Azilsartan Medoxomil for Treating Hypertension - Clinical Implications of Recent Trials

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Objective: To evaluate the efficacy, safety, and clinical role of azilsartan medoxomil, an angiotensin-II receptor blocker (ARB) that recently gained US Food and Drug Administration approval for lowering of blood pressure (BP) in patients with hypertension. Methods: A systematic review of the literature was performed through October 2011 using the keywords and medical subject headings azilsartan, azilsartan medoxomil, TAK-491, TAK-536, and Edarbi. Citations eligible for inclusion were in vitro or in vivo evaluations of azilsartan medoxomil with no restrictions on patient population or indication used. Data related to the patient populations and outcomes of interest were extracted from each citation. Results: Three trials are available in full publication form, with others available only as abstracts. Azilsartan medoxomil 40 mg and 80 mg daily significantly improves both systolic and diastolic BP from baseline compared with placebo, and the 80 mg dose has greater efficacy than other ARBs, including olmesartan 40 mg daily and valsartan 320 mg daily. Improvements in both 24-hour BP using ambulatory monitoring and clinic BPs, as well as a higher proportion of patients reaching goal, have been seen with azilsartan medoxomil. Additional information shows added BP lowering when azilsartan medoxomil is combined with chlorthalidone. Adverse events are similar with azilsartan medoxomil compared to other ARBs and include headache, dizziness, urinary tract infections, and fatigue. Conclusions: Azilsartan medoxomil is a safe and effective ARB with a unique pharmacologic profile compared with other agents, including slowed angiotensin-II type 1 (AT1) receptor dissociation rates and improved receptor specificity. Studies have shown azilsartan medoxomil 80 mg once daily to reduce BP to a greater extent than valsartan and olmesartan, with similar safety and tolerability.

Disclosure:William L Baker, PharmD, BCPS (AQ Cardiology), has no conflicts of interest to declare. William B White, MD, FACP, FAHA, FASH, discloses that his division has received research funding from Takeda Global Research and Development, manufacturer of azilsartan medoxomil, between 2007 and 2009. He is a paid safety consultant to Takeda for chairing the adjudication committee of the febuxostat cardiovascular outcomes study. He chairs the steering committee of the Examination of cardiovascular outcomes: alogliptin versus standard of care in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) trial assessing the cardiovascular safety of alogliptin.



Support:The publication costs of this article were supported by Takeda Pharmaceuticals North America. Takeda Pharmaceuticals North America has had no involvement in the content of this article beyond review for factual accuracy. William L Baker, PharmD, BCPS (AQ Cardiology), and William B White, MD, FACP, FAHA, FASH, were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of the manuscript.

Acknowledgements:Supported in part by funding from the National Institutes of Health R01 AG022092-06 (PI: Dr White).

Correspondence Details:William L Baker, PharmD, BCPS (AQ Cardiology), Assistant Professor of Pharmacy and Medicine, University of Connecticut Schools of Pharmacy and Medicine, 263 Farmington Avenue, MC2205, Farmington, CT 06030. E:

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Despite advances in diagnostic and treatment modalities, hypertension remains a prevalent medical condition, affecting over 26 % of the adult population, a number expected to rise to nearly 30 % by the year 2025.1 It is a major risk factor for cardiovascular disease morbidity and mortality, including stroke, heart failure, and renal disease.2,3 Numerous investigations have demonstrated the ability of various pharmacologic treatment regimens to decrease major cardiovascular event rates.4,5 Despite this evidence, adequate control of blood pressure (BP) remains poor.2,6 Pharmacologic agents that attenuate the actions of the renin–angiotensin–aldosterone system (RAAS) comprise one of the most popular antihypertensive strategies for patients with elevated BP.2,7 These include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), direct renin inhibitors, and aldosterone antagonists. ARBs attenuate the action of angiotensin-II by binding to and inhibiting the angiotensin-II type 1 (AT1) receptor, inducing a dose-dependent decrease in peripheral resistance, reduction in vascular smooth muscle contraction, and reduced synthesis and effects of aldosterone on the kidney.8 These pharmacologic properties have led to improved outcomes with ARB use across a number of disease states, including coronary heart disease, diabetic patients with kidney disease, and heart failure.9,10

