Azilsartan: Current Evidence and Perspectives in Management of Hypertension

Hypertension continues to be global pandemic with huge mortality, morbidity, and financial burden on the health system. Unfortunately, most patients with hypertension would eventually require two or more drugs in combination to achieve their target blood pressure (BP). To this end, emergence of more potent antihypertensive drugs is a welcome sign. Angiotensin receptor blockers (ARBs) are cornerstones of hypertension management in daily practice. Among all ARBs, azilsartan is proven to be more potent in most of the head-to-head trials till date. Azilsartan is the latest ARB approved for hypertension with greater potency and minimal side effects. This review highlights the role of azilsartan in management of hypertension in the current era.


Introduction
Hypertension continues to be a global health pandemic causing huge mortality and morbidity. It contributes for almost half of CVD and stroke deaths [1,2]. Unfortunately, it is no more a disease of western world and in South Asia itself, almost one third of population is suffering from hypertension [3]. To compound the situation, the recent NHANES data peg the disease treatment rates at only 71-80%, whereas the overall control rates are dismal at 45-50% [4]. More importantly, a majority of them would require two or more drug combinations to achieve their blood pressure goals [5,6].
Drugs targeting the renin-angiotensin-aldosterone system (RAAS) are cornerstone of the management of hypertension. Four classes of molecules make it to the list of RAAS blockers: angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonist, and direct renin inhibitors (DRI) (Figure 1). Aldosterone antagonists are primarily reserved for resistant hypertension, whereas major trials of DRI did not meet their primary end points. Hence, RAAS modulators in daily practice of hypertension include ACEi and ARB. Because of a favourable side effect profile, many practitioners choose ARB over ACEi as firstline therapy.

Evolution of ARBs in Hypertension
ARBs act via inhibiting the angiotensin II type 1 receptor and decreasing RAAS-associated adverse effects. e first ARB which was approved for hypertension was losartan, way back in 1986 [7]. Till March 2018, Food and Drug Administration (FDA) approved 8 ARBs for various indications. In chronological order the list includes losartan, valsartan,candesarten, irbesartan,eposartan, telminsartan, olmesartan, and azilsartan, being the latest addition ( Figure 2).
As ARBs cause dose-dependent decrease in peripheral resistance, it decreases the effect of aldosterone on the kidney and peripheral vasculature including decrease in smooth muscle vascular tone. ARBs have been successfully used in management of hypertension, coronary heart disease, heart failure, chronic kidney disease, and other miscellaneous conditions. Because of difference in affinity for the angiotensin receptor and other mechanisms, various ARBs differ in their pharmacokinetics and pharmacodynamics in human body. Major trials of different ARBs approved in our country for treating hypertension are LIFE (Losartan), ROADMAP (Olmesartan), VALUE (Valsartan), and ON TARGET (Telmisartan) [8][9][10][11] (see Table 1).

Azilsartan: ARB with a Difference
Azilsartan medoxomil (development code: TAK-491) has been developed by Takeda Global Research & Development Centre, Inc., U.S. and got FDA approval in February 2011 for treatment in hypertension in adults [12]. Azilsartan is now worldwide approved for hypertension either as a prodrug (Azilsartan medoxomil) or primary compound.

Mechanism of Action, Pharmacodynamics, and Pharmacokinetics
Azilsartan medoxomil is a prodrug which is hydrolysed in the gastrointestinal tract before getting absorbed in the system. Azilsartan acts against angiotensin II in a dose-dependent manner. After administration of azilsartan to healthy subjects, plasma angiotensin I and II concentrations increased, while plasma renin activity increased while plasma aldosterone concentrations decreased. Azilsartan does not cause any clinical significant effects on serum sodium or potassium. After oral administration, bioavailability of azilsartan medoxomil is approximately 60% with peak plasma concentration reached within 1.5 to 3 hours. ere is no food interaction on bioavailability of azilsartan [13].
Azilsartan is closely related to candesartan with greater potency and prolonged duration of action as compared with other ARBs. Unlike candesartan which must be orally administrated as the prodrug (candesartan cilexetil) for better bioavailability, azilsartan is equally effective as either ester prodrug (azilsartan medoxomil) or primary compound itself. Azilsartan contains an oxo-oxadiazole ring which is not found in any of clinically approved ARBs, which makes azilsartan less acidic and more lipophilic than others.

