Olmesartan medoxomil: recent clinical and experimental acquisitions

Drug Evaluation

10.1517/17425250903203811 © 2009 Informa UK Ltd ISSN 1742-5255 1149All rights reserved: reproduction in whole or in part not permitted

Olmesartanmedoxomil:recentclinicalandexperimentalacquisitionsMaurizio Destro†, Paola Preti, Antonio D’Ospina, Ngu Njwe Christian Achiri, Alessandra Rossi Ricci & Francesca Cagnoni†AO della Provincia di Pavia, Medical Ward, Via Achilli 3, Stradella (PV), 27049, Italy

Angiotensin II is a vasoactive hormone of the renin-angiotensin system and plays an important role in the pathophysiology of several organ damages. Angiotensin II receptor blockers have been shown to be effective in treat-ing both hypertension and connected organ damages. It is well known that although the angiotensin II receptor blockers have structural and pharma-cokinetic differences, few pharmacological differences separate them. One of these is the degree of binding to the angiotensin II receptor type 1 com-pared with the angiotensin II receptor type 2; olmesartan medoxomil exhib-its more than a 12,500-fold greater affinity for the angiotensin II receptor type 1 receptor than for the angiotensin II receptor type 2, making it theo-retically the second most potent agent. However, olmesartan’s excellent receptor interaction is based on the combination of several specific pharma-cokinetic factors. Potential advantages of this drug include once-daily dos-ing, a very low incidence of significant adverse reactions and/or events and a well-tolerated side effect profile. Nowadays, we have a lot of information about the pharmacology, antihypertensive efficacy and safety of olmesartan medoxomil, to further extend many clinical studies are still continuing to evaluate the potential benefits of high dosages and/or combination of this molecule.

Keywords: angiotensin II, ARBs, hypertension, olmesartan, therapeutic effects

Expert Opin. Drug Metab. Toxicol. (2009) 5(9):1149-1157

1. Introduction

It is well established that chronic, poorly controlled hypertension is an independent risk factor for cardiovascular morbidity and mortality, stroke and renal failure.

The renin-angiotensin-aldosterone system (RAAS) is an important mediator in the pathophysiology of hypertension, with excessive activity in the RAAS playing a key role in target end-organ damage, such as coronary artery disease and myocardial infarction, congestive heart failure and renal disease.

Angiotensin II (A II) is the primary vasoactive hormone of the renin-angiotensin system (RAS) and plays an important role in the pathophysiology of several chronic disease states. It is found in a variety of tissues and formed primarily from the conversion of angiotensin I to A II. A II produces its ‘negative’ biologi-cal effects by binding the A II–AT1 (angiotensin II receptor type 1); meanwhile, when it binds the A II receptor type 2 receptor subtype it produces mostly ‘posi-tive’ effects both in the control of blood pressure (BP) and in the reduction and prevention of organ damage (Figure 1). The AT1 receptor is found mostly in brain, renal, myocardial, vascular and adrenal tissue. A II–A II receptor type 2 receptors are mostly located in the adrenal medullary tissue, uterus and brain.

The vasoactive action and potentially harmful pressor effect of A II has been fully recognized, and A II blockade, first by using ACE inhibitors and afterwards

1. Introduction

2. Overview of the market

3. Pharmacodynamics

4. Pharmacokinetic and chemistry

5. Clinical efficacy

6. Safety and tolerability

7. Expert opinion

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Olmesartanmedoxomil

1150 ExpertOpin.DrugMetab.Toxicol.(2009) 5(9)

↓ Vasoconstriction↓ Prohypertrophic

Blocked AT1R

Sartan

A II

A I

ACE 2

ACE 2

A (1 – 9)

A (1 – 7)

↑ Vasodilation↑ Antihypertrophic

Unopposed AT2R(not desensitized)

A (1 – 7)receptor ?