Azilsartan medoxomil (Edarbi™, Takeda Pharmaceuticals America, Inc., Deerfield, IL) is a highly selective ARB and was approved by the US Food and Drug Administration (FDA) (February 2011) for the treatment of adults with hypertension.11 Given the large number of ARBs that are currently available in the US, it is important to understand the pharmacologic and clinical characteristics of azilsartan medoxomil that may differentiate the drug for contemporary hypertension management.

Pharmacology and Pharmacokinetics

Azilsartan medoxomil is a prodrug that is hydrolyzed within the gastrointestinal tract to azilsartan prior to and/or during absorption. It is structurally related to candesartan with the exception of a chemical alteration that increases the lipophilicity of azilsartan medoxomil and potentially improves its oral bioavailability.12 Azilsartan appears to be an insurmountable selective AT1 antagonist with greater potency and a longer-lasting pharmacologic effect compared with other ARBs. Ojima et al. showed that azilsartan is more potent and has more slowly dissociating AT1 antagonist properties compared with other agents in the ARB class.13

A variety of potential pleiotropic effects with azilsartan medoxomil or azilsartan have been demonstrated, potentially supporting its investigation for treating concomitant disorders in patients with hypertension. These include a dose-dependent suppression of increases in plasma glucose levels following an oral glucose tolerance test, improved insulin sensitivity, decreased epididymal adipose tissue weight, suppression of plasminogen activator inhibitor type 1 (PAI-1), and a dose-dependent reduction in myocardial infarction.14–17

Minimal published data exist on the pharmacokinetic properties of azilsartan medoxomil, which is rapidly hydrolyzed to azilsartan, as it is not detectable in human plasma.11 Azilsartan is then metabolized, primarily by cytochrome P450 2C9 (CYP2C9), to a major metabolite (M-II), via O-dealkylation, and a minor metabolite (M-I), via decarboxylation. M-I and M-II do not contribute to the pharmacologic activity of azilsartan. No clinically significant drug interactions have been noted; however, the prescribing information for all ARBs does caution about concomitant use with non-steroidal anti-inflammatory agents (NSAIDs) (including cyclooxygenase-2 inhibitors), particularly in patients who are elderly or volume-depleted, due to an increased risk of deterioration of renal function. The terminal half-life is approximately 11 hours, with an estimated renal clearance of 2.3 ml/min.

Clinical Efficacy

Evidence supporting the clinical efficacy and safety of azilsartan medoxomil comes from three large clinical trials available in full publication form, and a number of other studies of azilsartan medoxomil for treating patients with various stages of hypertension have been presented at various professional medical meetings and are available in abstract form (see Table 1).18–25 A unique feature of the azilsartan medoxomil clinical studies is the use of 24-hour systolic BP (SBP) as the primary efficacy measurement to evaluate the comparative effects of azilsartan medoxomil versus other antihypertensives. There are theoretical advantages to using ambulatory BP monitoring (ABPM) to assess a new antihypertensive drug. Firstly, ABPM is superior in assessing the trough:peak ratio of antihypertensive medications compared with clinic BP26 and has been shown to be a more reliable predictor of cardiovascular outcomes compared with traditional clinic or office BP readings.27,28

Secondly, using ABPM-derived values both as inclusion criteria as well as for endpoint evaluation avoids inclusion of patients with proposed ‘white-coat’ hypertension, which can skew clinic BP readings in clinical trials.29 Moreover, ABPM produces lower variance with repeated studies compared with clinic BP measures and, from a clinical trials standpoint, allows lower numbers of patients to be required to show the desired effect of the drug under study.30,31