Comparison with Other Sartans: Clinical Evidence
All major head-to-head randomized controlled trials indicate that azilsartan exhibits more potent antihypertensive action than any other drugs in its class. is potent antihypertensive action includes better clinical systolic blood pressure (SBP), diastolic blood pressure (DBP), and 24 hour ambulatory blood pressure ( Figure 3, Table 2). In a randomized, double-blinded, placebo-controlled trial, Sica et al. compared azilsartan medoxomil and valsartan in primary hypertension using ambulatory and clinic BP measurement [13]. In the trial, azilsartan 40 mg (− 14.9 mm Hg) and 80 mg (− 15.3 mm Hg) significantly improved 24-hour mean SBP than valsartan (− 11.3 mm Hg; p < 0.001).
Finally, Takagi et al. performed a meta-analysis which included a total of 6152 patients from 7 randomized-controlled trials with azilsartan [18]. e pooled analysis suggested a significant reduction in BP changes among patients randomized to 40 mg of azilsartan versus control therapy (clinic SBP:

Azilsartan in Combination Therapy
ere are a few studies available in the literature comparing azilsartan-based combination therapies and most of them have used azilsartan in combination with chlorthalidone. In the largest such study, Cushman et al. compared azilsartan (40/80 mg) and chlorthalidone combination with olmesartan (40 mg) and hydrochlorothiazide combination [20]. ey enrolled 1071 patients with stage 2 hypertension and Losartan prevents more cardiovascular morbidity and death than atenolol for similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefits beyond reduction in blood pressure Telmesartan ONTARGET [9] 25,620 2008 Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. e combination of the two drugs was associated with more adverse events without an increase in benefit Olmesartan ROADMAP [10] 1147 2015 Additive treatment with an angiotensin receptor blocker, olmesartan, did not improve clinical outcome in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both Valsartan VALUE [11] 15,425 2004 e hypothesis with equivalent amount of blood pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients with high cardiovascular risk could not be proved Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. e findings emphasise the importance of prompt blood-pressure control in hypertensive patients with high cardiovascular risk    Figure 4). Similarly, Bakris et al. compared an azilsartan plus chlorthalidone regimen with azilsartan with hydrochlorothiazide in 609 patients with moderate-to-severe hypertension [21]. e dose of azilsartan was 40 mg while diuretic doses were titrated from 12.5 mg to 25 mg. e fall in clinical systolic BP from the baseline was higher in the chlorthalidone-based regimen (-37.8 mm Hg vs. -32.8 mm Hg, respectively, p < 0.001).
Interestingly, the blood pressure-lowering efficacy was maintained across both white and black races as demonstrated by Ferdinand et al. [22]. In this pooled analysis from two RCTs, azilsartan-based combination as well as monotherapy resulted in better BP control among both black and whites alike when pitted against an olmesartan-based regimes.

