III
Darusentan	Gilead Sciences (Uxbridge, England)	Endothelin A receptor antagonist	Phase III
Naproxcinod	NicOx (Sophia Antipolis, France)	Nitric oxide releasing COX inhibitor	Phase I

Abbreviations: ACE, angiotensin-converting enzyme; AT2R, angiotensin II type 2 receptor; COX, cyclooxygenase; ECE, endothelin-converting enzyme.

^a Adapted with permission from Ludovit Paulis and Thomas Unger. Novel therapeutic targets for hypertension. Nat Rev Cardiol. 2010;7(8):431-41.

Neprilysin is responsible for breaking down natriuretic peptides and thus potentiating their diuretic, natriuretic, and vasorelaxant effects.⁵ However, the antihypertensive effect of neprilysin inhibitors was found to be decidedly weak most likely due to the increased concentration of several vasoconstrictor peptides (angiotensin II and endothelin 1) that are also inhibited by neprilysin. This led to the development of a combined inhibitor of the NEP (neprilysin) and of the angiotensin-converting enzyme (ACE) or angiotensin receptor to further enhance their antihypertensive effect. These novel antihypertensive drugs are commonly referred to as “dual vasopeptidase inhibitors (VPIs).”

Omapatrilat

Historically, omapatrilat was the first in-class VPI. It was shown to be a more effective BP-lowering drug than an ACE inhibitor (ACEI) enelapril.⁶ Unfortunately, omapatrilat was associated with a greater incidence of angioedema (2.17%) compared to an ACEI—enalapril—(0.68%) in the Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) trial, the largest clinical trial of omapatrilat in hypertension with more than 25 000 patients with hypertension randomized to omapatrilat or enalapril. Moreover, angioedema was substantially more frequent among blacks (5.5%) treated with omapatrilat compared to enalapril (1.6%) and more frequent among smokers (3.9% vs 0.8%). Angioedema was attributed to accumulation of bradykinin and to a lesser extent substance P and neurokinin. This excess risk of angioedema resulted in the cessation of further clinical research with this promising novel agent that was never approved for commercial use.

However, the experience with omapatrilat did not deter scientists from the development of other novel dual VPIs but refocused the drug development to molecules with different profiles of enzyme inhibition with higher inhibition of ACE as compared to neprilysin. Sanofi-aventis (formerly Aventis Pharma AG) has developed a dual VPI ilepatril (or AVE-7688) for the treatment of hypertension and diabetic nephropathy. The only clinical trial of ilepatril listed on the clinicaltrials.gov Web site is the “Double-blind, Randomized, Parallel-group, Dose Ranging, Multicenter Study to Evaluate the Efficacy and Safety of 2.5, 10, 35, and 50 mg AVE 7688 Once Daily, Using 100 mg Losartan-potassium Once Daily as Calibrator, for 12 Months Treatment, in Patients With Mild to Moderate Hypertension” intended to enroll about 1900 patients with hypertension. However, the results of this clinical trial which was to be started in December 2005 and be completed in March 2008 are yet to be published.

Combination of neprilysin inhibitor and angiotensin receptor blocker

Another offshoot of the omapatrilat experience was the development of combinations of a neprilysin (or NEP) inhibitor and an angiotensin II type 1 receptor (so-called AT1R) blocker. To minimize or avoid concerns over the potential risk of angioedema, which largely halted the development of omapatrilat, the first in-class VPI, the novel approach of combining a neprilysin inhibitor with an angiotensin receptor blocker (ARB) rather than an ACEI was used. To accomplish this aim, LCZ696 developed by Novartis is an experimental antihypertensive drug that combines neprilysin inhibition with AT1R blockade in a novel molecule composed of the novel neprilysin inhibitor AHU377 and the ARB valsartan in 1:1 ratio.⁷ This was evaluated in a randomized “proof-of-concept” clinical trial of 1328 patients with mild to moderate hypertension in which LCZ696 resulted in about a 2 to 3 mm Hg greater reduction in diastolic BP and a 4 mm Hg greater reduction in systolic BP after 8 weeks of treatment when compared to the ARB valsartan moiety alone, confirming an additive reduction in BP with this dual VPI and a sustained reduction in BP during ambulatory BP monitoring in a subset of 427 patients in the same trial.⁸ In this study, there were—in fact as predicted—no cases of angioedema reported with the use of LCZ696, suggesting that neprilysin inhibition does not lead to bradykinin accumulation when activation of the ACE is preserved (a hypothesis that needs to be tested in a larger and more definitive prospective clinical trial). However, it is worthwhile noting that only 8% of the 1328 patients with hypertension in this trial were black, thus the absence of reported angioedema with LCZ696 in this largely caucasian clinical trial—albeit promising—may need to be reconfirmed in a more racially diverse and larger population. LCZ696 is not currently undergoing any further clinical trials in hypertension.