Monotherapy Trials

A total of four clinical trials, three in full publication form18,21,25 and one in abstract-only form,19 evaluated azilsartan medoxomil as monotherapy in patients with hypertension. Bakris et al. randomized 1,275 patients (mean age 58 ± 11 years) with a diagnosis of primary hypertension to receive azilsartan medoxomil, olmesartan, or placebo for a total of six weeks.18 Each of the azilsartan medoxomil doses, as well as olmesartan, significantly reduced 24-hour SBP compared with placebo (p<0.001 for all). As compared with olmesartan 40 mg, azilsartan medoxomil 40 mg was non-inferior, whereas the azilsartan medoxomil 80 mg dose produced significant reductions in both 24-hour mean SBP and trough sitting clinic SBP from baseline (p<0.05 for both). Similar results to the primary analysis were seen for both 24-hour mean diastolic BP (DBP) and clinic DBP for each comparison. These results were consistent among a variety of subgroups based on age, sex, baseline 24-hour mean SBP, and renal function. In the subgroup analysis by race, there was a moderately decreased effect among black patients, compared with the non-black subgroups, with all active treatments. These results suggest that azilsartan medoxomil is as effective as olmesartan at reducing both SBP and DBP using either ABPM or clinic readings, with similar tolerability.

White et al. evaluated azilsartan medoxomil versus both olmesartan and valsartan in 1,291 patients with stage I and II hypertension.25 Significantly greater reductions in mean 24-hour SBP were seen in the azilsartan medoxomil 80 mg group versus both olmesartan (p=0.009) and valsartan (p<0.001), whereas the azilsartan medoxomil 40 mg dose was non-inferior to olmesartan (see Figure 1). Similar findings were seen in changes from baseline in clinic SBP, 24-hour mean DBP, and clinic DBP. When evaluating the ABPM findings, azilsartan medoxomil 80 mg had lower SBP readings at most time points than either valsartan or olmesartan, suggesting its potential to provide greater 24-hour BP control.

In contrast to the results of Bakris et al.,18 a significantly greater proportion of patients in the azilsartan medoxomil 80 mg group were considered responders (58 %) (defined as either reaching a clinic SBP target of <140 mmHg and/or a >20 mmHg reduction in SBP from baseline) than placebo (22 %), valsartan (49 %), and olmesartan (49 %) (p<0.05 for all). As was seen in prior studies, black patients seemed to experience less effect from azilsartan medoxomil and other ARBs compared with white patients (p-value for interaction=0.06).

The most recently published study21 extended the study duration to 24 weeks as opposed to the two previously discussed six-week trials.18,25 Sica et al. randomized 984 patients to receive azilsartan medoxomil or maximum-dose valsartan.21 Changes from baseline in 24-hour mean SBP were significantly greater for both the azilsartan medoxomil 40 mg (-14.9 mmHg) and 80 mg (-15.3 mmHg) groups versus valsartan (-11.3 mmHg, p<0.001 for both). Similar patterns of response were seen for clinic SBP, as well as 24-hour mean DBP and clinic DBP. The proportion of patients considered responders was significantly lower in the valsartan 320 mg group (47 %) than the azilsartan medoxomil 40 mg (56 %, p=0.016) or 80 mg (59%, p=0.002) groups. Additionally, a smaller treatment effect was seen among black patients treated with either dose of azilsartan medoxomil and valsartan, compared with non-black patients (p-value for interaction=0.071).

A study of 884 patients (available in abstract-only form) showed significant reductions in trough sitting clinic SBP from baseline (range 160.9–161.5 mmHg) with both azilsartan medoxomil 40 mg (-20.6 ± 0.9 mmHg) and 80 mg (-21.2 ± 0.9 mmHg) versus ramipril (-12.2 ± 0.9 mmHg, p<0.001 for both azilsartan doses).19 Response rates reflecting both SBP and DBP targets were also significantly higher with azilsartan medoxomil 40 and 80 mg (54.0 % and 53.6 %, respectively) versus ramipril (33.8 %; p<0.001 for both).

