Hypertension in Kidney Transplant Recipients: Where Are We Today?

PURPOSE OF REVIEW: Cardiovascular disease is the leading cause of death and allograft loss among kidney transplant recipients, and hypertension is an independent risk factor for cardiovascular morbidity of this patient population. The etiology of hypertension is multifactorial, including pre-transplant volume overload, post-transplant recipient and donor-associated variables, and transplant-specific causes (immunosuppressive medications, allograft dysfunction and surgical complications such as transplant artery stenosis). RECENT FINDINGS: No randomized controlled trials have assessed the optimal blood pressure targets and explored the best antihypertensive regimen for kidney transplant recipients. According to the large observational studies, it is reasonable to achieve a blood pressure goal of equal to or less than 130/80 mmHg in the long-term follow-up for minimizing the cardiovascular morbidity. The selection of antihypertensive agents should be based on the patient's co-morbidities; however, the initial choice could be calcium channel blockers especially in the first few months of transplantation. In patients with cardiovascular indications of renin-angiotensin-aldosterone system inhibition, given the well-described benefits in diabetic and proteinuric patients, it is reasonable to consider the use of renin-angiotensin-aldosterone system inhibitors. There is a need for future prospective trials in the transplant population to define optimal blood pressure goals and therapies.

Endocan, a novel marker of endothelial dysfunction in patients with essential hypertension: comparative effects of amlodipine and valsartan.

Vascular inflammation plays an important role in the pathophysiology of hypertension and high levels of endocan may reflect ongoing vascular inflammation in hypertensive patients. In the present hypothesis-generating study, we aimed at investigating the comparative effects of amlodipine and valsartan on endocan levels in newly diagnosed hypertensive patients. The study population consisted of 37 untreated hypertensive patients who were randomized to the two treatment arms. After baseline assessment, each patient was randomly allocated to either 10 mg daily of amlodipine (n = 18, 7 males) or 160 mg daily of valsartan (n = 19, 3 males) and treated for a 3-month period. Sphygmomanometric blood pressure (BP) and serum endocan were measured before and every 2 weeks during drug treatment. There was no statistically significant difference between the two treatment arms as far as baseline socio-demographic and clinical characteristics are concerned. After a 3-month treatment period, systolic and diastolic BP values significantly reduced by antihypertensive treatment (p < 0.001). Furthermore, endocan levels were significantly decreased in both treatment arms (p < 0.05). However, amlodipine caused a greater percent decrease in circulating endocan levels compared with valsartan at the end of the treatment period. Both drugs reduced high sensitivity C-reactive protein values. However, the statistical significant difference vs baseline was achieved only in the group treated with amlodipine. No correlation was found between endocan plasma levels and BP reduction. The results of this hypothesis-generating study suggest that amlodipine and valsartan decrease endocan levels in newly diagnosed hypertensive patients. The effects, which are more evident with amlodipine, may contribute to the anti-inflammatory effects exerted by the two drugs on the vascular target.

Comparative effects of nebivolol and metoprolol on red cell distribution width and neutrophil/lymphocyte ratio in patients with newly diagnosed essential hypertension.

High level of circulating red cell distribution width (RDW) and neutrophil/lymphocyte (N/L) ratio may reflect ongoing vascular inflammation and play an important role in pathophysiology of hypertension. We evaluate the effects of nebivolol and metoprolol on the RDW and N/L in new essential hypertensive patients. After baseline assessment, 72 patients were randomly allocated to 5 mg/d of nebivolol (n = 37, 20 men) or 100 mg/d of metoprolol (n = 35, 18 men) and treated for 6 months. Blood pressure (BP), heart rate (HR), RDW, and N/L were measured before and after treatment. BP significantly decreased with both drugs (P < 0.001). Analog reduction was observed for resting HRs (P < 0.001), but metoprolol caused greater HR fall as compared with nebivolol (P < 0.001). After 6 months of treatment, nebivolol significantly lowered not only RDW but also the total white blood cell and N/L (P < 0.001, P = 0.023, P = 0.017, respectively). No changes were observed in metoprolol group. Percent decrease in RDW was found to be significantly higher in nebivolol than in the metoprolol group (P = 0.001) and remained also after correction for confounders (P = 0.012). Nebivolol improved RDW and N/L to a greater extent than metoprolol in patients with hypertension. These favorable effects may participate, together with the BP reduction, at the favorable properties of the drug in hypertension.