Combination of neprilysin inhibitor and ECE inhibitor

Endothelin is a potent vasoconstrictor peptide. Endothelin-converting enzyme cleaves inactive endothelin 1 to active endothelin which subsequently exerts its vasoconstrictor, proinflammatory, and profibrotic effects by binding to endothelin type A receptor.⁹ The advantage of the combination of a VPI and an ECE inhibitor is that the combination of ECE and NEP inhibition is expected to both minimize the increased concentration of endothelin 1 seen with NEP inhibition and enhance the diuresis and natriuresis while reducing the adverse effect of fluid retention seen with ECE blockade (see Figure 1). Daglutril (SLV 306) is a novel dual inhibitor of neprilysin (or NEP) and ECE (NEP/ECE inihibitor) developed by Solvay Pharmaceuticals for the treatment of hypertension. An initial proof-of-concept study in normal human volunteers was published in November 2012.¹⁰ In this study, daglutril at its highest doses attenuated in a dose-dependent manner the BP rise after big endothelin 1 infusion and resulted in a significant increase in circulating big endothelin 1 levels, compared with placebo, indicating that it is effective in inhibiting endogenous ECE activity. Daglutril was also shown to significantly increase the plasma atrial natriuretic peptide levels consistent with systemic neprilysin (or NEP) inhibition.¹⁰ Two clinical trials (listed on the clinicaltrials.gov Web site) were designed to evaluate efficacy and safety of daglutril on top of an ARB losartan in patients with type 2 diabetes having nephropathy with a well-controlled hypertension and the BP-lowering efficacy of various doses of daglutril in combination with amlodipine in patients with hypertension. Unfortunately, none of these 2 clinical trials of daglutril in patients with diabetic nephropathy or hypertension started in 2005 and expected to be completed in 2009 were published many years later.

Figure 1.

The ECE/NEP pathways. Ang II indicates angiotensin II; ANP, atrial natriuretic peptide; ECE, endothelin-converting enzyme; ET-1, endothelin 1; ATAR, endothelin A receptor; ETBR, endothelin B receptor; NEP, neutral endopeptidase. Adapted with permission from the Dhaun N and Webb D. J Hypertension. American Heart Association. 2011;57:667-669.

Limitations of Dual VPIs

Despite the initial excitement about the dual VPIs as a potentially promising novel approach to hypertension treatment, important concerns remain about their clinical utility. Some limitations of dual VPIs include:

unavailability of publications of many completed early efficacy and safety initial clinical trials of dual VPIs;

early clinical trials data focus on surrogate end points with no currently planned major CV outcome trials of novel agents;

the development of omapatrilat, the oldest and most extensively studied dual VPI—inhibitor of ACE and NEP—in hypertension, heart failure, and chronic angina pectoris, was halted due to a high frequency of angioedema among African Americans that was appreciated only when large randomized clinical trials of more than 10 000 patients have been conducted.

