Journal of Human (2007) 21, 699–708 & 2007 Nature Publishing Group All rights reserved 0950-9240/07 $30.00 www.nature.com/jhh REVIEW Treatment of hypertension with medoxomil, alone and in combination with a diuretic: an update

SG Chrysant1, B Dimas2 and M Shiraz1 1Oklahoma Cardiovascular and Hypertension Center, University of Oklahoma School of Medicine, Oklahoma City, OK, USA and 2Division of Cardiology, Southwestern University School of Medicine, Dallas, TX, USA

Olmesartan medoxomil is an II (Ang II) lowering effects in hypertensive patients. A medline receptor blocker (ARB) that has been approved by search for the preparation of this manuscript was the US Food and Drug Administration (FDA) for the conducted and revealed 128 references, from 2000 to treatment of hypertension. It is a prodrug that is hydrol- 2007. Of these, only 16 well-designed prospective clinical ysed in the gut into its active metabolite, olmesartan trials were selected. The remaining were either animal (RNH-6270). Olmesartan is highly selective for the Ang II studies, reviews or studies in progress. In well-designed type 1 receptor (AT1) to which it binds completely and clinical trials, olmesartan medoxomil has demonstrated insurmountably and has very little affinity for the other similar antihypertensive actions to the other antihyper- receptor subtypes AT2 and AT4. After oral administra- tensive drugs, as well as other members of its class tion, in animals and humans, it achieves a maximal given the highest recommended doses. In addition, the blood drug concentration within a maximal time of BP lowering effect of olmesartan, like the other mem- approximately 2 h. It is then slowly eliminated in the bers of its class, is greatly enhanced in combination urine and faeces. His half-life is approximately 13 h, with a diuretic. Its safety profile is similar to the other which makes it suitable for once-daily administration. ARBs and no different than placebo. Olmesartan medoxomil given orally in single daily doses of Journal of Human Hypertension (2007) 21, 699–708; 20–40 mg has demonstrated significant blood pressure (BP) doi:10.1038/sj.jhh.1002241; published online 7 June 2007