Vascular inflammation and aortic stiffness relate to early left ventricular diastolic dysfunction in prehypertension.

Prehypertension is characterized by an increased cardiovascular risk and by an increased prevalence of target organ damage compared with the pure normotensive state. The present study was designed to assess in prehypertensive subjects the possible relationships between early left ventricular dysfunction, vascular inflammation and aortic stiffness. The study population consisted of 31 untreated prehypertensive subjects (age: 34 ± 6 years, mean ± SD) and 31 age-matched pure normotensive controls. Left ventricular function was assessed by echocardiography, aortic distensibility parameters were derived from aortic diameters measured by ultrasonography, and high-sensitivity C-reactive protein was assessed by latex-enhanced reagent. Prehypertensive subjects displayed a significantly lower E/A ratio and a significantly greater deceleration time and isovolumetric relaxation time compared with normotensive controls. They also displayed aortic systolic diameter, diastolic diameter and mean aortic stiffness index beta significantly increased while systo-diastolic diameter change, mean aortic distensibility and aortic strain were significantly reduced compared with controls. Values of inflammatory markers were increased. At multiple regression analysis, E/A ratio was significantly related to high-sensitivity C-reactive protein and aortic stiffness index beta, after correction for age, left ventricular mass index and mean blood pressure (ß coefficient = -0.49, overall r(2) = 0.24, p = 0.01 and ß coefficient =-0.46, overall r(2) = 0.21, p = 0.02, respectively). Thus, in prehypertension, left ventricular dysfunction is significantly related to vascular inflammation and aortic stiffness, suggesting that early cardiac and vascular alterations may have an increased inflammatory process as a common pathophysiological link.

Beta-Blockers and Hypertension: Some Questions and Answers.

INTRODUCTION: International guidelines have removed b-blockers from first-line treatment of hypertension, limiting their use to patients with compelling indications. The position of guidelines stems from the results of studies performed with the 1st and 2nd generation of b-blockers, which concluded that these drugs have lower cardiovascular protection, compared with other antihypertensive agents. AIM: The aim of our mini review is to answer to some questions about the effect of b-blockers on hypertension and cardiovascular protection and if these effects are different from those of other antihypertensive drugs, particularly in young and elderly patients. METHODS: We evaluated the relevant systematic reviews and meta-analyses, which reported the effectiveness of b-blockers on blood pressure and cardiovascular outcomes, compared with placebo/no treatment and with other antihypertensive agents. RESULTS: Beta-blockers, decreased high blood pressure with no significant difference from other common antihypertensive agents. Moreover b-blockers, compared with placebo, lowered the risk of major cardiovascular outcomes, while, compared with other drug classes, the reported results are very heterogeneous. Therefore it is difficult, globally, to find a difference between b-blockers and other drug classes. CONCLUSIONS: Rather than looking for differences in the cardiovascular protective effect between b-blockers and other antihypertensive agents, we have to consider the different pathophysiology of hypertension in young [sympathetic hyperactivity] and elderly patients [arterial stiffness, high aortic systolic pressure]. Considering these aspects, non-vasodilating b-blockers are preferred, as first-line, in young/middle aged hypertensive subjects, while vasodilating b-blockers, are most appropriate, in elderly patients, for the favourable hemodynamic profile.

Do Statins Counteract the Effect of Antidiabetic Drugs? Results of the SCEAD Study.