Combination Therapy Trials

A total of four clinical trials were found, all in abstract-only form, evaluating azilsartan medoxomil in combination with other antihypertensive drugs. One trial combined azilsartan medoxomil with amlodipine24 and three trials combined azilsartan medoxomil with chlorthalidone.20,22,23 The first one, a study of 562 patients, showed that amlodipine 5 mg plus azilsartan medoxomil 40 mg (-24.8/-15.3 mmHg) and 80 mg (-24.5/-15.4 mmHg) reduced 24-hour SBP/DBP, measured by ABPM, to a greater extent than amlodipine 5 mg alone (-13.6/ -7.8 mmHg, p<0.001 for both).24

Moreover, response rates reflecting both SBP and DBP targets for the combination (66 % and 69 %, respectively) were higher than for the single agent (43 %). This investigation is of particular clinical relevance given the recent data showing outcome benefits when combining blockers of the RAAS with a calcium channel blocker (CCB) as opposed to with a thiazide diuretic (hydrochlorothiazide).32

The tree other trials published in abstract form compared the combination of azilsartan medoxomil plus the thiazide-like diuretic chlorthalidone as a fixed-dose combination versus either monotherapy,22 chlorthalidone alone,23 or the combination of olmesartan plus hydrochlorothiazide.20 The choice of chlorthalidone as the diuretic for these investigations is notable, given the recently published data suggesting improved BP control (on a mg-to-mg basis) and improved outcomes as compared with hydrochlorothiazide alone.33,34 These studies show that combining azilsartan medoxomil with chlorthalidone produces significant reductions in 24-hour mean SBP across a number of dosing combinations (see Table 1) compared with chlorthalidone alone or the combination of olmesartan plus hydrochlorothiazide.22,23 Furthermore, this combination significantly reduced clinic SBP to a greater degree than the combination of olmesartan plus hydrochlorothiazide (see Figure 2).20

Clinical Safety

Angiotensin-II receptor antagonists have been shown to have tolerability similar to that of placebo and other antihypertensive drug classes.35,36 This favorable adverse event profile probably explains the greater persistence rates over years of use compared with other agents.37 Data from the three published clinical trials show similar tolerability of azilsartan medoxomil to placebo18,21 and other ARBs.18,21,25 The most commonly reported adverse events with azilsartan medoxomil included headache, dizziness, urinary tract infections, and fatigue, all occurring in ~10 % of patients and at rates similar to placebo. The rates of adverse events leading to study medication discontinuation with azilsartan medoxomil 40 mg and 80 mg ranged from 1.1 to 7.0 % and 2.1 to 8.2 %, versus 1.9–4.2 % with placebo, 1.4–2.1 % with olmesartan 40 mg, and 2.5–6.1 % with valsartan 320 mg. Statistical comparisons between these different groups are not available. Hyperkalemia, defined as serum potassium >6.0 mmol/l, did not occur in any patients in the study by White et al.25 and was reported in 1.8 % and 0.3 % of patients in the azilsartan medoxomil 40 mg and 80 mg arms, respectively, by Sica et al.,21 versus 0.6 % in the valsartan 320 mg arm.

Other laboratory findings, such as increases in serum creatinine or liver enzymes, occurred infrequently and at similar rates between all groups compared across studies. Of the 3,550 patients included in the three published studies, two deaths occurred in the azilsartan medoxomil group18,21 and one occurred in the valsartan 320 mg group.21 Whether these deaths could be attributed to the study drug was not made clear.
The safety and tolerability data for azilsartan medoxomil combined with other antihypertensive agents are only available in the studies published in abstract form, thus providing relatively little information. The incidences of hypotension and elevations in serum creatinine from baseline were higher with azilsartan medoxomil plus chlorthalidone versus chlorthalidone alone, while hypokalemia occurred less frequently with combination use.23 The rate of peripheral edema was lower when azilsartan medoxomil was combined with amlodipine (2.1 %) versus amlodipine alone (4.9 %).24 A more detailed review of the safety and tolerability of combination therapies with azilsartan medoxomil will have to wait until the full publications of these studies are made available.