Figure1.RASandpossiblemechanismscontributingtothetherapeuticseffectsofAT1Rantagonists.A I: Angiotensin I; A II: Angiotensin II; AT1R: Angiotensin II receptor type 1; AT2R: Angiotensin II receptor type 2; RAS: Renin-angiotensin system.

with A II–AT1 antagonists, has been a new, but we could say ‘revolutionary’, way, to consider the management of clinical and subclinical hypertension. Orally active olmesar-tan medoxomil (Box 1) is among the latest A II antagonists to be developed.

2. Overviewofthemarket

Notwithstanding the wide therapeutic possibilities we had before the discovery of drug inhibiting the RAS, the treatment

of hypertension and subsequent organ damage was still poor, being hypertension controlled only in a minimal part of the patients.

At first, there have been the ACE-inhibitors, the drug used in the attempt to reduce the harmful effects of A II, followed by the A II receptor blockers (ARBs). Nowadays, we have seven ARBs used all over the world. Of these, losartan was the first to be marketed, followed by valsartan, irbesartan, candesartan, telmisartan, eprosartan and, the newest member of the class, olmesartan medoxomil.

Box1.Drugsummary.

Drug name Olmesartan medoxomil

Phase Launched

Indication Hypertension

Pharmacology description Angiotensin II type 1 antagonistAngiotensin II antagonist

Route of administration Alimentary, by mouth

Chemical structure

N

NN

N

N

N

O

OO

O

O

O

Pivotal trial(s) Placebo-controlled, 20-country European study (ROADMAP) in 4446 hypertensive type 2 diabetic patientsORIENT trial

Pharmaprojects, copyright to Citeline Drug Intelligence (an Informa business).

Readers are referred to Informa-Pipeline (http://informa-pipeline.citeline.com) and Citeline (http://informa.citeline.com).

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Destro,Preti,D’Ospina,ChristianAchiri,Ricci&Cagnoni

ExpertOpin.DrugMetab.Toxicol.(2009) 5(9) 1151

3. Pharmacodynamics

Olmesartan medoxomil is a nonpeptide A II receptor antago-nist. Peak plasma concentrations of olmesartan occur 1 – 3 h after administration and then decrease with an elimination half-life of ∼ 10 – 15 h. Olmesartan takes ∼ 72 – 120 h to reach the steady-state, and there is no significant accumulation in plasma with once-daily dosing.

4. Pharmacokineticandchemistry

Olmesartan medoxomil is a prodrug that is rapidly and completely de-esterified to the active metabolite olmesartan (RNH-6270) during absorption from the gastrointestinal tract (Figure 2). The medoxomil ester of olmesartan was developed in preference to the active compound olmesar-tan, because the oral bioavailability of the latter is low (4.5%) and is increased (to 28.6%) [1]. Olmesartan is the only metabolite of olmesartan medoxomil, and is excreted in the feces (∼ 60%) and the urine. Olmesartan is not metabolized by cytochrome P-450 enzymes and is unlikely to interact with drugs that inhibit, induce or are metabo-lized by cytochrome P-450 enzymes [2]. Interactions between olmesartan medoxomil and co-administered warfarin, digoxin or the antacid aluminium magnesium hydroxide are not clinically significant. The bioavailability of olmesar-tan does not seem to be affected by food [3,4]. The drug is highly bound to plasma proteins (99%) and does not affect erythrocytes. Olmesartan takes ∼ 3 – 5 days to reach a steady-state, and has not shown accumulation in plasma with once-daily dosing. Concerning particular potential risk-groups, four studies evaluated the influence of hyper-tensive patients’ risk status on pharmacokinetic parameters of olmesartan medoxomil [5]. Basing the analysis on the same criteria, the parameters in elderly, very elderly, renally impaired and hepatically impaired patients were compared with appropriate controls as follows:

elderly patients (65 – 75 years) (n • = 12) versus 12 younger patients (18 – 45 years), 80 mg/day for 10 days

N

N

HO

O

O

O

O

O

N

NH

N

N

Figure2.Olmesartanmedoxomil,chemicalstructure.

very elderly patients (• ≥ 75 years old (y.o.)) (n = 17) versus 16 younger patients (18 – 45 y.o.), 10 mg/day for 14 daysrenally impaired patients (65 – 75 y.o.) (eight mild, nine mod-•erate, nine severe) versus eight healthy controls (41 – 47 y.o.), 10 mg/day for 7 days and(in the US only) hepatically impaired patients (26 – 72 •y.o.) (four mild, eight moderate) versus 12 healthy controls (45 – 59 y.o.), single oral dose of 10 mg olmesartan medox-omil and after 10 days washout 8 mg olmesartan medoxomil intravenously over 5 min [5].