Vaccine Targeting Angiotensin

Vaccination for reducing systemic hypertension is a novel approach associated with improved patient compliance as well as the ability to control the BP throughout the day and attenuate the early morning surge of BP. Vaccination against components of the RAAS has the potential of convenience of twice yearly administration, an attractive option for patients with noncompliant hypertension and a potential use to prevent future hypertension development in patients with prehypertension. This approach was first evaluated in 1950s with vaccines against renin which were found to be associated with the development of severe autoimmune kidney disease.¹⁰ Newer approaches target angiotensin and so far include 2 vaccines that have reached clinical testing. PMD3117, an antiangiotensin I vaccine, was found to lower BP in hypertensive rats but failed to simulate similar results in humans.¹¹ CYT006-AngQb, an angiotensin II vaccine (Cytos Biotechnology, AG), was found to significantly reduce systolic BP by up to 21 mm Hg (P = .025) and to a lesser extent diastolic BP (P = .064) and was in fact well tolerated in Phase I studies.¹² It showed modest reductions in ambulatory mean daytime BP (9 mm Hg systolic BP, P = .015, and 4 mm Hg diastolic BP, P = .064) at 14 weeks compared to placebo in a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of 72 patients with mild to moderate hypertension and a significant reduction in the early morning BP surge by 25/13 mm Hg (P < .001) compared to placebo.¹³ However, further studies with shorter dosing intervals of the vaccine were associated with increased antibody titers with lesser affinity resulting in an attenuated BP response.¹⁴ An Angiotensin Vaccine (ATV) with Co-Vaccine HT Adjuvant developed by Protherics was tested in a clinical trial in 124 patients with mild to moderate hypertension in the United Kingdom but was terminated in October 2010 due to dose-limiting side effects. Importantly, none of the tested vaccines so far resulted in a reduction in BP comparable with the effect of commercially and widely available inhibitors of the RAAS, thus substantially limiting their potential clinical utility.

Angiotensin II Type 2 Receptor Agonists

Activation of angiotensin II type 2 receptor (AT2R) is associated with several effects that counteract the effect of AT1R stimulation including antiproliferative and proapoptotic effects,¹⁵ enhanced nitric oxide formation in vascular tissues¹⁶ as well as reducing neointimal growth, cardiac remodeling, and proliferative retinopathy. This is the basis of AT2R activation as an exciting new pharmacological target for treating hypertension. The early development of AT2R agonists has been significantly limited by the unavailability of a specific and selective agonist of AT2R with in vivo stability until compound 21 was developed.

Compound 21 is the only available AT2R agonist extensively studied in animals¹⁷ and humans but like other AT2R agonists despite having significant vascular and cardiac protective effects, it has not been shown to be an effective BP-lowering drug significantly limiting its clinical utility.

Aldosterone Receptor Antagonists

Spironolactone and eplerenone are the currently available aldosterone receptor antagonists that block the epithelial and nonepithelial actions of aldosterone and are being increasingly used in resistant hypertension^18,19 and have been convincingly demonstrated to significantly reduce mortality in patients with congestive heart failure^20,21 who are on background therapy with ACEIs and β-blockers. The antihypertensive efficacy of spironolactone and eplerenone is similar in head-to-head trials of patients with essential or hyperaldosteronism-associated hypertension.²² However, a higher dose of eplerenone is needed to achieve a reduction in BP as spironolactone. However, poor selectivity of spironolactone for the mineralocorticoid receptor is associated with progesterone and testosterone-dependent side effects including gynecomastia, menstrual irregularities as well as loss of libido.²³ Eplerenone is associated with lesser side effects, especially less gynecomastia compared to spironolactone. However, both spironolactone and eplerenone are associated with hyperkalemia, especially in patients with renal impairment and both are contraindicated in patients with significant renal disease, a major limitation for their clinical utility in older and/or diabetic patients with hypertension who have a high prevalence of chronic kidney disease.

Additionally, some dihydropyridine Ca²⁺ channel blockers (CCBs) such as nimodipine have been found to have mineralocorticoid receptor antagonism as well.²⁴ These agents may have potent antihypertensive effect and may consequently reduce end-organ damage beyond their BP-lowering effects. Some such compounds with more selective and potent action on the mineralocorticoid receptor are already in development (WO2005097118; DE102005034267, BR-4628).²⁵

Aldosterone Synthase Inhibitors

Another approach to blocking the effect of the mineralocorticoid aldosterone is to reduce its formation rather than blocking its receptor-mediated effect. Thus, inhibition of the aldosterone synthase, a key enzyme mediating the formation of aldosterone, is another novel approach in hypertension management. Inhibitors of aldosterone synthase reduce the reactive increase in aldosterone levels and thus prevent the activation of both genomic and nongenomic effects of aldosterone and represent one of the newer potential targets for treatment of hypertension.