Keywords: olmesartan medoxomil; ARB; treatment; diuretic; combination

Introduction Pharmacokinetic and pharmacodynamic profile Olmesartan medoxomil is the 7th latest angiotensin II (Ang II) receptor blocker ARB approved by the Pharmacokinetic profile Food and Drug Administration (FDA) for the Olmesartan medoxomil is a prodrug that is rapidly treatment of hypertension. In several randomised absorbed and completely hydrolysed in the gastro- placebo-controlled studies, olmesartan medoxomil intestinal tract into its active metabolite olmesartan has demonstrated significant antihypertensive ef- (RNH6270). The chemical structures of both drugs fects compared to placebo.1,2 In other comparative are depicted in Figure 1. Olmesartan has 100 000 studies, olmesartan medoxomil showed similar times greater affinity for the Ang II type 1 receptor blood pressure (BP) lowering efficacy with angio- AT1 compared to the AT2 receptor, to which it binds tensin converting enzyme (ACE) inhibitors, calcium competitively and insurmountably.15,16 In in vitro channel blockers, b-blockers and diuretics,3–9 but studies, the concentration of olmesartan medoxomil superior antihypertensive potency against other required to produce a 50% inhibition of Ang II 10–13 7 ARBs given in equivalent starting doses. In binding to AT1 receptor (IC50) was 8.0 0.8 nmol/l, other studies, olmesartan medoxomil given in the whereas the amount of the drug needed to produce highest recommended daily doses, its antihyperten- the same IC50 binding of Ang II to the AT2 receptor sive effect was similar to other ARBs.14 In addition, was greater than 100 000 nmol/l. After oral adminis- olmesartan medoxomil, like the other members of its tration, olmesartan medoxomil given in single class, has demonstrated an excellent safety profile.3 doses of 10–160 mg in healthy volunteers, reaches a maximal concentration (Cmax) within a maximal 17,18 time of 1.4–2.8 h. Both the Cmax and the mean Correspondence: Dr SG Chrysant, 5850 W. Wilshire Blvd., area under the plasma concentration curve (AUC) Oklahoma City, OK 73132-4904, USA. E-mail: [email protected] showed similar linear relationships to the doses Received 20 January 2007; revised 4 May 2007; accepted 5 May given and they were not significantly affected after 2007; published online 7 June 2007 multiple dose administration.16 Also, a steady-state Treatment of hypertension with olmesartan medoxomil SG Chrysant et al 700 of plasma concentration of the drug is usually urinary protein excretion of diabetic Zucker rats, achieved within 3 days of drug administration in and prevented atherosclerotic plaque formation in 17 both young and elderly subjects. However, the Cmax the aorta of high-cholesterol fed rabbits and cyano- and AUC were 44% higher and the elimination half- molgus monkeys, compared to controls.15,21–23 In life longer (16.5 vs 12.3 h) in the older (475 years) addition, in human volunteers, administration of vs the younger (446 years of age) subjects.17,19 In olmesartan medoxomil 10–40 mg/day blocked the addition the Cmax was affected by renal and liver hypertensive response to exogenously administered function, being higher (82 vs 39%) in patients with angiotensin I by greater than 75% for 24 h, compared renal failure vs controls and (48 vs 30%) in patients to controls.5 with moderately severe vs mild liver failure.19 Olmesartan medoxomil has a 26% after oral administration and is mainly eliminated Mechanism of action through the gastrointestinal tract and the kidney Ang II exerts its main haemodynamic and structural (50–65 and 10–16%) respectively.17,20 The terminal effects through stimulation of its AT1 receptor. On half-life of olmesartan is approximately 13 h, which the contrary, olmesartan medoxomil, like the other makes it suitable for once daily administration. The ARBs, interferes with this action of Ang II by pharmacokinetic profiles of olmesartan medoxomil selectively blocking the AT1 receptor for which it and the other members of its class are listed in has a very high affinity and to which it binds Table 1. selectively and insurmountably. In this respect, the action of the ARBs is indifferent to which pathway the Ang II was generated and they differ from the Pharmacodynamic profile ACE inhibitors, which only interfere with the In vitro studies have shown that the active metabo- generation of Ang II through classical ACE pathway. lite of olmesartan medoxomil (RNH 6270) is more Recent clinical and experimental studies have potent than the active metabolite of (EXP shown that up to 40% of Ang II in the blood vessels, 3174), since they blocked the Ang II-induced heart and kidneys is generated through the alternate contractions of guinea-pig aorta by 90 and 35%, pathway via other enzymes and especially Chy- respectively.21 Also, the duration of the inhibitory mase.24–26 Olmesartan and the other ARBs in effect of RNH 6270 was longer than that of EXP 3174 difference to ACE inhibitors, exert a dual haemody- (90 vs 60 min, respectively). namic effect by selectively blocking the haemody- In vivo studies in rats, rabbits and monkeys have namic and remodelling actions of Ang II through the shown that olmesartan medoxomil possesses anti- AT1 receptor27 and in addition allowing the Ang II hypertensive, antiproteinuric and antiatherogenic to bind to the unoccupied AT2 receptors. These properties, since it blocked the pressor response receptors have effects opposite to those of the AT1 from the administration of Ang II, reduced the receptors (Table 2). The clinical effects of olmesartan medoxomil in patients with different stages of hypertension have been tested in several multi- center, randomised, double-blind studies, against placebo or active drugs. Most of the studies used patients with a mean sitting diastolic blood pressure (MSDBP) of 4100 o115 mm Hg.

Placebo comparative studies The studies in this group compared the active drug Figure 1 This figure depicts the chemical structure of olmesartan olmesartan medoxomil in doses ranging from 2.5– medoxomil and its metabolite olmesartan (RNH 6270). 80 mg/day against placebo. The duration of most of

Table 1 Comparative pharmacokinetic profile of angiotensin-II receptor antagonists

Telmisartan Losartan Eprosartan Olmesartan

Usual dosage range (mg) 40–80 25–100 75–300 8–32 400–800 80–320 20–40 Dosing frequency Once daily Once-/twice-daily Once-daily Once-daily Once-/twice-daily Once-daily Once-daily Terminal half-life B24 6–9 11–15 5–9 5–9 6–9 13 h Bioavailability (%) 30–60 B30 60–80 40 13 25 26 Protein binding (%) 498 99.8 90–92 499 98 94–97 99 Volume of distribution 500 I 34 I 53–93 I 0.13 I/kg 308 I 17 I 17 I Renal elimination (%) 0.49–0.91 4 20 26 7 13 35–50

Journal of Human Hypertension Treatment of hypertension with olmesartan medoxomil SG Chrysant et al 701 Table 2 Functions of angiotensin II receptors (AT1 and AT2)

AT1 receptor AT2 receptor

Most important Less important Always expressed in adults A fetal receptor expressed in adults during stress or injury Mediates vasoconstriction Mediates vasodilation Increases renal tubular sodium reabsorption Decreases renal tubular sodium reabsorption Promotes cell growth Inhibits cell growth Decreases endothelial function Increases endothelial function Stimulates connective tissue deposition Inhibits connective tissue deposition Facilitates LDL-C transport to media possibly No known effect on cholesterol transport through the LOX-1 receptor

LDL-C: low-density lipoprotein cholesterol.