PURPOSE: Diabetes and dyslipidemia are leading causes of mortality and morbidity. According to international guidelines, statins are the cornerstone of treatment in patients with diabetes and/or dyslipidemia. However, statins and antidiabetic agents have opposite pharmacological effects, because statins, particularly atorvastatin and rosuvastatin, impair glucose homeostasis, increasing the risk of new-onset diabetes, whereas antidiabetic drugs improve glycemic homeostasis. The aim of this study was to investigate the effect of atorvastatin, rosuvastatin, and pitavastatin on glucose homeostasis in patients with type 2 diabetes mellitus (T2DM) and dyslipidemia during stable treatment with hypoglycemic drugs. MATERIALS AND METHODS: The study was conducted as a pilot, prospective, randomized, open label, parallel group with blinded-endpoints (PROBE) study. Of 180 recruited patients with T2DM and dyslipidemia, 131 were randomized to atorvastatin (n=44), rosuvastatin (n=45), and pitavastatin (n=42) and treated for 6 months. RESULTS: Fasting plasma glucose (FPG) marginally decreased in patients assigned to atorvastatin (-3.5 mg/dL, p=0.42) and rosuvastatin (-6.5 mg/dL, p=0.17), while it decreased much more in patients treated with pitavastatin (-19.0 mg/dL, p<0.001). Mean glycated hemoglobin A1c (HbA1c ) values remained unchanged during treatment with atorvastatin (-0.10%, p=0.53) and rosuvastatin (0.20%, p=0.40), but were significantly reduced with pitavastatin (-0.75%, p=0.01). Atorvastatin, rosuvastatin, and pitavastatin significantly lowered (p<0.001) plasma levels of total cholesterol, low-density lipoprotein-cholesterol, and triglycerides, while high-density lipoprotein-cholesterol (HDL-C) levels increased significantly (p=0.04) only in the pitavastatin group. CONCLUSION: The results of the present study suggest that pitavastatin affects FPG and HbA1c less than atorvastatin and rosuvastatin in patients with T2DM and concomitant dyslipidemia. Lipid-lowering efficacies were not significantly different among the three statins, with the exception of HDL-C, which increased significantly with pitavastatin. Although the pharmacological mechanism of pitavastatin on glucose homeostasis in patients with T2DM during stable antidiabetic therapy is not known, it can be assumed that pitavastatin has less drug interaction with hypoglycemic agents or that it increases plasma levels of adiponectin.

Left ventricular diastolic dysfunction in newly diagnosed untreated hypertensive patients.

Essential hypertension is characterized by a left ventricular dysfunction. However, the majority of the studies performed so far investigated patients under drug treatment and/or with concomitant diseases, such as obesity, diabetes, metabolic syndrome or coronary heart disease, which per se may affect diastolic function independently on the blood pressure elevation. The present study aimed at investigating left ventricular diastolic function in untreated, uncomplicated and newly diagnosed hypertensive patients by employing both routine echo-Doppler and pulse tissue-Doppler technique. Data were collected in 86 middle-aged essential hypertensive patients and in 18 sex-matched normotensive controls. At the echo-Doppler approach, about half of the hypertensive patients displayed a diastolic dysfunction (n = 44, E/A: 0.79 ± 0.02). They showed body mass index values slightly greater than hypertensive patients without diastolic dysfunction but superimposable blood pressure values and metabolic variables. When assessed via the pulse tissue-Doppler approach, patients with a reduced E/A displayed an Em/Am ratio significantly lower than patients without diastolic dysfunction and control subjects. This was the case when the data were related to the lateral and septal mitral annulus or averaged together. Furthermore, whereas myocardial systolic peak velocity (Sm) was lower in hypertensive patients than in control subjects, no significant between-groups difference in E/Em ratio was observed. Differently from the data obtained via the echo-Doppler approach, the tissue-Doppler method in patients without diastolic dysfunction showed a significant higher deceleration and isovolumetric relaxation times, with a lower Em velocity compared with the normotensive subjects. At the stepwise multiple regression analysis E/A ratio and E'/A' values were related with left ventricular mass index and body mass index after correction for age. These data provide evidence that diastolic dysfunction is of frequent detection in the earlier uncomplicated phases of the disease and that tissue Doppler detects an initial impairment of left ventricular relaxation in the patients in which at echo Doppler is still normal.

Pitavastatin: Coronary Atherosclerotic Plaques Changes and Cardiovascular Prevention.