Fadrozole (FAD 286) developed by Novartis was initially shown to inhibit aldosterone synthase and reduce cardiac hypertrophy, albuminuria, cell infiltration, and matrix deposition in the kidney in rats with overexpression of renin and angiotensinogen, but this effect was limited by a slow onset of this effect starting 7 weeks after its initial administration.²⁶

Another aldosterone synthase inhibitor LCI699 developed by Novartis, the first in-class orally administered inhibitor of aldosterone synthase,²⁷ was recently evaluated in a randomized trial of 524 patients with primary hypertension.²⁸ Aldosterone synthase inhibition by 1 mg LCI699 given once daily for 4 weeks significantly (P = .046) reduced clinic and ambulatory BP compared to placebo, and its antihypertensive efficacy was similar to that of the aldosterone receptor antagonist eplerenone 50 mg twice daily. Adrenocorticotropic hormone stimulation of cortisol was suppressed in about 20% of patients receiving LCI699, suggesting a blunted adenocorticotropic hormone-stimulated release of cortisol. However, the development of LCI699 was stopped in the second quarter of 2010 in favor of seeking more specific aldosterone synthase inhibitors. Several aldosterone synthase CYP11B2 inhibitors are currently being developed.

Several dihydropyridine CCBs, which block t-type channel, inhibit aldosterone synthesis in vitro in addition to their effect on mineralocorticoid receptor antagonism. Newer molecules that utilize the dihydropyridine structure for dual blockade of aldosterone synthase and mineralocorticoid receptor as well as inhibition of L-type Ca²⁺ channels for better antihypertensive effect may be potential targets for newer antihypertensive drugs.

Direct Renin Inhibitors

Although direct renin inhibition was evaluated as a target for antihypertensive therapy even before ACE inhibition, the greater bioavailability and potency of ACEIs overshadowed their development. The increase in renin levels seen in patients treated with ACEIs as well as AT1R blockers is the basis for directly targeting renin for treating hypertension. Aliskiren, the first orally active direct renin inhibitor (RI) to become available for clinical use, has been shown to be well tolerated, efficacious, and has a dose-dependent effect on plasma renin activity and is noninferior to AT1R blockers, ACEIs, hydrochlorothiazide, and atenolol for BP control. Newer direct RIs include more recently developed compounds SPP635, SPP676, SPP1148, and SPP1234 developed by Speedel Pharmaceuticals and VTP2799 developed by Vitae Pharmaceuticals. The first phase IIa 4-week placebo-controlled trial of SPP635, the most well-studied member of the novel SPP family of direct RIs developed by Speedel Pharma, was reported in June 2007 by the Sponsor Speedel Pharma. SPP635 was found to be effective in reducing seated BP by 18/10 mm Hg, P < .001, at 4 weeks compared to placebo with similar reduction in the ambulatory BP in 35 patients with mild to moderate hypertension. A subsequent Phase IIa double-blind, randomized 4-week study of 2 different doses of SPP635 on ambulatory and seated BP in patients with type 2 diabetes having mild to moderate hypertension and albuminuria was started in November 2007 and was completed in September 2008 with a planned maximum enrollment of 50 patients—as reflected on the www.clinicaltrials.gov Web site—but the results of this Phase IIa trial are neither reported nor published. None of the other novel direct RIs have been evaluated in a clinical trial and thus they all currently remain in phase I drug development.

Prorenin Receptor Blockade

The angiotensin-independent actions of renin are believed to be at least partially controlled through binding with the prorenin receptor.²⁹ Prorenin receptor agonist is associated with proproliferative and antiapoptotic effects³⁰ in addition to upregulation of transforming growth factor β1, plasminogen activator inhibitor 1, fibronectin, and collagen. Prorenin receptor blockade has been shown to reduce diabetic nephropathy in rats,³¹ cardiac fibrosis in stroke-prone hypertensive rats,³² and improve renal and cardiac function in hypertensive rats on a high-salt diet. Prorenin receptor antagonism with simultaneous inhibition of RAAS pathway is an interesting target for future targeted therapies for hypertension. Currently, there are no clinical studies supporting the clinical utility for prorenin receptor blockade in patients with hypertension.

Renalase

Renalase is the first known circulating amine oxidase—mainly produced by the kidneys—that can metabolize catecholamines.³³ Downregulation of renalase has been associated with elevated BP and 2 single-nucleotide polymorphisms (rs2576178 and rs2296545) are reportedly associated with essential hypertension in a Han Chinese population. Thus, increasing renalase concentrations may possibly lower BP, particularly in patients with some degree of renalase deficiency or with a renalase polymorphism. Recombinant renalase has been shown to reduce BP and minimize myocardial ischemia–reperfusion injury.³⁴ However, it is unclear whether renalase would likely have any future role as a target for hypertension therapy and more research is needed to gain greater insight into the potential role of renalase targeted antihypertensive therapy.