Table 3 Blood pressure reduction by various doses of olmesartan medoxomil compared to placebo (mm Hg)

Placebo Olmesartan medoxomil (mg) Duration (weeks)

0 2.5 5 10 20 40 80

Puchler et al.3 8 SSBP (n ¼ 2702) 6.8 12.7 14.6 16 16.9 20.7 18.1 SDBP (n ¼ 2709) 7.6 11 12.2 13.1 13.5 15.7 13.4 Response SDBP (%) 39 59 63 70 70 81 79

Neutel et al.4 8 SSBP (n ¼ 334) 0 — 5 — 20 — 80 SDBP (n ¼ 334) — — 14.5 — 16.5 — 15.4 Response SDBP (%) — — 9.6 — 12.2 — 10.6

Brunner et al.5 8 SSBP (n ¼ 790) 9.1 14.3 14.5 17.1 18.4 20.6 20.7 SDBP (n ¼ 770) 9.5 11.8 11.2 12.9 14.1 15.5 15.6 Response SDBP (%) 45.5 59.5 50.4 66.4 72.1 73.8 77.8

Abbreviations: SSBP, sitting systolic blood pressure; SDBP, sitting diastolic blood pressure. Response SDBP: p90 mm Hg or X10 mm Hg decreased from baseline. these studies was short (6–12 weeks) with some 80 mg/day dose, whereas the response to placebo extended to 52 weeks. Good BP response to treat- was 45.5%. ment was considered a mean sitting diastolic blood In another similar study by Neutel et al.,4 535 pressure (MSDBP) reduction of p90 mm Hg or a patients with MSDBP X100p115 mm Hg were decrease in MSDBP X10 mm Hg from baseline. The treated with similar daily doses of olmesartan results of these studies are summarised in Table 3, medoxomil given in single doses of 5, 20 and and will be briefly discussed here. 80 mg or in divided doses of 2.5, 10 and 40 mg, Pu¨ chler et al.,3 analysed the results of 3055 compared to placebo. The BP response to treatment patients from seven US and European studies. was monitored besides office visits, with ambulatory In these studies, olmesartan medoxomil was used BP monitoring (ABPM). The BP response to active in daily doses ranging from 2.5 to 80 mg and resulted treatment was dose-dependent and similar with in significant, dose dependent reduction of BP up to once a day or twice daily administration of the a dose of 40 mg/day with no further BP reduction drug, indicating that olmesartan medoxomil is a true with the 80 mg dose. The BP response ranged from once daily drug. 59 to 81% for 2.5 and 40 mg/day dose of olmesartan medoxomil, and 39% for placebo. In a similar study by Brunner and Nussberger,5 790 patients with a Active comparative studies MSDBP X100p115 mm Hg were treated with olmesartan medoxomil 2.5–80 mg/day compared to Olmesartan medoxomil has been compared for placebo. Olmesartan medoxomil decreased dose- antihypertensive effectiveness with other members dependently the MSDBP and mean sitting systolic of its class as well as other antihypertensive drugs in blood pressure (MSSBP) up to 40 mg/day with no several multicenter randomised studies, and the further reduction of BP with the 80 mg/day dose. results are summarised in Table 3. In three different The response of MSDBP to active treatment ranged studies by Ball et al.,6 olmesartan medoxomil was from 59% for the 2.5 mg/day dose to 77.8% for the compared with atenolol, losartan and .

