The rennin–angiotensin–aldosteron system (RAAS) is a target for drugs used in the treatment of hypertension. ARBs inhibit the RAAS by competitive binding to the type 1 receptor for angiotensin II, which blocks the enzyme actions: vasoconstriction, increased aldosteron secretion and sympathetic activation, salt and fluid retention.

Olmesartan, as other ARBs, is a potent angiotensin II type – 1 receptor (AT1 receptor) antagonist, without any effect on angiotensin II type – 2 receptor [3]. Its affinity for the AT1 receptor is greater than that of losartan and similar to that of candesartan [4]. Olmesartan esterification with the medoxomil moiety increases bioavailability of the drug [5]. The mean plasma half-life of olmesartan during chronic treatment is 10–15 h. The drug is excreted mainly in feces, with about 10–16 % excreted in the urine (briefly revised in [6]). Dosage adjustment for patients with renal or hepatic impairment as well as for elderly is not indicated; however, some manufacturers of the drug recommend lower initial dose [6].

Efficacy and tolerability of olmesartan (5–80 mg/day) in the treatment of hypertension in different populations of patients was examined in placebo-controlled trials as well as in the studies comparing it with different other classes of antihypertensives (among others amlodypine, hydrochlorotiazyd, atenolol, captopril) [7–12]. The researchers proved the efficacy of monotherapy as well as combined therapy of olmesartan with calcium channel blocker or diuretic in the treatment of mild to moderate hypertension, masked hypertension, or white coat hypertension. They also showed no more adverse effects of olmesartan as compared to placebo or amlodypine/calcium channel blocker alone, but slightly higher incidence of adverse effects was observed in the elderly population treated with olmesartan and diuretic [7–12]. Other conclusions of these studies were as follow: (1) higher possibility to achieve goal blood pressure with olmesartan than with other hypertensives, (2) olmesartan plus calcium channel blocker could be more effective in reducing risk of stroke than olmesartan plus diuretic in the elderly, (3) higher doses of olmesartan or addition of hydrochlorotiazyd to olmesartan therapy are equally effective and safe for patients who didn’t respond to monotherapy with olmesartan alone [7–12].

Efficacy of olmesartan was also compared with other ARBs and summarized in a meta-analysis of 22 randomized controlled trials [13]. The study showed better efficacy of olmesartan in systolic blood pressure (SBP) reduction as compared to losartan or valsartan, and also better efficacy in diastolic blood pressure (DBP) reduction than losartan; when compared with valsartan, olmesartan was equally effective in DBP reduction [13]. No difference in the total number of adverse events was described while comparing olmesartan with losartan and valsartan [13].

Recent years’ trials point on a link between hypertension and vascular inflammation/atherosclerosis, where the key player is angiotensin II (Ang II) [14].

Ang II proinflammatory actions are (1) in human endothelial and smooth muscle cells as well as in monocytes, increases the expression of different proinflammatory cytokines and adhesion molecules, such as interleukin 6 (Il-6), interleukin 1 beta (Il-1β), tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NF-kappaB), monocyte chemoattractant protein 1 (MCP-1), and vascular cell adhesion molecule (VCAM); (2) induces recruitment of inflammatory cells; (3) induces production of superoxide anions and activates NADH/NADPH signaling – increases the oxidative stress and decreases nitric oxide bioavailability; (4) induces cell hypertrophy and activates fibrosis [14–19].

Olmesartan medoxomil as a long-acting antagonist of AT1 receptor is able to improve endothelial dysfunction/atherosclerosis in animal models and human studies.

Olmesartan’s influence on oxidative stress mediators was shown in rat studies. After treatment of methotrexate-induced mucositis model in Wistar rats with olmesartan (5 mg/kg/day), reductions in mucosal inflammatory infiltrations, ulcerations, and hemorrhagic areas were observed as well as decrease in concentrations of proinflammatory cytokines Il-1β and TNFα [20]. Moreover, authors noticed an increase in anti-inflammatory cytokine interleukin 10 (Il-10) concentration [20]. In a rat model of high-salt diet-induced glomerular and tubulointerstitial kidney injury, treatment with olmesartan (10 mg/kg/day) as well as with olmesartan and calcium channel blocker (CCB) caused a significant regression of morphological changes [21]. It was explained by the reductions in expression of other proinflammatory cytokines: MCP-1 and tumor growth factor β (TGF-β). Also, decrease in NADPH oxidase activity and NADPH oxidase-dependent superoxide production was observed [21]. Similar decrease in NADPH oxidase activity was noticed in olmesartan-treated rats with a stroke model (permanent middle cerebral artery occlusion) [22]. Significantly better functional scores and reduced infarct sizes were confirmed in a group of rats treated with olmesartan (10 mg/kg/day) 7 days before and 14 days after infarct, but also in the group only pretreated with this ARB or treated after infarct induction [22]. In a previous study, the antioxidative properties of olmesartan measured as the decrease in superoxide production and NADPH oxidase activity were confirmed for the lower dose of ARB – 3 mg/kg/day – in apolipoprotein E knockout mice [23].