Endothelin Receptor Blockers

Endothelin 1 mediates vasoconstriction and inflammation through endothelin A and endothelin B receptors, and endothelin receptor antagonists have been effective in lowering pulmonary arterial pressure and have been extensively marketed and widely used for the treatment of pulmonary arterial hypertension.³⁵ Bosentan, an orally active endothelin A and B receptor antagonist developed by Actelion Pharmaceuticals, was evaluated in a multicenter prospective randomized placebo and active-controlled clinical trial comparing bosentan once-daily doses of 500 to 2000 mg to placebo and enalapril 20 mg once daily for 4 weeks in 279 patients with mild to moderate hypertension. In this clinical trial, bosentan was found to be as effective as enalapril in significantly lowering clinic and ambulatory diastolic BP by about 6 mm Hg.³⁶ However, bosentan clinical trials has been restricted to patients with resistant hypertension because of significant side effects, particularly increases in liver transaminases, water retention, and edema. Darusentan, another mixed endothelin A and B antagonist developed by Gilead Pharmaceuticals, was evaluated in 3 doses of 50, 100, or 300 mg once-daily doses in a prospective, multicenter, randomized, placebo–controlled, 14-week clinical trial of 379 patients with resistant hypertension defined as a BP of at least 140/90 mm Hg or higher despite 3 antihypertensive drugs including a diuretic at full or maximally tolerated doses. Darusentan was found to be effective in reducing seated clinic BP compared to placebo by up to 18/11 mm Hg on the highest dose of 300 mg darusentan,³⁷ confirming its clinical utility as an add-on antihypertensive drug in resistant hypertension. About 25% of darusentan-treated patients developed edema and/or fluid retention compared to 14% of placebo-assigned patients: this common side effect of potent arterial vasodilators including other endothelin antagonists was successfully managed by higher doses of diuretics. However, the clinical development of darusentan has been halted due to inconsistent BP-lowering efficacy and divergent results on clinic and ambulatory BP in a subsequent larger multicenter prospective randomized placebo and active-controlled 14-week multicenter clinical trial of darusentan compared to placebo and guanfacine in 849 patients with resistant hypertension.³⁸

Nitric Oxide Donors

The use of nitrates in treating hypertension is limited due to associated tachyphylaxis, headache, and short duration of action. Tachyphylaxis occurs due to biotransformation of organic nitrates into their active forms and can be overcome by developing drugs that directly release nitric oxide. These nitric oxide donors include nitrosyl-cobinamide, nonpeptidic RI nitroderivatives, and naproxcinod, a cyclooxygenase inhibitor and donator of nitric oxide.³⁹ The only nitric oxide donor evaluated in phase 3 clinical trials is naproxcinod.⁴⁰ In an 8-week, double-blind, crossover study in 131 patients with hypertension aged 50 to 74 years with arthritis randomized to naproxcinod 750 mg twice daily or naproxen 500 mg twice daily, each for 14 days, naproxcinod was more effective than naproxen in reducing seated and ambulatory systolic BP by about 2 to 4 mm Hg.⁴⁰ The clinical utility of nitric oxide donors such as naproxcinod is limited by their restricted use in patients with both arthritis and hypertension, the relatively weak BP-lowering efficacy compared to other commercially available drugs, and the lack of long-term efficacy and safety data.

Novel Approaches to Hypertension Management: Newer Combinations of Older Antihypertensive Drugs

Another novel antihypertensive strategy that has attractive substantial clinical attention is the combination of various inhibitors of the RAAS or of various Food and Drug Administration (FDA)-approved commercially available antihypertensive drugs.

Combinations of a RI With an ACEI or an ARB

Aliskiren is a direct RI and is the first RI to be approved by the FDA for the treatment of hypertension in April 2007, based on its BP-lowering efficacy in 6 placebo-controlled, 8-week clinical trials involving >2000 patients with hypertension and an acceptable safety profile in >6460 patients⁴¹ However, a postmarketing clinical trial, ALTITUDE, designed to test whether aliskiren reduces cardiovascular and renal events was prematurely terminated after the second interim analysis because of an increased risk of adverse clinical outcomes—stroke, hypotension, and hyperkalemia—in diabetic patients with chronic kidney disease or both.⁴² This prompted regulatory agencies such as the FDA and the European Medicine Agency to recommend avoidance of aliskiren in patients with diabetes mellitus or moderate to severe renal dysfunction who are already on an ACEI or ARB. Moreover, diabetics are being excluded from ongoing clinical trials of aliskiren as add-on in patients on an ACEI or ARB.