Journal of Human Hypertension Treatment of hypertension with olmesartan medoxomil SG Chrysant et al 702 In study 1, patients with MSDBP 100–120 mm Hg Comparative Antihypertensive Effects of on (HCTZ) 25 mg/day, were Olmesartan with Other ARBs randomised to olmesartan medoxomil 10 mg/day or OLM LOS VAL IRB OLM CAN atenolol 50 mg/day. The dose of the study drugs 20 mg/d 50 mg/d 80 mg/d 150 mg/d 20 mg/d 8 mg/d (n=145) (n=146) (n=142) (n=145) (n=320) (n=325) could be doubled for better BP control. Of 351 0 patients 328 were randomised and 318 completed −2 the study. Both drugs decreased the MSDBP/MSSBP to a similar degree, and only 26.2% of olmesartan −4 medoxomil and 28.1% of atenolol received the higher dose. −6 In study 2, 316 patients with MSDBP 95–114 mm −8 * − * − Hg, were randomised to either olmesartan medoxomil −8.2* −8.4* 7.9 7.8 −9.3 −10 * * 10 mg/day or losartan 50 mg/day, with the doses −9.5 −9.9 − SBP −11.0 − * doubled at 4 weeks if necessary. Of the 316 patients, −12 11.3 11.3 BP Changes from Baseline (mmHg) −11.5 DBP 271 completed the study. Olmesartan medoxomil −12.9 produced a greater BP response than losartan −14 and 41.8% of the olmesartan medoxomil vs 63.2% Figure 2 This figure compares the BP reduction by the starting of the losartan group required the doubling of the dose of olmesartan (OLM) vs the starting doses of losartan, dose. valsartan and irbesartan (IRB) *P o0.05. Adopted from Oparil 10 In study 3, 291 patients with MSDBP 95–114 mm et al. In addition a comparison of olmesartan vs candesartan (CAN) is depicted. P 0.05. Adopted from Brunner et al.13 Hg were randomised to either olmesartan medoxomil o 5 mg/day or captopril 12.5 mg twice daily. Of these, 236 completed the study. Olmesartan medoxomil produced a greater reduction in MSDBP/MSSBP patients with MSDBP 100–120 mm Hg. In this study, than captopril. olmesartan medoxomil 20 mg/day was more effec- In another study by Stumpe et al.,7 381 patients tive than candesartan cilexetil 8 mg/day (Po0.05) in with MSDBP 100–120 mm Hg were randomised to reducing the MSSBP/MSDBP by clinic as well as by olmesartan medoxomil 20 mg/day, or felodipine ABPM (Figure 2). In a recently published study,14 5 mg/day. Both drugs lowered the MSDBP/MSSBP the escalating doses of olmesartan medoxomil 20– to the same degree. 40 mg/day were compared against placebo, losartan Chrysant et al.8 compared the BP lowering effects 50–100 mg/day and valsartan 80–320 mg/day in 4 of olmesartan medoxomil 20 mg/day to amlodipine weekly intervals for a total of 12 weeks in 696 5 mg/day in 440 patients with a MSDBP 100– patients with MSDBP 100–120 mm Hg. In this study 115 mm Hg. The BP was monitored by office visits the starting dose of olmesartan medoxomil 20 mg/ as well as ABPM. Both drugs had similar BP day had a greater BP lowering effect than the starting lowering effects by both office visits as well as mean doses of losartan 50 mg/day and valsartan 80 mg/day 24-h ABPM. In a subanalysis of the ABPM results of (Po0.05). However, as the doses were escalated to this study,28 it was shown that a greater percentage the maximal recommended daily doses, the BP of patients treated with olmesartan medoxomil differences between the three treatment regimens 20 mg/day achieved the BP goal of o140/90 mm disappeared. Hg (48%) compared to amlodipine 5 mg/day, (41.9%) and also more patients on olmesartan achieved the more aggressive BP goal of o130/ Combination treatment 85 mm Hg (30.4%) compared with amlodipine (14.0%) or the still more aggressive BP goal of The antihypertensive efficacy of olmesartan medoxomil o130/80 mm Hg (18 vs 7.0%) for olmesartan alone and in combination with HCTZ was studied medoxomil and amlodipine, respectively. The anti- by Chrysant et al.9 in a factorial design study in hypertensive effectiveness of olmesartan medoxomil 502 hypertensive patients with MSDBP X100 and against other members of its class were studied by p115 mm Hg. In this study, olmesartan medoxomil Oparil et al.10 in 588 hypertensive patients. In this 10, 20 or 40 mg/day alone and in combination with study, the recommended starting dose of olmesartan HCTZ 12.5 and 25.0 mg/day were used. Olmesartan medoxomil 20 mg/day was tested against starting medoxomil in combination with HCTZ produced doses of losartan 50 mg/day, valsartan 80 mg/day greater reductions in MSDBP/MSBP than mono- and irbesartan 150 mg/day, by both clinic and therapy with either olmesartan medoxomil or HCTZ. ABPM. In this study, the SBP and DBP lowering In addition, the response rate to treatment was effects of olmesartan were greater than those of higher with the drug combination than the individual losartan and valsartan (Po0.05) with the exception drugs (Table 4). of SBP which was similar with that of irbesartan In another study, Sellin et al.,29 added HCTZ 12.5, (Figure 2). In another similar study, Brunner et al.13 25.0 mg or placebo in 535 hypertensive patients studied the antihypertensive properties of olmesartan pretreated with olmesartan medoxomil 20 mg/day medoxomil against candesartan cilexetil in 645 with uncontrolled BP. The addition of HCTZ 12.5 or

Journal of Human Hypertension Treatment of hypertension with olmesartan medoxomil SG Chrysant et al 703 Table 4 Blood pressure lowering effects of olmesartan medoxomil compared to other antihypertensive drugs

Author Drug (mg/day) Baseline BP mm Hg Change (mm Hg) Response (%) Time (weeks) (SSBP/SDBP) (SSBP/SDBP)