Stains remain the first therapeutic approach in patients with dyslipidemia to control plasma lipids levels and cardiovascular risk. Multiple clinical trials have demonstrated the benefits of statins in reducing major cardiovascular adverse events in primary and secondary prevention. Moreover, in patients with coronary artery disease, statins decrease coronary atherosclerotic plaque volume and composition, inducing atheroma stabilization. Pitavastatin, is a new-generation lipophilic statin, indicated for the treatment of dyslipidemia and prevention of cardiovascular diseases. The purpose of this review, the first at our knowledge on this topic, is to summarize and examine the current knowledge about the effectiveness of pitavastatin in patients with coronary artery disease. The available data suggest that pitavastatin significantly, lowers the rate of adverse cardiovascular events, in patients at a high risk of atherosclerotic disease, with stable angina pectoris or with acute coronary syndrome. Moreover intravascular ultrasound have shown that pitavastatin induces favorable changes in plaque morphology, increasing the fibrous cap thickness, and decreasing both plaque and lipid volume indexes. Globally the efficacy of pitavastatin is greater or similar to other statins.

Antiretroviral Treatment and Antihypertensive Therapy.

The presence of hypertension among the population with human immunodeficiency virus (HIV) has become a new threat to the health and well-being of people living with this disease, in particular, among those who received antiretroviral therapy. The estimated prevalence of high blood pressure in HIV-infected patients is significantly higher than the rate observed in HIV-uninfected subjects. The approach to the HIV-positive patient requires the assessment of individual cardiovascular risk and its consideration when designing the individualized target. On the other hand, the numerous pharmacological interactions of antiretroviral (ARV) drugs are essential elements to take into account. Serum levels of any kind of antihypertensive drugs may be influenced by the coadministration of protease inhibitors, non-nucleoside reverse transcriptase inhibitor, or other antiretroviral. Similarly, plasma concentrations of antiretroviral drugs can be increased by the concomitant use of calcium channel blockers or diuretics. In this regard, the treatment of high blood pressure in HIV patients should be preferentially based on ACE inhibitors or thiazide/thiazide-like diuretics or their combination.

PAIT-Survey Follow-Up: Changes in Albuminuria in Hypertensive Diabetic Patients with Mild-Moderate Chronic Kidney Disease.

INTRODUCTION: Albuminuria is an early marker of kidney disease and reduction of albuminuria translates into a decreased occurrence of cardiovascular and renal outcomes. AIMS: To evaluate the changes in the prevalence of albuminuria in diabetic hypertensive patients treated with several combinations of renin-angiotensin aldosterone system with calcium channel blockers. METHODS: We analysed data from 668 unselected patients from the PAIT survey (mean age 60.4 ± 10.2 years, prevalence of males 38%), with and without albuminuria, maintained for 6 months with the previous treatment with amlodipine-valsartan, amlodipine perindopril, lercanidipine-enalapril, verapamil-trandolapril, nitrendipine-enalapril and felodipine-ramipril Albuminuria was assessed, as urinary albumin-creatinine ratio, using a Multistic-Clinitek device analyzer. Microalbuminuria was defined as a loss of 3.4-33.9 mg albumin/mmol creatinine (30-300 mg/g) and macroalbuminuria as a loss of > 33.9 mg albumin/mmol creatinine (> 300 mg/g). Blood pressure was measured with a validated digital device. RESULTS: At baseline, albuminuria was present in 310 subjects (46.4%) (microalbuminuria in 263 (84.8%), macroalbuminuria in 15.2%), and normoalbuminuria in 53.6% 358. After 6 months, the prevalence of subjects with albuminuria was significantly lowered (p < 0.01) by 23.5% (microalbuminuria - 23.9%, p < 0.01 and macroalbuminuria - 21.3%). The prevalence of subjects with microalbuminuria was reduced with all treatments: amlodipine-valsartan - 15.6%, amlodipine-perindopril - 11.8%, lercanidipine-enalapril - 41.3% and verapamil-trandolapril - 19.2%. Data with nitrendipine-enalapril and felodipine-ramipril were not analyzed, due to the low number of patients. The frequency of patients with normoalbuminuria was significantly higher (p < 0.01) with lercanidipine-enalapril compared with any other treatment. Blood pressure was significantly (p < 0.01) reduced, with a similar effect between treatments. CONCLUSIONS: The treatments decrease the prevalence of subjects with albuminuria, showing a significant difference among the different drug combinations, favoring the use of new dihydropyridine calcium channel blockers, such as lercanidipine, combined with RAAS inhibitors, to control albuminuria in diabetic hypertensive patients.