The exact role azilsartan medoxomil will have in clinical practice is currently unclear. Although clinical studies have shown that azilsartan medoxomil 80 mg (recommended starting dose) will lower BP to a greater extent than other currently available ARBs, information demonstrating reduction of clinical outcomes with azilsartan medoxomil is lacking and that is unlikely to change in the near future. Alternatively, a number of other ARBs have robust clinical data showing outcome reduction. As an example, the Candesartan in heart failure assessment of reduction in mortality and morbidity (CHARM) studies demonstrated significant reductions in cardiovascular deaths (p=0.012) and heart failure hospitalizations (p<0.0001) with candesartan versus placebo in patients receiving concomitant diuretic and beta-blocker therapy.38 Two large clinical trials have shown beneficial effects of telmisartan on major outcomes compared with placebo39 and similar effects to the ACEI ramipril.40 The FDA recently added wording to the package inserts of select ARBs, including azilsartan medoxomil, discussing reductions in major outcomes, such as fatal and non-fatal myocardial infarction and stroke. Given this labeling change and the well-recognized effects of BP lowering in certain disease states, it is unclear whether large outcome-based trials of azilsartan medoxomil will be conducted or required.

Azilsartan medoxomil is approved by the FDA to lower BP in patients with hypertension and should be given as 80 mg orally once daily, without regard to food, with the lower dose (40 mg once daily) given to patients treated with high-dose diuretics. No dosage adjustments are recommended for special populations, including elderly patients, those with renal impairment (mild to moderate and end-stage), and mild to moderate hepatic impairment.11 Data from studies available only in abstract form suggest that azilsartan medoxomil can be combined with either the CCBs (amlodipine) or thiazide diuretics (chlorthalidone) in patients who require additional BP lowering to get to their goal.20,22–24 The manufacturer is also anticipated to market a fixed-dose combination azilsartan–chlorthalidone due to its large BP-lowering effects, potentially obviating the need for other agents. This could provide both BP benefit and a compliance benefit for patients with stage II hypertension. Similarly to other ARBs, azilsartan medoxomil use should be avoided in female patients who become pregnant, in order to avoid fetal injury and death.41 It should also be used with caution, and held or dose-reduced, in patients experiencing symptomatic hypotension in the presence of appreciable volume or salt depletion. Similar precautions are given in the manufacturer’s prescribing information related to patients with impaired renal function and heart failure, renal artery stenosis, or volume depletion, due to a risk of acute worsening when azilsartan medoxomil is initiated.11


Azilsartan medoxomil is a highly specific, potent ARB that is currently FDA-approved to lower BP in patients with hypertension. Its pharmacologic profile suggests that it may offer advantages over other currently available ARBs. Direct comparative studies have demonstrated the ability of azilsartan medoxomil to reduce BP to a greater extent than other currently available ARBs, including valsartan and olmesartan. The observed benefits on either 24-hour mean SBP or trough sitting clinic SBP with azilsartan medoxomil versus other ARBs may be related to its pharmacologic profile, including slowed AT1 receptor dissociation rates and improved receptor specificity. Data detailing whether these properties lead to reductions in clinical outcomes are not currently available. It is available as a 40 mg and 80 mg tablet and can be given once daily without regard to meals. The FDA recommends 80 mg as the initial dose of azilsartan medoxomil, with 40 mg being reserved for those on high-dose diuretics. The lack of clinically significant drug interactions is an added benefit to its use. The continued study of azilsartan medoxomil in different patient populations (e.g., diabetes mellitus, chronic kidney disease) could aid in further identifying where it fits in contemporary medical management.


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