Azilsartan: Effects beyond Blood Pressure Control
Because of its inverse agonistic effects, azilsartan has potential effects beyond BP control which include amelioration of deleterious effects of angiotensin II such as cardiac hypertrophy, fibrosis, insulin resistance, and stabilization of coronary plaques [23].
In patients with heart failure with preserved ejection fraction (HfpEF), azilsartan improved parameters of diastolic function of left ventricle [24]. In their study of fifteen patients with HfpEF by Sakomoto et al., mitral annular E/e' ratio on echocardiography decreased with azilsartan therapy at six months while there was no change with candesartan treatment. is was despite comparable with reductions in blood pressure with both drugs. Azilsartan also decreased heart rate in the study while candesartan did not.
Azilsartan also improved endothelial dysfunction better than amlodipine as assessed by flow-mediated dilatation in brachial artery. In a group of twenty four hypertensive patients, 3 months of azilsartan therapy achieved superior flow-mediated dilatation, higher plasma renin activity, and lower plasma aldosterone levels [25]. Azilsartan therapy was also associated with improvement in arterial stiffness parameters (assessed by carotid-femoral pulse wave velocity) at 6 months [26].
In the CHAOS study published by Sezai et al., the effect of azilsartan and olmesartan on plasma renin activity, aldosterone II, and angiotensin in patients with essential hypertension after cardiac surgery was studied [27]. Apart from the primary endpoint, CHAOS study also included left ventricular mass index (LVMI), estimated glomerular filtration rate (eGFR), and urinalysis as secondary end point. e plasma renin levels were not different between the groups but aldosterone and angiotensin II levels were lower with olmesartan arm. ere was no difference in two groups in terms of eGFR and urinalysis. LVMI was significantly lower in the olmesartan group than in the azilsartan group (p < 0.0001).
A cost effectiveness analysis between various ARB-based combination therapy has been published [28]. Azilsartan plus chlorthalidone combination therapy proved to have maximal incremental cost effectiveness followed by losartan plus hydrochlorthiazide-based therapy. Because of increased efficacy, azilsartan-based group was dominant despite an increment in price.

Side Effect of Drug
e various side effects of the drug seen in clinical studies include dizziness (8.9%), increased serum creatinine (3.6%), fatigue (2%), diarrhoea (2%), hypotension (1.7%), and syncope (0.3%) [12,29]. Hypotension was the commonest cause of drug discontinuation with monotherapy, whereas raised serum creatinine and dizziness were most abundant causes in combination with chlorthalidone. Other side effects reported by the manufacturer include fatigue, muscle spasm, nausea, and abnormalities in hemogram. Increases in serum creatinine were often transient and related to a large fall in blood pressure. ey were exacerbated by old age (>75 years) as well as coadministration of diuretics. On a similar note, manufacturers warn that volume and salt-depleted individuals are more prone to hypotensive effects of the drug. As with other ARBs, it should not be administered during pregnancy.

Current Indications
ARB has the best patient satisfaction profile (as assessed by the lowest rate of treatment discontinuation) among contemporary drugs [30]. With plethora of data establishing the superiority of azilsartan in controlling BP, it can be recommended that wherever blood pressure is not controlled on combination therapy with or without ARBs, adding azilsartan or replacing other ARBs with azilsartan can be an acceptable  International Journal of Hypertension approach. For de novo hypertension too, azilsartan is an attractive option. However, for patients whose blood pressure is already well controlled by other ARBs, it is not imperative to switch to azilsartan. e drug is listed as the first-line ARB in the recent ACC/AHA 2017 Hypertension guidelines [5]. Azilsartan was also used in the pivotal SPRINT trial which has redefined blood pressure goals [31]. Based on the data from the available clinical trials, the dose equivalence between azilsartan and other ARBs is summarized in Table 3.

Conclusion
Hypertension is a global pandemic with huge morbidity and mortality. Unfortunately, the awareness and control rates remain dismal even in the western world. Azilsartan is the latest ARB to be added to the armamentarium of hypertension ( Figure 5). It has emerged as a potent ARB which has demonstrated superior BP control in both monotherapy and combination therapy not only against other ARBs but also against other class of antihypertensive agents. e drug becomes the first-line choice in patients whose BP is not at goal despite combination therapy. In de novo hypertension, ARB is often the first-line choice due to their better tolerability and potency. In this scenario, it is the discretion of the treating physician to initiate any ARB of his choice but the wealth of data discussed above makes azilsartan an attractive first-line ARB.

Conflicts of Interest
e authors declare that they have no conflicts of interest.  [19] Azilsartan is the latest ARB available worldwide Dose ranges from 20-80 mg once a day ough none of the major hypertension guidelines mentions azilsartan as a superior ARB, it is widely used worldwide as a preferred ARB ere is no reason to believe that azilsartan is not superior to other ARBs according to recent published data Azilsartan has almost similar side effect profile as other ARBs with better blood pressure control International Journal of Hypertension 7