Ball 6 Study 1 (n ¼ 318) OM 10 161/105 À20.4/À17.3 86.0 12 ATE 50 162/105 À19.6/À17.2 84.8 12 Study 2 (n ¼ 271) OM 10 159/101 À14.9/À10.6 63 12 LO 50 160/102 À11.6/À8.5 52 12 Study 3 (n ¼ 236) OM 5 161/101 À14.7/À9.9 53 12 CAP 25 161/102 À7.1/À6.8 38 12 Stumpe 7 OM 20 SDBP 105 À19.9 82.8 12 (n ¼ 381) FEL 5 SDBP 105 À19.1 83.3 12

+Chrysant 8 OM 20 155/104 À10.3/À10.8 50 8 (n ¼ 440) AML 5 155/104 À10.3/À10.1 51 8

Chrysant 9 OM 10 154/104 À10.7/À11.3 66.7 8 (n ¼ 502) OM 20 155/103 À15.5/À13.8 68.3 8 OM 40 153/103 À16.0/À14.6 68.9 8 OM/HCTZ 10/12.5 157/104 À17.4/À13.5 77.1 8 OM/HCTZ 20/12.5 152/103 À20.1/À16.4 78.6 8 OM/HCTZ 40/12/5 152/104 À20.6/À17.3 81.0 8 OM/HCTZ 10/25 154/104 À23.0/À17.1 89.5 8 OM/HCTZ 20/25 155/104 À27.1/À20.0 89.1 8 OM/HCTZ 40/25 154/103 À26.8/À21.9 92.3 8 Oparil 10 OM 20 157/104 À14.7/À10.2* — 8 (n ¼ 588) LO 50 157/104 À10.9/À7.2 — 8 VAL 80 155/104 À10.2/À7.0 — 8 IRB 150 156/104 À13.8/À8.8 — 8 +Brunner 13 OM 20 146/92 À12.7/À9.1* — 8 (n ¼ 635) CAN 8 146/92 À11.0/À7.7 — 8

Giles 14 DM 20 154/104 À13.5/À10.6* 27.4 4 (n ¼ 596) LO 50 155/104 À9.6/À9.1 20.6 4 VAL 80 154/103 À10.6/À9.2 22 4 OM 40 154/104 À15.2/À12.9* 39.7* 4 LO 100 155/104 À10.9/À9.4 19.8 4 VAL 160 154/103 À13.0/À11.6 29.0 4 OM 40 154/104 À13.9/À11.7 35.3 4 LO 50 Â 2 155/104 À13.4/À11.5 33.3 4 VAL 320 154/103 À14.8/À12.4 30.6 4 +Sellin 29 OM 20+PL 146/92 À13.2/À10/2 48.3 12 (n ¼ 535) OM 20+HCTZ 12.5 145/92 À17.3/À11.5 57.6 12 OM 20+HCTZ 25.0 146/91 À19.9/À13.6 69.5 12 Fogari 30 OM 20 170/104 À17.8/À10.2 — 4 (n ¼ 130) VAL 160 170/104 À20.9/À10.9 — 4 OM 20+HCTZ 12.5 152/94 À5.9/À5.1 — 4 VAL 160+HCTZ 149/93 À7.2/À6.8* — 4 12.5

Izzo 31 OM 20 170/97 À17.7/À65 19.0 12 (n ¼ 169) OM 40 170/97 À19.0/À7.3 23.8 OM/HCTZ 40/12.5 170/97 À31.3/À13.0 57.1 OM/HCTZ 40/25 170/97 À33.2/À14.0 66.7 Izzo 32 OM/HCTZ 40/25 170/97 À34.5/À13.7 70.4 16 (n ¼ 105) OM/HCTZ 40/50 170/97 À38.1/À15.7 77.5

Abbreviations: ABPM, ambulatory blood pressure monitoring; AML, Amlodipine; ATE, Atenolol; CAN, Candesartan; CAP, Captopril; FEL, Felodipine; IRB, Irbesartan; LO, Losartan; OM, Olmesartan; VAL, Valsartan. +Pressures measured by ABPM. *Po0.05 OM vs comparator drug (see also text).

25.0 mg/day to olmesartan medoxomil 20 mg/day, study, Fogari et al.30 added HCTZ 12.5 mg/day to 130 produced a greater reduction in BP compared to hypertensive patients treated with olmesartan placebo added treatment (Table 4). In a similar 20 mg/day or valsartan 160 mg/day in which their

Journal of Human Hypertension Treatment of hypertension with olmesartan medoxomil SG Chrysant et al 704 Effects of Olmesartan with and without HCTZ in Hypertensive Effects of Olmesartan with and without HCTZ in Patients with Different BMIs Hypertensive Patients with Different BMIs in Achieving OLM 20 mg/day OLM 40 mg/day OLM/HCTZ 40/12.5 OLM/HCTZ 40/25 BP Goals (BP <140/90 mmHg) (n=168) (n=159) mg/day(n=155) mg/day(n=142) 80 0 72.1 70.9 70 66.7 −2 60 57.1 55.7 55.8 −4 50 − −6 −5.4 -5.35.3 * −6.1 40 −6.7 * − −6.8 − 7.0 31.1 8 * 29.1 * * 30 * 23.8 −10 19.0 −10.0 20 16.4 14.0 −