As shown in Table 1, Cmax and AUC at steady-state were greater than controls for all patient groups except for those with mild hepatic impairment. In patients with severe renal impairment, in whom exposure is increased 2.79-fold com-pared with healthy subjects, caution is required when start-ing therapy, and the daily dose of olmesartan medoxomil should not exceed 20 mg.

5. Clinicalefficacy

A clinical programme based on multi-center international studies of Phase II, III and IV, confirmed the BP-lowering activity and the reduction in organ damage rate of olmesartan medoxomil.

We will just consider the results coming from some of the most recent studies to assess and prove the efficacy of olm-esartan, with particular regard to the prevention of the organ damage.

Assessing the ability of ARBs to block the AT1 receptor is quite difficult because it is affected by various factors includ-ing elimination half-life, bioavailability and differences in interactions with the AT1 receptors. For instance, elimina-tion half-life, a pharmacokinetic measure, ranges from 2 h in the case of losartan to ∼ 24 h in the case of telmisartan [6]. However, plasma half-life is just a part of the mechanisms involved in the blockage of the RAS; meanwhile, the length of time that the agents remain bound to the receptors also affects potency. As a matter of fact, a recent study of the interactions between olmesartan medoxomil and telmisartan and the AT1 receptors showed that olmesartan has a higher affinity for the receptor and a slower dissociation rate than telmisartan [7].

In addition, plasma renin activity, which increases as a compensatory feedback response to AT1 blockade, can also provide an insight into RAAS inhibition. Studies in normo-tensive subjects have shown that olmesartan medoxomil 40 mg produces a larger increase in mean plasma renin activity over 24 h compared with other sartans at their highest recommended doses [8].

The efficacy of olmesartan medoxomil treatment in reduc-ing pulse pressure, which is considered to be a risk factor for cardiovascular disease in people aged > 50 years, has been evaluated in a meta-analysis of seven randomized, double-blind trials [9]. In these studies, three cohorts of patients were examined (total, < than 65 y.o., > than 65 y.o.; all of them

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with a wide baseline pulse pressure, defined as > 55 mmHg); all of them showed an improvement of their pulse pressure under treatment with olmesartan medoxomil.

In their study Fernandes-Santos et al. [10] evaluated the action of long-term treatment with olmesartan versus hydral-azine on cardiac and aortic adverse remodeling and its rela-tionship on BP and tensile forces acting on the aortic wall. Five-month-old male rats were divided in: WKY (normoten-sive Wistar-Kyoto rat) group (n = 6), SHR (spontaneously hypertensive rat) group (n = 6), and SHRs treated with hydralazine 30 mg/(kg day) (SHR-H, n = 8) or olmesartan 10 mg/(kg day) (SHR-O, n = 8). Medications were admin-istered for 16 weeks. The SHR group showed hypertension (189 ± 4 mmHg), cardiomyocyte hypertrophy (+107%), interstitial fibrosis (5.7 versus 1.9% in WKY) and reduced intramyocardial vascularization (9.1 versus 22.8% in WKY). In aorta, the SHRs showed outward hypertrophic remodel-ing, increased elastic fibers content (+36%), and increased circumferential wall tension (2.79 × 104 dyn/cm) and tensile stress (261.4 × 104 dyn/cm2). Hydralazine and olmesartan decreased BP (-45% approximately) and likewise circumfer-ential wall tension and tensile stress (-45% and -35% approximately). Both medications prevented left ventricle remodeling, but olmesartan reduced cardiomyocyte hyper-trophy better than hydralazine. Hydralazine did not alter media hypertrophy, but the group on this treatment showed an enlargement of the lumen diameter and an increased number of elastic fibers.