J-shaped curve for cardiovascular mortality: systolic or diastolic blood pressure?

Aggressive reduction of blood pressure (BP) may increase cardiovascular events (the J-curve phenomenon) in certain populations. There is a high number of available studies of antihypertensive treatment that provide strong evidence for J-shaped relationships between both diastolic and systolic BP and main cardiovascular outcomes. Nonetheless, most available studies were observational, and randomized trials might not have or lost their statistical power in post-hoc analysis. Contrariwise, most of prospective trial to demonstrate the benefits of intensive blood pressure control were inconclusive. Therefore, further studies are still necessary in order to clarify this issue.

Efficacy and tolerability of nebivolol compared with other antihypertensive drugs: a meta-analysis.

BACKGROUND AND OBJECTIVE: Lowering BP to normal levels without quality of life deterioration is the most important means of reducing cardiovascular risk. Recent studies have challenged the position of beta-adrenoceptor antagonists (beta-blockers) as first-line antihypertensive drugs. Nebivolol is a third-generation, highly selective beta(1)-blocker that causes vasodilation through nitric oxide (NO) release. This meta-analysis investigates the efficacy and tolerability of nebivolol compared with other antihypertensive drugs and placebo in patients with hypertension. METHODS: Twelve randomized controlled studies were included in which nebivolol 5 mg once daily was compared with the recommended clinical doses of other antihypertensive drugs (n = 9), placebo (n = 2), and both (n = 1). The clinical studies were selected after a MEDLINE search up to 2007 using the key words 'nebivolol' and 'hypertension.' RESULTS: Antihypertensive response rates (the percentage of patients achieving target BP levels or a defined DBP reduction) were higher with nebivolol than with ACE inhibitors (odds ratio [OR] 1.92; p = 0.001) and all antihypertensive drugs combined (OR 1.41; p = 0.001) and similar to beta-blockers, calcium channel antagonists (CCAs) and the angiotensin receptor antagonist (ARA) losartan. Moreover, a higher percentage of patients receiving nebivolol achieved target BP levels compared with patients treated with losartan (OR 1.98; p = 0.004), CCAs (OR 1.44; p = 0.024), and all antihypertensive drugs combined (OR 1.35; p = 0.012). The percentage of patients experiencing adverse events did not differ between nebivolol and placebo; adverse event rates were significantly lower with nebivolol than losartan (OR 0.52; p = 0.016), other beta-blockers (OR 0.56; p = 0.007), nifedipine (OR 0.49; p < 0.001), and all antihypertensive drugs combined (OR 0.59; p < 0.001). CONCLUSION: Results of previous pharmacokinetic studies suggest that nebivolol 5 mg may not conform completely to the definition of a classic beta-blocker demonstrating additional antihypertensive effect due to endothelial NO release-mediated vasodilation. This meta-analysis showed that nebivolol 5 mg achieved similar or better rates of treatment response and BP normalization than other drug classes and other antihypertensive drugs combined, with similar tolerability to placebo and significantly better tolerability than losartan, CCAs, other beta-blockers, and all antihypertensive drugs combined. Although not definitive, this meta-analysis suggests that nebivolol 5 mg is likely to have advantages over existing antihypertensives and may have a role in the first-line treatment of hypertension.

PAIT-survey-Prevalence of albuminuria in patients with diabetes and hypertension in Turkey.