** BP <140/90 mm Hg (% of patients) 12 −11.8 −11.7 10 −12.8 − ** ** −13.1 14 0 **−14.5 ** n=168 n=159 n=155 n=142 Mean change from baseline in SeDBP (mm Hg) −16 OLM 20 mg/day OLM 40 mg/day OLM/HCTZ 40/12.5 OLM/HCTZ 40/25 ** mg/day mg/day ≥ <25 kg/sq m 25–29 kg/sq m 30 kg/sq m <25 kg/sq m 25–29 kg/sq m ≥30 kg/sq m Figure 3 This figure depicts the BP response to various Figure 4 This figure depicts the percentage of same patients olmesartan medoxomil regimens in hypertensive patients with achieving BP goals. Adopted from Chrysant et al.30 different BMIs. Comparisons are vs baseline *Po0.01, *Po0.001. Adopted from Chrysant et al.29

patients with stage-1 hypertension (SBP 140– BP was not controlled with monotherapy. In this 159 mm Hg or DBP 90–99 mm Hg) treatment can be study the valsartan/HCTZ 160/12.5 mg/day, pro- initiated with the starting doses of olmesartan and if duced a greater (Po0.05) BP effect than the BP is not brought to goal, the dose could be combination of olmesartan/HCTZ 20/12.5 mg/day increased to maximum recommended dose of (Table 4). It should be noted, however, that the 40 mg/day, and if necessary, drugs from a different starting dose of valsartan 160 mg/day was not class with complimentary action can be added, equivalent to olmesartan 20 mg/day. In patients with preferably a diuretic, since such combination can stage 2 systolic hypertension, we have shown that bring the BP to goal in over 70% of the patients.31–34 olmesartan medoxomil given in escalating doses of In patients with stage 2 hypertension (SBP 20–40 mg alone and in combination with HCTZ X160 mm Hg or DBP X100 mm Hg), treatment can 12.5–25 mg/day was very effective in lowering the be initiated with a combination therapy. If BP is not BP.31 In 143 such patients OM/HCTZ 40/12.5 and brought to goal of o140/90 mm Hg for uncompli- 40/25 mg/day resulted in 30.5/12.2 and 35.1/ cated hypertensives or o130/80 mm Hg for hyper- 13.7 mm Hg BP reduction respectively. Also, 55.9 tensive patients with diabetes mellitus or renal and 72.7% of patients, respectively achieved goal failure35 additional drugs with complimentary BP (o140/90 mm Hg). In another study,32 olmesartan action should be added. Because of the beneficial medoxomil alone in daily doses of 20 and 40 mg effects of ARBs in diabetic patients, the American and in combination with HCTZ (40/12.5 mg/day, 40/ Diabetes Association has recommended the use of 25 mg) was equally effective in hypertensive pa- ARBs or ACE inhibitors as firstline therapy in such tients with different BMIs (o25, 25–29, X30). The patients.36 The angiotensin receptor blockers are OM/HCTZ 40/25 mg dose/day resulted in achieving truly pleiotropic drugs37 and have shown effective- BP goals (o140/90 mg) in 66.7, 72.1, 70.9% for BMIs ness in reversing left ventricular hypertrophy,38,39 in of o25, 25–29, or X30, respectively (Figures 3 and decreasing morbidity and mortality in patients with 4). In more recent studies33,34 Izzo et al. have heart failure40–44 and in patients with diabetic demonstrated that combination of olmesartan nephropathy by decreasing proteinuria and prevent- medoxomil 40 mg/day with HCTZ 25 or 50 mg/day, ing the progression of renal disease.45–48 No such resulted in BP goal of o140/90 mm Hg in 70.4 and studies are available for olmesartan as yet and this 77.6%, respectively. Also, 15.4 and 27.2% of drug is not approved by FDA for these conditions patients, respectively reached the more stringent (Table 5). In addition, ARBs have recently emerged BP goal of o120/80 mm Hg. as superior agents for stroke prevention in clinical and experimental studies.37,49–55 In these studies losartan compared to atenolol resulted in a 25 and Treatment indications of ARBs 40% stroke reduction, in the total study population and in patients with isolated systolic hypertension Olmesartan medoxomil and the other members of its (ISH) respectively.39,51 In other studies, candesartan class are recommended as first-line treatment of compared to conventional therapy resulted in 23.452 hypertension, either alone or in combination with and 40% stroke reduction in the study population other drugs based on the stage of hypertension.35 In and in patients with ISH, respectively.53,54 In a