Combinations of an ACEI and an ARB

Today, more than 200 000 patients are receiving a combination of 2 inhibitors of the RAAS most commonly an ACEI and an ARB based on presumed synergistic effects and seemingly beneficial effects on surrogate end points such as BP, proteinuria, or endothelial dysfunction. However, conclusive adequately powered clinical trials of the combination of an ACEI and ARB have not until recently been conducted.

The ONTARGET trial⁴³ of >25 000 patients with high vascular risk including patients with hypertension was designed to test whether the combination of an ACEI (ramipril) and an ARB (telmisartan) is more effective than either an ACEI or an ARB in preventing cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The combination of these inhibitors of the RAAS was associated with an increased risk of symptomatic hypotension (4.8% vs 1.7%, P < .001), syncope (0.3% vs 0.2%, P = .03), renal dysfunction (13.5% vs 10.2%, P < .001), and hyperkalemia (5.6% vs 3.4% had an increase in the potassium level of more than 5.5 mmoL per liter, P < .001) without any improvement in the primary composite cardiovascular end point, and no real clinical benefit. More recently, the VA Nephron D (Diabetes iN Nephropathy study), a multi-center, prospective, randomized, parallel group trial to test the efficacy of the combination of an ACEI (lisinopril) with an ARB (losartan) versus standard treatment with an ARB (losartan) on progression of kidney disease in 1850 patients with diabetes mellitus and overt proteinuria was terminated prematurely due to more frequent hyperkalemia (6.3 vs 2.6 events/100 person-years, P < .001), a near doubling of acute renal failure (12.2 vs 6.7 events/100 person-years, P < .001), and no improvement in the primary end point of a 50% decline in estimated glomerular filtration rate, dialysis, or death.⁴⁴

A recent meta-analysis of all published 33 randomized clinical trials of combinations of 2 RAAS inhibitors⁴⁵ in 68 405 patients consisting of 22 trials of ACEI + ARB, 3 trials of ACEI + RI, 7 trials of ARB + RI, and 1 trial of RI + either ACEI or ARB including ALTITUDE, ONTARGET, and many other smaller clinical trials conclusively showed that dual blockade of the RAAS does not have a favorable clinical effect on cardiovascular or renal outcomes.

These 3 trials—Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE), ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), and Diabetes iN Nephropathy Study (VA Nephron D)—and recent meta-analysis cast doubt on the broad clinical use of a combination of 2 inhibitors of the RAAS based on early benefit on surrogate end points such as BP or proteinuria before definitive and adequately powered hard cardiorenal clinical outcome trials are completed and raise serious safety concerns about combinations of 2 inhibitors of the RAAS in patients with hypertension, congestive heart failure, diabetes mellitus, and/or chronic kidney disease.

Triple Combinations of an ARB, CCB, and Thiazide Diuretic

Patients with moderate or severe hypertension or with concomitant disease—diabetes mellitus or chronic kidney disease—require >2 antihypertensive drugs with complimentary modes of action to achieve recommended stricter BP goals.⁴⁶ The combination of an ARB and CCB is an example of a combination of 2 antihypertensive drugs with complimentary mechanisms of antihypertensive efficacy and less side effects. Edema, a common side effect of the CCB, mediated by its potent arterial dilating effect and resultant increase in capillary hydrostatic pressure is at least partially normalized by the venodilatory effect of the ARB. Moreover, lower doses of the CCB and ARB may be sufficient when the combination is used, thus further minimizing dose-related side effects. The inclusion of a thiazide diuretic in the antihypertensive armamentarium is well in line with JNC 7thseventh and JNC 8th reports recommendation of preferentially using a thiazide diuretic alone or in combination with another antihypertensive drug as first-line therapy. The net result is a triple combination of an ARB, CCB, and thiazide diuretic.