The results coming from the olmesartan group of treatment suggest that there is a direct action of this molecule to block

growth stimulation by A II in cardiomyocytes and vascular smooth muscle cells, and to better prevent cardiovascular remodeling due to arterial hypertension. Because the comor-bidity of type 2 diabetes is one of the most pernicious case in the hypertensive patients, it is of great interest the result shown by the study of Fliser et al. by which, starting from the postulate that increased (intra)renal activity of the RAS may cause a persistent increase in renovascular resistance and intraglomerular pressure in patients with diabetes, thus, contributing to the development of diabetic renal damage, it has been confirmed that chronic A II–AT1 receptor block-ade decreases (intra)renal vascular resistance and increases renal perfusion despite significant BP reduction [11]. In addi-tion, it significantly reduces oxidative stress. To determine the relative effects of suppressing the RAS with the angio-tensin receptor antagonist olmesartan medoxomil versus suppressing sympathetic drive with the β-adrenoceptor antagonist atenolol on remodeling of the subcutaneous small resistance vessel, the VIOS study (Vascular Improvement with Olmesartan medoxomil Study) was performed [12]. In fact, remodeling of small resistance vessels may be the earli-est pathologic finding associated with hypertension and it may predate the onset of clinically apparent hypertension. The arteriolar dimensions (W/L ratios: wall thickness/lumen diameter) in the olmesartan medoxomil and atenolol-based treatment groups were similar before drug treat-ment (14.9 and 16%, respectively) whereas arteries from the normotensive subjects had significantly smaller W/L ratios (11%). At the end of the study, the W/L ratio in the olmesartan medoxomil-based treatment group was significantly

Table1.Pharmacokineticsofolmesartanmedoxomilinelderlyhypertensive,veryelderlyhypertensive,renallyimpairedandhepaticallyimpairedpatients.

Population n Definition Percentageincreaseversuscontrols

Cssmax AUCss

Elderly hypertensive 12 ≥ 65 ≤ 75 years 9 33‡

Very elderly hypertensive 17 ≥ 75 years 14* 44§

Renallyimpaired

Mild 8 CLCR 40 – 50 ml/min 27¶ 62¶

Moderate 9 CLCR 20 – 39 ml/min 39¶ 82¶

Severe 9 CLCR 40 – 50 ml/min 56¶ 179¶

Hepaticallyimpaired

Mild 4 Child-Pugh score ≤ 6 0# 30**

Moderate 8 Child-Pugh score 7 – 9 6# 48*,**

*p < 0.05.‡p < 0.01.§p < 0.005.¶Not statistically analyzed.#Cmax after single dose.

**AUC after single dose.

Data from [5].

AUCSS: AUC at steady-state; CSSmax: Cmax at steady-state; CLCR: Creatinine clearance.