Journal of Human Hypertension Treatment of hypertension with olmesartan medoxomil SG Chrysant et al 705 Table 5 Other conditions besides hypertension where ARBs have the olmesartan medoxomil (51.5%) and the placebo- shown beneficial effects treated ones (47.2%). The most commonly reported drug emergent side effects were headache, dizzi- Condition Drug Clinical trial ness, flu-like symptoms and bronchitis, which were Heart failure Losartan ELITE,39 OPTIMAAL40 no different from the placebo treated patients. Also, Valsartana Val-HeFT,41 VALIANT42 the metabolic profile of olmesartan medoxomil was Candesartana CHARM43 excellent and no different from placebo. In recent Post MI Valsartan VALIANT42 database reviews of more than 56 000 patients 38 High CAD risk Losartan LIFE followed for 1–4.5 years, ARBs were better Diabetes Losartan LIFE38 Valsartan VALUE54 tolerated and much less discontinued than ACE Diabetic nephropathy Irbesartana IDNT46 inhibitors, calcium channel blockers, diuretics or Losartana RENAAL47 b-blockers.64,65 Primary strokeb Losartana LIFE38,50 Candesartan SCOPE51,52 Valsartan Jikei Heart Study55 Recurrent strokeb Eprosartan MOSES53 Future studies There are several large clinical outcome studies with Abbreviations: ARB, Ang II receptor blocker; FDA, US Food and Drug Administration. ARBs in progress, which when completed will aFDA approved indication. provide useful clinical information. The Ongoing bThese conditions are not listed by the JNC-7 in their compelling Alone and in combination with indications for the use of ARBs. Global Endpoint Trial (ONTARGET), is evaluating the effects of telmisartan 80 mg/day, ramipril 10 mg/day and their combination in a parallel group recent study, eprosartan reduced recurrent strokes design study on cardiovascular and cerebrovascular by 25% compared to nitrendipine for a similar BP morbidity and mortality, and new onset diabetes control, in hypertensive patients with a previous mellitus in 23 400 high risk patients.66 A sister stroke. Similar results were also reported from a study, the Telmisartan Randomised Assessment recent Japanese study, in which high-risk patients Study in ACEI intolerant patients with Cardiovas- treated with a valsartan-based regimen had a 40% cular Disease (TRANSCEND) is testing telmisartan lower stroke incidence than patients treated with 80 mg/day vs placebo in the ONTARGET population other drugs for the same BP reduction.55 The results who are intolerant to ACEIs.66 An important study, of the VALUE study,56 where valsartan was com- which will be complementary to these studies is pared to amlodipine55 were disappointing initially the Prevention Regimen For Effectively avoiding due to poor BP control with valsartan. However, as Second Strokes (PRoFESS), in which 15 500 patients the study progressed and the BP differences between with a previous stroke are being treated with either the two treatment groups were narrowed, the stroke telmisartan 80 mg/day or extended release dipyrida- incidence decreased in the valsartan treated group mole 200 mg þ clopidogrel 75 mg/day.67 This study even though the BP was 1.8/1.5 mm Hg higher will be completed in 2007. Another very important compared to amlodipine treated group. Despite this, study is the Randomised Olmesartan And Diabetes the overall stroke incidence was higher by 15% in Microalbuminuria Prevention Study (ROADMAP), the valsartan treated group accounting for the higher which is evaluating the antiproteinuric and renal incidence of early strokes. This study clearly protective effects of olmesartan medoxomil 40 mg/ demonstrated the critical role of early and sustained day in type II diabetic patients without proteinuria BP control in stroke prevention. The conditions for at study enrollment.68 This study will enroll 4400 which the ARBs have shown benefit and their use is such patients and monitor them for 5 years. The recommended by the JNC-7,35 except for stroke, are results of the ONTARGFET and TRANSCEND listed in Table 5. Other beneficial effects of some of studies are expected to be reported in 2007, whereas the ARBs include their; those of the ROADMAP in 2015. (a) antiatherogenic,57,58 (b) antioxidant,59 (c) antidia- betic,60 (d) antiplatelet61 and (e) atrial anti- fibrillatory effects.62,63 All these effects of ARBs Discussion could contribute to their stroke protective effects independent of BP control. No such data are It is now well established that the —angioten- available for olmesartan medoxomil as yet. sin–aldosterone system plays an important role in cardiovascular homeostasis. Its effector hormone, Ang II exerts its haemodynamic and cardiovascular Safety profile of olmesartan medoxomil remodelling effects through stimulation of the AT1 receptors. Drugs that interfere with its actions by Olmesartan medoxomil is a safe and well-tolerated blocking its binding to the AT1 receptors (ARBs) drug, like the other members of its class. The offer the greatest protection against the deleterious incidence of adverse events reported by the patients effects of Ang II. Several small, as well as from the various clinical trials was similar between large clinical outcome studies have demonstrated