BACKGROUND: Albuminuria is an early marker of kidney disease in patients with diabetes and/or hypertension undetected or untreated albuminuria is a leading cause of chronic kidney disease and cardiovascular events, The purpose of the present survey was to assess the prevalence of albuminuria in patients with diabetes and hypertension, treated with a combinations of renin angiotensin aldosterone system inhibitors and dihydropyridine calcium channel blockers. METHODS: The survey was performed in 105 Primary Care Units in Turkey and involved outpatients, routinely visited by either a specialist or a non-specialist physician. Albuminuria was evaluated in a spot morning urine sample, as albumin-creatinine ratio, using the Multistic-Clinitek-device analyzer (Siemens), that has a strong correlation with 24-h urinary albumin excretion. Microalbuminuria was defined as a loss of 3.4-33.9mg albumin/mmol creatinine and macroalbuminuria as a loss of >33.9mg albumin/mmol creatinine. Diabetes was assessed through documented blood glucose concentration or use antidiabetic drugs, whereas hypertension through blood pressure measurement and current antihypertensive treatment. RESULTS: The survey enrolled 1708 subjects with a prevalence of type 2 diabetes (87.6%). Albuminuria was detected in 52.0% of patients. Blood pressure was controlled in 37.0% and diabetes in 56.7%. The risk of albuminuria was significantly high in patients with uncontrolled diabetes (p<0.001) and blood pressure (p=0.009). CONCLUSIONS: In a large cohort of treated hypertensive patients with diabetes, albuminuria was present in about 50% and was correlated with poor diabetes and blood pressure control. Systematic screening of albuminuria, particularly in Primary Care, is an important tool for the early diagnosis of nephropathy.

Dihydropyridine calcium channel blockers and renal disease.

Although blood pressure control is considered the main mechanism for preventing the progression of chronic kidney disease (CKD), angiotensin-converting enzyme inhibitors and angiotensin receptors blockers have an additional organ-protective role. The effects of calcium channel blockers (CCBs) in renal disease are not so clearly defined. CCBs have pleiotropic effects that might contribute to protection of the kidney, such as attenuating the mesangial entrapment of macromolecules, countervailing the mitogenic effect of platelet-derived growth factors and platelet-activating factors and suppressing mesangial cell proliferation. Some evidence has accumulated in recent years demonstrating that the new dihydropyridinic CCBs (such as lercanidipine or efonidipine) may affect both postglomerular and preglomerular vessels, resulting in a decreased filtration fraction and nephroprotective effect. Increasing clinical and experimental evidence supports this view and the use of CCBs in CKD hypertensive patients.

Lercanidipine in the Management of Hypertension: An Update.

Calcium channel blockers (CCBs), particularly dihydropyridine-CCBs, (DHP-CCBs), have an established role in antihypertensive therapy, either as monotherapy or in combination with other antihypertensive drugs. Two hundred and fifty-one papers published in PubMed in English between January 1, 1990, and October 31, 2016, were identified using the keyword "lercanidipine." Lercanidipine is a lipophilic third-generation DHP-CCB, characterized by high vascular selectivity and persistence in the smooth muscle cell membranes. Lercanidipine is devoid of sympathetic activation, and unlike the first and second generation of DHP-CCBs, it dilates both the afferent and the efferent glomerular arteries, while preserving the intraglomerular pressure. In addition, lercanidipine prevents renal damage induced by angiotensin II and demonstrates anti-inflammatory, antioxidant, and anti-atherogenic properties through an increasing bioavailability of endothelial nitric oxide. It is associated with a regression of microvascular structural modifications in hypertensive patients. The efficacy of lercanidipine has been demonstrated in patients with different degrees of hypertension, in the young and elderly and in patients with isolated systolic hypertension. In patients with diabetes and renal impairment, lercanidipine displays a renal protection with a significant decrease of microalbuminuria and improvement of creatinine clearance. Lercanidipine is well tolerated and is associated with a very low rate of adverse events, particularly ankle edema, compared with amlodipine and nifedipine. In conclusion, lercanidipine produces a sustained blood pressure-lowering activity with a high rate of responder/normalized patients, associated with a favorable tolerability profile.

Does a blood pressure J curve exist for patients with chronic kidney disease?

Aggressive reduction of blood pressure may increase cardiovascular events (the J-curve phenomenon) in certain populations. In this regard, most studies in patients with chronic kidney disease have shown a J curve for cardiovascular morbidity and mortality, and this phenomenon persists after adjusting for confounding factors. Since there is no evidence that a straighter blood pressure target (<130/70 mm Hg) could improve renal outcomes, the increased cardiovascular risk associated with extreme blood pressure reduction should be seen as undesirable. Moreover, the intensive control of blood pressure may induce an unintended reduction of renal function and this decrease, in turn, may increase cardiovascular risk.