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reduced (from 14.9% to a mean of 11.1%, p < 0.01). No significant change was observed in arteries of atenolol-treated patients (from 16.0 to 15.5%; p = NS). The difference between olmesartan medoxomil-treated and atenolol- treated patients at 1 year was significant (11.1 versus 15.5%, p < 0.001). BP reductions from baseline occurred in 12 weeks for both treatments and were statistically signifi-cant (p < 0.05); BP reductions were similar between the two treatments for the remainder of the study. The Multicentre Olmesartan atherosclerosis Regression Evaluation (MORE) study was a double-blind trial in patients with hypertension at increased cardiovascular risk with carotid wall thickening and a defined atherosclerotic plaque that used non-invasive 2 and 3D ultrasound (US), to compare the effects of a 2-year treatment based on either olmesartan medoxomil or atenolol on common carotid intima-media thickness (IMT) and plaque volume [13]. The primary efficacy outcome was the change from baseline (δ) in common carotid-IMT assessed by 2D US. Secondary outcomes included δ plaque volume assessed by 3D US and BP. Carotid IMT and BP decreased similarly with olmesartan and atenolol, but only olmesartan reduced the volume of larger atherosclerotic plaques. In their study, Fukuda et al. have shown that as renal function deteriorated, night time fall in both BP and urinary sodium excretion were diminished [14]. They also reported that sodium intake restriction and diuretics both normalized circadian BP rhythm from non-dipper to dipper patterns. They investigated whether an ARB, olmesartan, could restore night time BP fall. Twenty patients with chronic kidney disease were studied. At baseline and 8 weeks after the treatment with olmesartan medoxomil (10 – 40 mg/day), 24-h BP monitoring and urinary sampling for both daytime and night time were repeated to compare the circa-dian rhythms of BP and urinary sodium excretion. The results showed that 24-h mean arterial pressure was lowered by olmesartan, while urinary sodium excretion remained unchanged. On the other hand, daytime urinary sodium excretion was increased, while night time urinary sodium excretion tended to be reduced. These findings demonstrated that olmesartan could restore night time BP fall, as seen with diuretics and sodium restriction, possibly by enhancing daytime sodium excretion. Because nocturnal BP is a strong predictor of cardiovascular events, olmesartan could relieve cardiorenal load through normalization of circadian BP rhythm besides having a powerful ability to block the RAS. To compare the antihypertensive efficacy of the starting dose of olmesartan medoxomil with that of the calcium channel blocker (CCB) amlodipine besylate (amlodipine) in subjects with mild-to-moderate hypertension, Chrysant et al. con-ducted an interesting research [15]. Following a 4-week, single-blind, placebo run-in period, 440 subjects aged ≥ 18 years were randomized to the starting dose of olmesartan medoxomil (20 mg/day), amlodipine (5 mg/day) or placebo for 8 weeks. Subjects were evaluated by 24-h ambulatory BP monitoring (ABPM) and by seated cuff BP measurements at trough.

Olmesartan medoxomil and amlodipine produced signifi-cantly greater reductions in ambulatory and seated DBP (diastolic blood pressure) and SBP (systolic blood pressure) compared with placebo. Mean reductions in ambulatory and seated BP were similar between the two active agents; how-ever, in the olmesartan medoxomil group, significantly more patients achieved the SBP goal of < 130 mmHg and the DBP goal of < 85 mmHg. Both drugs were well tolerated at the recommended starting dose. Because previous experi-mental studies revealed pro-inflammatory properties of A II, Fliser et al. evaluated anti-inflammatory effects of the A II subtype 1 receptor antagonist olmesartan medoxomil alone and in co-therapy with the HMG-CoA reductase inhibitor pravastatin in patients with essential hypertension and micro-inflammation [16]. A panel of vascular inflammation markers were measured, including high-sensitivity C-reactive protein and lipid levels during 12 weeks of therapy with olmesartan or placebo in EUTOPIA, a prospective double-blind multi-center study. Pravastatin was added to the double-blind therapy at week 6 in both treatment arms. BP control was achieved with addition of hydrochlorothiazide. Olme-sartan treatment had already significantly reduced serum levels of high-sensitivity C-reactive protein (-15.1%; p < 0.05), high-sensitivity TNF-α (-8.9%; p < 0.02), IL-6 (-14.0%; p < 0.05) and monocyte chemotactic protein-1 (-6.5%; p < 0.01) after 6 weeks of therapy, whereas placebo treatment had no major effect on inflammation markers. After 12 weeks of therapy, high-sensitivity C-reactive protein (-21.1%; p < 0.02), high-sensitivity TNF-α (-13.6%; p < 0.01) and IL-6 (-18.0%; p < 0.01) decreased further with olmesartan and pravastatin co-therapy, but treatment with pravastatin alone (i.e., co-therapy with placebo) did not significantly alter inflammation markers. In contrast, addition of pravastatin led to a significant (p < 0.001) reduction in low-density lipoprotein cholesterol serum con-centrations in the olmesartan and placebo treatment groups (-15.1% and -12.1%, respectively). In conclusion, A II recep-tor blockade significantly reduces vascular micro-inflammation in patients with essential hypertension by as early as week 6 of therapy. This anti-inflammatory action of A II receptor antagonists may contribute to their beneficial cardiovascular effects. Finally, the results coming from the OlmeSartan and Calcium Antagonists Randomized (OSCAR) study will be very interesting [17]. In this study, Ogawa et al. compare the incidence of cardiovascular events between high-dose ARB monotherapy and combination therapy of ARB with CCB in Japanese elderly high-risk hypertensive patients. Higher doses of ARBs are expected to exert more protective effects against cardiovascular diseases. However, the significance of treatment of hypertension with high-dose ARB remains to be defined. The OSCAR study was designed to determine whether high-dose ARB monotherapy is superior to the combination therapy of ARB plus CCB in the prevention of cardiovascular morbidity/mortality in Japanese elderly high-risk hyperten-sive patients. OSCAR study is a multi-center, active-controlled, two-arm parallel group comparison, using the prospective