Amelioration of oxidative stress in the endothelium improves its function. In spontaneously hypertensive rats treated with olmesartan (5 mg/kg/day) for 4 weeks and subsequently divided into 5 groups – increased dose of olmesartan (10 mg/kg/day) or addition of azelnidipine or temocapril or atenolol or hydrochlorothiazide, endothelial function, assessed by evaluating dilatory response to acetylcholine, was significantly improved compared to the control group [24]. Beneficial effects of olmesartan were probably connected with the upregulation or inhibition of the disruption of endothelial nitric oxide synthase (eNOS) [25, 26]. Antiatherogenic effects of olmesartan administration are further confirmed also by amelioration of atherosclerotic areas in the thoracic aorta, perivascular fibrosis, and medial thickness of the coronary arteries in diabetic apolipoprotein E-deficient mice treated with the combination of this ARB and CCB [26].

Olmesartan’s effects on interstitial matrix were also evaluated. In spontaneously hypertensive rats treated with high (15 mg/kg/day) or low (1 mg/kg/day) dose of olmesartan, left ventricular weight–to–body weight ratio (RLVM) was measured, and cardiac, aortic, and glomerular interstitial collagen content was evaluated [27]. Both high and low dose of olmesartan normalized, increased in control group rats, collagen content in hart, kidneys and aorta. The significantly increased RLVM in untreated rats was decreased in high-dose olmesartan-treated group [27]. In addition, reduction in expression of matrix metalloproteinases 2 and 9 could also contribute to antifibrotic effects of this ARB [20]. Attenuation of cardiac hypertrophy, remodeling, and improved cardiac diastolic function by olmesartan might be also a result of the influence of olmesartan on other molecular pathways: activation of delta-like ligand 4/Notch 1 pathway or calcineurin pathway [28, 29].

Olmesartan’s observed renoprotective effects in animal models (based on improvement in urinary protein excretion and histological kidney injury/fibrosis) might be augmented by the increased expression of klotho mRNA in olmesartan + alfadiol-treated chronic renal failure rats [21, 30].

Not only in study animals but also in hypertensive patients, olmesartan medoxomil therapy results in improvements in endothelial function. In a double-blinded, placebo-controlled study (EUTOPIA), authors showed that 12 weeks of olmesartan therapy (20 mg/day), in contrast to placebo, significantly reduced serum concentration of high-sensitivity C reactive protein (hsCRP), TNF-α, IL-6, and MCP-1 [31]. The effect was observed already after 6 weeks of treatment, and further augmented during the next 12 weeks of therapy [31].

Amelioration of the endothelial function was documented by other authors who investigated arterial dilation after treatment with this ARB. In a Japanese study, 26 patients with essential hypertension, previously untreated, were assigned to the treatment either with olmesartan (20 mg/day; dose was doubled in case of not reaching desirable blood pressure or halved in case of too low blood pressure) or amlodypine for 12 weeks [32]. The protocol resulted in significant increase in the corrected myocardial blood flow and decrease in the change of coronary vascular resistance in the olmesartan group; effects were not observed in amlodypine-treated patients. What more, serum superoxide dismutase (SOD) concentration increased in the olmesartan group during the treatment period, but not in the amlodypine group, and could at least partially explain ameliorated myocardial blood flow [32]. Improved endothelial function evaluated by flow-mediated dilation (FMD) of brachial artery was also found in a 12 week trial of olmesartan vs amlodypine therapy [33].

Other studies concentrated on vascular hypertrophy and remodeling. Hypertensive, nondiabetic patients after a 4 week washout period were randomized to olmesartan (20–40 mg/day) or atenolol (50–100 mg/day) plus additional hypotensive drugs if needed (hydrochlorothiazide, amlodypine, hydralazine) [34]. At baseline and after a year of treatment upon biopsies, subcutaneous gluteal resistance arteries were examined to evaluate remodeling. In the control group, the wall-to-lumen ratio was 11 %. After the treatment period, the wall-to-lumen ratio in the olmesartan-treated group significantly decreased from 14.9 to 11.1 %. No significant change was observed in the atenolol group [34]. In the MORE study, in patients with hypertension and increased cardiovascular risk with carotid wall thickening (measured by means of ultrasound), olmesartan’s or atenolol’s influence on common carotid intima-media thickness (IMT) and atherosclerotic plaque volume was investigated [35]. After 2 years of treatment, olmesartan and atenolol produced similar significant reductions in IMT. However, only olmesartan reduced the volume of large atherosclerotic plaques [35].

In diabetic patients, olmesartan treatment was shown to be associated not only with delayed onset of microalbuminuria (early predictor of diabetic nephropathy and cardiovascular disease) but also delayed development of left ventricular remodeling [36, 37]. The latter effect was assessed during a randomized trial; signs of left ventricular hypertrophy were evaluated based on a 12-lead ECG at baseline and after 2 years of treatment with olmesartan or placebo (non-RAAS-influencing antihypertensive drugs were allowed) [36].

HMGCoA reductase inhibitors are nowadays commonly used agents for lowering cholesterol concentration and thus preventing cardiovascular events. Competitive inhibition of HMGCoA reductase results in decreased hepatic cholesterol synthesis and apolipoprotein B-containing lipoproteins, increase in hepatic low-density lipoprotein (LDL) receptor expression, and enhanced LDL cholesterol uptake from plasma.