Multicenter Randomized Double-Blind Comparison of Nebivolol plus HCTZ and Irbesartan plus HCTZ in the Treatment of Isolated Systolic Hypertension in Elderly Patients: Results of the NEHIS Study.

INTRODUCTION: The present study was aimed at comparing the antihypertensive efficacy, tolerability, and side effects profile of nebivolol/hydrochlorothiazide (NH) vs irbesartan/hydrochlorothiazide (IH) combination in elderly patients with isolated systolic hypertension (ISH). METHODS: 124 ISH patients aged 69.1 ± 5.1 years (mean ± SD) were enrolled by 13 general practitioners in Netherlands and Belgium and randomized in a double-blind fashion to receive either NH (5/12.5 mg day, n = 62) or IH (150/12.5 mg day, n = 62) for a 12-week period. The primary efficacy endpoint of the study was the comparison of the two combinations in terms of sitting office systolic blood pressure (BP) reduction after 12 weeks of treatment. In addition ambulatory BP, 24-h BP variability, tolerability, and safety profile were also investigated. RESULTS: 122 patients were included in the intention-to-treat analysis. After 12 weeks of treatment the reduction of systolic BP with NH was significantly greater than IH (-25.8 ± 12 vs -21.2 ± 14 mm Hg, P < 0.03). Diastolic BP reduction was significantly greater with NH after 4 and 8 weeks of treatment but similar at the end of the study (or after 12 weeks). In contrast, the magnitude of the 24-h, daytime, and nighttime systolic and diastolic BP reduction was almost similar in the two groups, while heart rate reduction induced by NH was significantly (P < 0.001) greater during the 24-h, daytime, and nighttime period than that induced by IH. NH caused a reduction in 24-h BP variability significantly greater than IH (standard deviation -4.4 ± 2.7 vs -2.2 ± 5.1 mm Hg, P < 0.02, variation coefficient -2.0 ± 2.6 vs -0.3 ± 3.4%, P < 0.01). Both treatment regimens were well tolerated. CONCLUSIONS: These data provide evidence that NH reduces office BP more than IH but has similar effects on 24-h BP. NH reduces 24-h systolic and diastolic BP variability more than IH, suggesting a greater protective effect on a variable known to adversely affect prognosis. TRIAL REGISTRATION: EU clinical Trials Register identifier, 2010-023104-28. FUNDING: Menarini International Operations Luxembourg.

Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients.

OBJECTIVES: To determine the effects of nebivolol on oxidative stress, insulin resistance, adiponectin and plasma soluble P-selectin levels in hypertensive patients in comparison with metoprolol. MATERIAL AND METHODS: Eighty newly diagnosed hypertensive patients in grade 1 hypertension according to the European Society of Hypertension and European Society of Cardiology guidelines were enrolled in this prospective, blinded, randomized study. Seventy-two patients completed the study. After baseline assessment, each patient was randomly allocated to a 5 mg daily dose of nebivolol (n = 37, 20 male) or a 100 mg daily dose of metoprolol (n = 35, 18 male) and treated for 6 months. Blood pressure, heart rate, oxidative stress (malonyldialdehyde), homeostasis model assessment: insulin resistance, adiponectin and plasma soluble P-selectin levels were measured before and after treatment. RESULTS: At the end of treatment, nebivolol and metoprolol significantly decreased blood pressure and heart rate, with a more pronounced bradycardic effect of metoprolol. Nebivolol, but not metoprolol, significantly lowered oxidative stress (P = 0.03), the insulin resistance index (P = 0.003) and plasma soluble P-selectin levels (P = 0.008), and increased adiponectin levels (P = 0.04). CONCLUSION: Nebivolol, in contrast to metoprolol, improved oxidative stress, insulin sensitivity, decreased plasma soluble P-selectin and increased adiponectin levels in hypertensive patients. These beneficial effects of nebivolol may contribute to a reduction in cardiovascular risk in hypertensive patients.