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Olmesartanmedoxomil


randomized open-blinded end point method. In the ‘Step 1’ period, elderly hypertensive patients with diabetes or cardio-vascular disease received monotherapy with ARB olmesartan medoxomil at a dose of 20 mg day(-1). If the target BP control (< 140/90 mmHg) was not achieved by ARB mono-therapy, the patients were randomized to receive either the increased dose of olmesartan at 40 mg day(-1) (high-dose ARB monotherapy) or the addition of a CCB (amlodipine or azelnidipine) to 20 mg day(-1) olmesartan (ARB plus CCB combination) in the ‘Step 2’ period. The follow-up duration will be 3 years. The primary end points will be the compos-ite of fatal and non-fatal cardiovascular events, and death from any cause. Recruitment for the OSCAR study (around 1200 patients) was completed by the end of May 2007.

In conclusion, studies such as LIFE [18], MARVAL [19], RENAAL [20], IDNT [21], IRMA 2 [22] and MORE [13] have shown that ARBs have the ability to retard or regress cardio-renal organ damage.

New studies such as the ROADMAP (Randomised Olme-sartan And Diabetes MicroAlbuminuria Prevention) Study [23], which is inquiring whether the onset of microalbuminuria can be prevented or delayed in type 2 diabetics with nor-moalbuminuria, will help to establish whether olmesartan treatment gives a benefit at all stages, even very early in the cardiorenal continuum.

6. Safetyandtolerability

The safety and tolerability of olmesartan medoxomil have been evaluated in several clinical trials.

Overall, patients tolerated the drug well, and the incidence of adverse events was similar to that for placebo (42.2 and 42.7%, respectively) [24-27]. The most commonly reported side effects were headache, upper respiratory tract infections, dizziness and influenza-like symptoms.

Considering drugs acting on the RAS, angioedema and a dry, persistent cough are two important class-related adverse events that may limit the use of ACE inhibitors. Levels of circulating ACE and, subsequently, substance P and brady-kinin are unaffected by the ARBs, thereby, reducing the potential for ACE inhibitor-induced cough or angioedema.

In clinical trials, the incidence of cough was similar for olmesartan medoxomil (0.9%) and placebo (0.7%) [28]. This rate is much lower than that reported in users of the ACE inhibitors; in these patients, cough has been noted to occur in up to 39% of cases [29]. Angioedema has rarely occurred with ARB therapy, although facial edema has been reported in five patients receiving olmesartan medoxomil [28]. During preg-nancy, olmesartan medoxomil should not be used because of its potential to cause fetal and neonatal injury; however, it is considered a pregnancy category D drug during the last

180

160

150

140

130

120

1108 10 12 14 16 18 20

Olmesartan

Hours

SB

P (

mm

Hg

)

22 0 2 4 6 8

120

110

100

90

80

70

608 10 12 14 16 18 20

Hours

DB

P (

mm

Hg

)

22 0 2 4 6 8

Baseline2 weeks8 weeks

Figure3.24hSBPandDBPatbaselineandafter2and8weeksoftreatmentwitholmesartan.Data from [33].

BP: Blood pressure; DBP: Diastolic BP; SBP: Systolic BP.