Rosuvastatin is one of the most recently available synthetic statins. It is rapidly absorbed after oral administration (briefly revised in [38]). Half-life of rosuvastatin is 19 h, which results in similar pharmacokinetics of the drug irrespective of the morning or evening dosing [39]. The drug is about 88 % reversibly bound to plasma proteins, mainly to albumin; it is eliminated in 90 % as unchanged drug with feces and remaining 10 % with the urine [38, 39]. In consequence, rosuvastatin administration is contraindicated in patients with active liver disease and unexplained transaminase elevations, and dosage adjustment is needed for patients with eGFR <30 ml/min/1.73 m² – 5–10 mg/day. However, in end-stage kidney disease patients on continuous ambulatory peritoneal dialysis, pharmacokinetics of 10 mg/day of rosuvastatin was similar as in healthy volunteers [40]. Similar observations were made in a small study of 10 mg of rosuvastatin in 11 hemodialysis patients, suggesting that no dose adjustment is needed for these patients [41].

Rosuvastatin shows higher efficacy in modifying atherogenic lipid profile in patients with hypercholesterolemia than other statins. In several meta-analyses and clinical trials, rosuvastatin was not only more efficacious in decreasing LDL cholesterol and increasing HDL cholesterol when compared to simvastatin, fluvastatin, lovastatin, or pravastatin but also in comparison to atorvastatin [42–44]. Rosuvastatin decreased LDL cholesterol levels better at the same dose of atorvastatin and 1:2 dose ratio; no significant difference in lipid profile goals was observed at 4 times higher atorvastatin doses [43]. What more, the same results were observed for different patient age-groups, and the incidence of adverse effects was the same for all the statins compared [42–44]. Rosuvastatin was also better than simvastatin in attaining LDL goals after switching patients from atorvastatin therapy – authors concluded it might be the drug of choice for lipid-lowering therapy in patients who failed to achieve cholesterol goals during atorvastatin treatment [45].

Rosuvastatin’s efficacy in improving lipid profile and achieving target goals of cholesterol were also studied for so-called high-risk populations including patients with diabetes mellitus (DM) or metabolic syndrome, acute coronary syndrome (ACS) or chronic kidney disease (CKD) [38]. Additional effects of the drug were also observed: (1) rosuvastatin administration (2.5–10 mg/day for 24 weeks) reduced albuminuria, serum cystatin C levels in CKD patients regardless of presence or absence of DM; (2) rosuvastatin administration (2.5–20 mg/day for 24 weeks) decreased hsCRP and malondialdehyde-modified LDL (effect of oxidative stress) in diabetic nephropathy patients with eGFR >60 ml/min/1.73 m²; (3) rosuvastatin (5–20 mg/day for 24 months) induced lasting decrease in carotid plaque lipid content in lipid treatment subjects as assessed by magnetic resonance; (4) rosuvastatin treatment decreased the incidence of heart failure hospitalizations in heart failure patients over 60 years of age; (5) rosuvastatin treatment (10 mg/day for 1 year) significantly improved coronary flow reserve in hypertensive patients without coronary artery disease [46–50].

Rosuvastatin’s influence on oxidative stress, independent of lipid-lowering properties, is also under investigation (briefly revised in [51]). This statin is able to ameliorate NADPH oxidase-mediated damage by reducing NADPH oxidase activity in rats and NADPH oxidase-dependent superoxide production in obese rats [52, 53]. Rosuvastatin also inhibits angiotensin II-mediated vascular impairment by decreasing NADPH oxidase-derived oxidant excess, stimulation of endogenous antioxidant mechanisms, and restoring NO availability [54].

In addition, rosuvastatin increases endothelial NO synthesis and attenuates myocardial necrosis (the effect of ischemia and reperfusion) in mice [55]. Inhibiting HMGCoA reductase increases NO bioavailability and improves endothelial function in congestive heart failure rats [56]. Finally, it also upregulates eNOS expression in mice protecting the animals from cerebral ischemia [57]. Rosuvastatin reduces also other prooxidative cytokines like Il-6 or TNFα [58]. The restoration of antioxidant defense is mediated by rosuvastatin-dependent improvement in SOD1 expression [59].

To effectively decrease cardiovascular adverse events in patients with multiple risk factors, it is required to act synergistically against all of them on different fields: change lifestyle to lose weight, change the dietary and exercise habits, and use the pharmacological measures. The doctor should notice that in hypertensive patients with other risk factors not only blood pressure goal achievement but also improved lipid profile or proper glycemia control significantly decreases cardiovascular risk [60]. Patients’ adherence to the pharmacological therapy significantly decreases the risk of long-term adverse events including mortality [61]. However, treatment regimens for combined blood pressure, cholesterol, and glycemia control and antiplatelet therapy in high cardiovascular risk is often complicated and for the patients is the main reason for poor compliance [62]. Benefits of the use of single-pill combination therapy are not only good effects of free therapy but also better patient compliance [62].