Two large prospective randomized controlled clinical trials evaluated the efficacy of 2 commercially available triple combinations of an ARB (valsartan or olmesartan) + CCB (amlodipine) + hydrochlorothiazide (HCTZ) in 2271 and 2492 patients with moderate -to severe hypertension for 8 and 12 weeks.^47,48 A recent meta-analysis of these 2 larger clinical trials and 9 other smaller clinical trials of triple combinations of ARB, CCB, and diuretic for 8 to 20 weeks in 7563 patients with varying severity of hypertension confirmed that the triple combination of ARB (olmesartan or valsartan), amlodipine, and HCTZ at any dose provided greater reductions in office and ambulatory BP and better achievement of BP goals without significantly increasing adverse effect profile.⁴⁹ The recommendation to use a triple combination of ARB + CCB + HCTZ is consistent and in line with the 2013 European Society of Hypertension/European Society of Cardiology Guidelines to improve compliance and adherence as well as BP goal achievements.^50,51 Currently, several combinations of antihypertensive drugs are FDA approved and commercially available including hydrochlorothiazide-based, amlodipine-based, and other combinations and 2 triple antihypertensive drug combinations, namely amlodipine/olmesartan/HCTZ and amlodipine/valsartan/HCTZ.⁵² A list of these fixed low-dose antihypertensive drug combinations is summarized in Table 2. The 3 more favorable combinations of antihypertensive drugs include:

RAAS inhibitor—ACEI, ARB, or RI—+ a diuretic;

RAAS inhibitor—ACEI, ARB, or RI—+ a dihydropyridine calcium channel or;

diuretic + a β-blocker.

Table 2.

FDA-Approved Antihypertensive Drug Combinations.^a

Generic	Brand	Starting Dose, mg	Maximum Dose^b, mg
Amlodipine-based combinations
Aliskiren:amlodipine	Tekamlo	150:5	300:10
Benazepril:amlodipine	Lotrel	10:2.5	40:10
Olmesartan:amlodipine	Azor	20:5	40:10
Telmisartan:amlodipine	Twynsta	40:5	80:10
Valsartan:amlodipine	Exforge	160:5	320:10
Aliskiren:amlodipine:HCTZ^c	Amturnide	150:5:12.5	300:10:25
Amlodipine:HCTZ:olmesartan^c	Tribenzor	5:12.5:20	10:25:40
Amlodipine:HCTZ:valsartan^c	Exforge HCT	5:12.5:160	10:25:320
HCTZ-based combinations
Aliskiren :HCTZ	Tekturna HCT	150:12.5	300:25
Amiloride:HCTZ	Moduretic	5:50	10:100
Benazepril:HCTZ	Lotensin HCT	5:6.25	20:25
Bisoprolol:HCTZ	Ziac	2.5:6.25	20:12.5
Candesartan:HCTZ	Atacand HCT	16:12.5	32:25
Captopril:HCTZ	Capozide	25:15	150:50
Enalapril:HCTZ	Vasoretic	5:12.5	20:50
Eprosartan:HCTZ	Teveten HCT	600:12.5	900:25
Fosinopril:HCTZ	Monopril HCT	10:12.5	80:50^d
Irbesartan:HCTZ	Avalide	150:12.5	300:25
Lisinopril:HCTZ	Prinzide or Zestoretic	10:12.5	80:50
Losartan:HCTZ	Hyzaar	50:12.5	100:25
Methyldopa:HCTZ	Aldoril or Aldoril D	250:15	750:50
Metoprolol:HCTZ	Dutoprol (extended release); or Lopressor HCT	100:12.5; 100:25	200:25; 200:50
Moexipril:HCTZ	Uniretic	15:7.5	30:50
Olmesartan:HCTZ	Benicar HCT	20:12.5	40:25
Propranolol:HCTZ	Inderide	40:25	160:50
Quinapril:HCTZ	Accuretic or Quinaretic	10:12.5	40:25
Spironolactone:HCTZ	Aldactazide	25:25	100:100
Telmisartan:HCTZ	Micardis HCT	40:12.5	160:25
Triamterene:HCTZ	Dyazide or Maxzide	37.5:25	75:50
Valsartan:HCTZ	Diovan HCT	160:12.5	320:25
Other combinations
Aliskiren:valsartan	Valturna	150:160	300:320
Atenolol:chlorthalidone	Tenoretic	50:25	100:25
Azilsartan:chlorthalidone	Edarbyclor	40:12.5	40:25
Bendroflumethiazide:nadolol	Corzide	5:40	5:80
Chlorthalidone:clonidine	Clopres or Combipres	15:0.1	30:0.6
Trandolapril:verapamil	Tarka	1:180^e	8:240

Abbreviations: FDA, Food and Drug Administration; HCTZ (or HCT), hydrochlorothiazide.