Journal of Human Hypertension Treatment of hypertension with olmesartan medoxomil SG Chrysant et al 706 that ARBs produce benefits beyond BP control. ambulatory blood pressure measurements. J Clin Olmesartan medoxomil, is a long-acting, highly Hypertens 2002; 4: 325–331. selective AT1 receptor blocker that has been shown 5 Brunner HR, Nussberger J. Relevance of clinical to be very effective in the treatment of hypertension pharmacological models for the evaluation of thera- alone and in combination with a diuretic. The most peutic dose range of an AT1 receptor antagonist. J Hypertens 2001; 19(Suppl 1): S15–S20. effective and clinically important doses are 20 or 6 Ball KJ, Williams PA, Stumpe KO. Relative efficacy of 40 mg once daily, alone or in combination with an angiotensin II antagonist compared with other HCTZ 12.5–25 mg once daily. Although there are not antihypertensive agents. Olmesartan medoxomil large outcomes studies published so far with versus antihypertensives. JHypertens2001; 19(Suppl 1): olmesartan medoxomil regarding its cardiovascular, S49–S56. cerebrovascular and renal protective effects, short 7 Stumpe KO, Ludwig M. Antihypertensive efficacy of term clinical and experimental studies have demon- olmesartan compared with other antihypertensive strated its antidiabetic, antiproteinuric and renopro- drugs. J Hum Hypertens 2002; 16(Suppl 2): S24–S28. tective properties.69,70 In addition, the ongoing large 8 Chrysant SG, Marbury TC, Robinson TD. Antihyper- clinical outcomes study (ROADMAP), will provide tensive efficacy and safety of olmesartan medoxomil compared with amlodipine for mild-to-moderate useful information regarding its renoprotective and hypertension. J Hum Hypertens 2003; 17: 425–432. antiproteinuric effects in type II diabetic patients 9 Chrysant SG, Weber MA, Wang AC, Hinman DJ. 68 when completed. However, despite the putative Evaluation of antihypertensive therapy with the cardioprotective, renoprotective and stroke protec- combination of olmesartan medoxomil and hydro- tive effects of ARBs beyond BP control, the major chlorothiazide. Am J Hypertens 2004; 17: 252–259. protection is conferred through good BP control. 10 Oparil S, Williams D, Chrysant SG, Marbury TC, According to the JNC-7 guidelines35 aggressive BP Neutel J. Comparative efficacy of olmesartan, losartan, control of o140/90 mm Hg for patients with un- valsartan, and irbesartan in the control of essential complicated hypertension, or o130/80 mm Hg for hypertension. J Clin Hypertens 2001; 3: 283–291. hypertensive patients with type II diabetes mellitus 11 Smith DH, Dubiel R, Jones M. Use 24-h ambulatory blood pressure monitoring to assess antihypertensive or renal disease is necessary to prevent BP related efficacy: a comparison of olmesartan medoxomil, complications. Since monotherapy only controls losartan potassium, valsartan and irbesartan. 50% of mild to moderate hypertensive patients, drug Am J Cardiovasc Drugs 2005; 5: 41–50. combination therapy is often required to achieve BP 12 Stumpe KO. Olmesartan compared with other angio- goals, and patients with a sitting office BP of X160/ tensin II receptor antagonists: head-to-head trials. 100 mm Hg, should be started with double therapy Clin Ther 2004; 26(Suppl A): A33–37. initially. The most effective combination therapy from 13 Brunner HR, Stumpe KO, Januszewicz A. Antihyper- the studies presented in this review, is an ARB with a tensive efficacy of olmesartan medoxomil and cande- low-dose diuretic. If this therapy is not effective, other sartan cilexetil assessed by 24-h ambulatory blood drugs from a different class with complimentary pressure monitoring in patients with essential hyper- tension. Clin Drug Invest 2003; 23: 419–430. action, such as a calcium channel blocker or a 14 Giles TD, Oparil S, Silfani TN, Wang A, Walker JF. b-blocker, should be added to achieve BP goal. In Comparison of increasing doses of olmesartan medoxomil, several cases, four or even five different antihyper- losartan potassium, and valsartan in patients with tensive drugs are needed to bring BP to goal. essential hypertension. J Clin Hypertens 2007; 9: 187–195. Disclosures 15 Koike H, Sada T, Mizuno M. In vitro and in vivo No financial or editorial support was provided for pharmacology of olmesartan medoxomil, an angioten- the preparation of this manuscript. There are no sin II type AT1 receptor antagonist. J Hypertens 2001; conflicts of interest. 19(Suppl 1): S3–S14. 16 Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol 2001; 41: 515–527. 17 Warner GT, Jarvis B. Olmesartan medoxomil. 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