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6 months of therapy and should not be used unless the bene-fits outweigh the potential risks. Once a patient becomes pregnant, in our opinion, efforts should be made to discon-tinue therapy [28]. To our knowledge, no studies evaluating the excretion of olmesartan in breast milk have been conducted, but is possible that olmesartan, as much as the other ARBs, might be excreted in human breast milk, and a decision to discontinue breast-feeding or the drug itself should be made.

7. Expertopinion

Hypertension is associated with high morbidity and mortal-ity worldwide, and is the third leading cause of death in the world [30]; as such, the condition places a considerable bur-den on healthcare systems worldwide [31]. The association between risk factors such as hypertension and diabetes and the risk of cardiovascular and/or renal damage forms a pro-gression known as the cardio-renal continuum [32]. The ben-efits of ARBs are seen at different stages of the cardio-renal continuum and because they have an important role to play in hypertension management, it raises the question: are all the ARBs the same? One way to address this is to use ABPM to look at 24-h BP control, an important factor for ARBs which are dosed once daily.

Extensive clinical evidence from several large well-designed trials and the clinical practice settings have confirmed the anti-hypertensive efficacy and good tolerability profile of oral olm-esartan medoxomil in patients with hypertension including elderly patients with isolated systolic hypertension.

Most importantly, SBP and DBP-control is sustained throughout the 24 h dosage interval, including the last 4 h of the examined period, as shown in a study [33] in which the examined patients were allocated to a treatment of 20 mg of olmesartan for a period of 8 weeks; ABPM were recorded at baseline, after 2 and 8 weeks of treatment (Figure 3).

This result should in our opinion be considered of great relevance because it is well known that BP values assessed using ABPM also provide a good prediction of cardiovascular mortality and are not affected by issues such as white-coat

effect, poor adherence or technique, which are associated with BP measurements made in the office or clinic setting, and with self or home measurement BP [34-36].

Although clinical data on the organ protective effects of olmesartan medoxomil are still limited, preliminary clinical evidences (including those from the VIOS [37,38], MORE [13] and EUTOPIA [16]) suggest that it prevents or reverses cardiac hypertrophy, cardiovascular remodeling, cerebral ischemia, renal injury, hepatic fibrosis, insulin resistance, endothelial dysfunction and the progression of atherosclerosis.

Because olmesartan has a dual method of elimination, with about 60% eliminated by the liver and the remaining by the kidney, in situations of impaired renal or hepatic functions, the alternative excretion pathway can compensate for the compromised one.

Olmesartan medoxomil has a good tolerability profile in patients with hypertension or isolated systolic hypertension. Pooled data and meta-analysis of placebo-controlled clinical trials (n > 3000 patients) indicated that the nature and inci-dence of treatment-emergent adverse events with olmesartan medoxomil monotherapy was generally similar to that seen with placebo [39-45]. In fact, the most common adverse events that occur in > 1% of patients and with the higher incidence in the olmesartan monotherapy than in placebo groups were dizziness, headache, upper respiratory tract infections and influenza-like symptoms, and resulted in < 2.4% of patients discontinuing treatment in clinical controlled studies.

Although the receptor binding interactions resulting from the unique structural features of olmesartan medoxomil are yet to be fully characterized, the observation made at the receptor, tissue, animal and clinical levels are consistent. This information provides a framework for comparing angiotensin receptor antagonists and may help explain the clinical differences seen in this class.

Declarationofinterest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

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AffiliationMaurizio Destro†1, Paola Preti2, Antonio D’Ospina1, Ngu Njwe Christian Achiri1, Alessandra Rossi Ricci1 & Francesca Cagnoni1†Author for correspondence1AO della Provincia di Pavia, Medical Ward, Via Achilli 3, Stradella (PV), 27049, Italy Tel: +39 335269517; Fax: +39 0385582182;E-mail: [email protected]à degli Studi di Pavia, Internal Medicine, P.le Golgi, Pavia, 27100, Italy

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Documents

Olmesartan medoxomil: recent clinical and experimental acquisitions