^a Reproduced with permission from Katherine.⁵²

^b The maximum dose of each drug studied in this particular combination.

^c Triple combination therapy is not recommended for initial treatment of hypertension.

^d These doses reflect maximum monotherapy doses.

^e 1:180 product is not available.

In contrast, combinations that should be avoided since they are potentially dangerous^42

–45 are any combinations of 2 inhibitors of the RAAS (dual RAAS inhibitors) such as ARB + ACEI or RI + ACEI or RI + ARB. The combination of a β-blocker and an ACEI or ARB generally is not optimal combinations for the treatment of hypertension due to limited incremental effect of adding a β-blocker to a RAAS inhibitor in further lowering BP.

The concept of combining various drugs with different modes of action also extends to the use of the polypill (combination of antihypertensive drugs + statin + aspirin) since most patients with hypertension have hyperlipidemia and most patients with hypertension have a high cardiovascular risk justifying the need for adding a statin and an aspirin to the antihypertensive drug combination. The recently reported Use of a Multidrug Pill in Reducing Cardiovascular Events (UMPIRE) open-label, randomized, blinded end point trial in 2004 participants with established cardiovascular disease or at risk of cardiovascular disease in Europe and India was designed to assess long-term adherence to indicated therapy and 2 major cardiovascular disease risk factors, systolic BP and low-density lipoprotein cholesterol. This trial showed a significant improvement in medication adherence at 15 months from 65% to 86% (P < .001) and statistically significant but small improvements in systolic BP and low-density lipoprotein cholesterol levels.⁵³ Whether such a polypill will be proven to reduce overall cardiovascular and/or renal risk profile remains to be seen.

Conclusion

Hypertension is the single most important contributor to worldwide death and morbidity and the most important cardiovascular risk factor. However, despite significant improvements in hypertension control over many decades, about a third of patients with hypertension are not at the recommended goal BP and long-term adherence to recommended treatment of hypertension, a chronic and life-long disease, remains challenging. Novel therapeutic approaches targeting new targets such as the NEP or the ECE or newer strategies to inhibit the renin–angiotensin system as well as novel combination of the currently available antihypertensive drugs and even of antihypertensive drugs in combination with other cardioprotective drugs such as statins and aspirin have now emerged. Clearly, there are promising early efficacy and safety results in relatively small clinical trials, but important concerns and limitations remain about the foreseeable future role of novel antihypertensive drugs and the eventual role of combinations of antihypertensive drugs—old or new—within the context of an expanding armamentarium of antihypertensive strategies. Most importantly, caution should be exercised at this juncture in the emerging development of such novel agents in view of safety concerns of similar novel drugs or drug combinations. The eventual clinical utility of novel pharmacologic therapies in hypertension will have to await definitive compelling large-scale hard cardiovascular and renal outcome trials and the results of large-scale trials of alternative nonpharmacologic treatment strategies such as percutaneous renal nerve radiofrequency denervation.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Are There Any New Pharmacologic Therapies on the Horizon to Better Treat Hypertension? A State-of-the-Art Paper

Abstract

Keywords

Novel Targets for Pharmacologic Treatment of Hypertension

Neutral Endopeptidase and Endothelin-Converting Enzymes as Novel Targets and the Role of Dual Vasopeptidase Inhibitors

Omapatrilat

Combination of neprilysin inhibitor and angiotensin receptor blocker

Combination of neprilysin inhibitor and ECE inhibitor

Limitations of Dual VPIs

Vaccine Targeting Angiotensin

Angiotensin II Type 2 Receptor Agonists

Aldosterone Receptor Antagonists

Aldosterone Synthase Inhibitors

Direct Renin Inhibitors

Prorenin Receptor Blockade

Renalase

Endothelin Receptor Blockers

Nitric Oxide Donors

Novel Approaches to Hypertension Management: Newer Combinations of Older Antihypertensive Drugs

Combinations of a RI With an ACEI or an ARB

Combinations of an ACEI and an ARB

Triple Combinations of an ARB, CCB, and Thiazide Diuretic

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References