Curr Hypertens Rep (2017) 19: 22 DOI 10.1007/s11906-017-0716-3 HYPERTENSION AND METABOLIC SYNDROME (J SPERATI, SECTION EDITOR) Differential Metabolic Effects of Beta-Blockers: an Updated Systematic Review of Nebivolol Maria Marketou1 & Yashaswi Gupta2 & Shashank Jain 2 & Panos Vardas1 Published online: 10 March 2017 # Springer Science+Business Media New York 2017 Abstract Blood pressure management in hypertensive pa- Introduction tients with metabolic abnormalities is challenging, since many of the antihypertensive drugs adversely affect metabolism. A high prevalence of metabolic abnormalities is observed in Besides effective control of blood pressure in patients with hypertensive patients. In particular, these patients have a 2.5- hypertension, third-generation beta-blockers such as nebivolol fold higher risk of developing type 2 diabetes when compared offer additional benefits for central hemodynamics and neutral to normotensives [1]. In addition, approximately 70% of hy- or beneficial effects on metabolism. Emerging clinical data pertensive patients are overweight. Along with other metabol- suggest that nebivolol also has similar effects on metabolism ic cardiovascular risk factors, such as insulin resistance and in obese hypertensive and hypertensive diabetic patients. The dyslipidemia, hypertension is also included among the criteria present article will provide a systematic analysis of the path- for metabolic syndrome [2]. ophysiological links among hypertension, insulin resistance, Over the last few years, many classes of antihypertensive and metabolic syndrome. We will also summarize the avail- drugs have been used to control blood pressure in hyperten- able clinical evidence regarding the metabolic effects of beta- sive patients. The metabolic effects of these antihypertensive blockers in hypertensive patients, with an emphasis on agents should be considered with a view to improving the nebivolol. Nebivolol exerts neutral or beneficial effects on long-term prognosis. The adverse metabolic effects of some insulin sensitivity and lipid metabolism in hypertensive pa- antihypertensive drugs, such as conventional beta-blockers, tients, owing to its nitric oxide-mediated vasodilatory and an- may offset their beneficial blood pressure (BP)-lowering ef- tioxidative properties. Thus, nebivolol could be a favorable fects. Hence, the chosen antihypertensive treatment should therapeutic option for the treatment of hypertension in patients offer benefits beyond BP control while avoiding adverse ef- with impaired glucose and lipid metabolism. fects that could have a prognostic impact. Nebivolol is a third-generation beta-blocker [3]. It is a ra- cemic mixture of a D- and an L-isomer (1:1), of which d- Keywords Hypertension . Insulin sensitivity . Lipid nebivolol displays antagonistic activity that is highly selective metabolism . Nebivolol . Obesity for the beta-1 adrenergic receptor. The affinity of d-nebivolol for beta-1 adrenoceptors is approximately 175 times greater than that of l-nebivolol [4]. The L-isomer of nebivolol causes the stimulation of endothelial nitric oxide synthase (eNOS) This article is part of the Topical Collection on Hypertension and Metabolic Syndrome and subsequent endothelium-dependent vasodilation. Nebivolol has a unique profile among antihypertensive drugs: * Panos Vardas high selectivity for the beta-1 adrenergic receptor, agonistic [email protected] action on beta-3 receptors, and nitric oxide (NO)-mediated vasodilatory and antioxidant properties. NO is an important 1 Cardiology Department, Heraklion University Hospital, bioactive signaling molecule that mediates a variety of normal P.O. Box 1352, Stavrakia, Heraklion, Crete, Greece physiological functions and may regulate glucose metabolism 2 SPRIM Asia-Pacific Pvt. Ltd., Singapore, Singapore through multiple pathophysiologic mechanisms (Table 1). 22 Page 2 of 10 Curr Hypertens Rep (2017) 19: 22 Table 1 Possible mechanisms of nitric oxide metabolic effects overactivated in hypertension, contributes to β-cell dysfunc- • Anti-inflammatory and antioxidant properties tion and has a detrimental effect on insulin secretion [15]. • Regulation of mitochondrial respiration and mitochondrial biogenesis Clinical studies have shown that approximately 50% of • Regulation of the binding and release of oxygen with hemoglobin individuals with elevated BP also have insulin resistance. Although the association between insulinemia and hyperten- • Activation of peroxisome proliferator-activated gamma receptors sion is controversial, there is evidence of a possible link be- • Smooth muscle relaxation and vasodilation tween insulin, hypertension, and type 2 diabetes [7]. Insulin • Increase of blood flow at sites of very low oxygen concentrations resistance may also lead to prediabetes and diabetes [16]. Insulin resistance increases pancreatic beta-cell activity; Owing to the combination of these properties, nebivolol is this leads to hyperinsulinemia, which causes impaired glucose associated with clinically significant improvement in BP con- tolerance, hyperglycemia, and overt diabetes. An association trol in hypertensive patients. It is well tolerated and appears to between hyperinsulinemia and hypertension has been reported exert far fewer adverse metabolic effects when compared to in both obese and nonobese individuals [17]. Insulin activates other beta blockers [5–8, 9••, 10]. the sympathetic nervous system (SNS), increases renal tubular In this review article, we will discuss the pathophysiolog- sodium reabsorption, alters ion transport, enhances sodium ical links between hypertension and other metabolic condi- reabsorption by the kidney, and causes hypertrophy of vascu- tions in patients with insulin resistance, obesity, dyslipidemia, lar smooth muscle [18]. SNS activation appears to be the and metabolic syndrome. We will summarize the clinical ev- common pathophysiological pathway linking insulin resis- idence concerning the metabolic effects of the commonly used tance and hypertension. In physiological conditions, insulin beta-blockers in hypertensive patients. We will also provide a stimulates NO production and vasorelaxation. In contrast, in critical review of the available clinical trial data regarding the insulin-resistant conditions, the insulin-stimulated NO path- effects of the new-generation beta-blockers in hypertensive way is impaired and compensatory hyperinsulinemia may ac- patients, emphasizing the impact of nebivolol on insulin resis- tivate inflammation and vasoconstriction. Diabetes and hyper- tance and dyslipidemia and its implications for comprehensive tension share common pathways, such as overactivation of the clinical management. SNS, the renin–angiotensin–aldosterone system (RAAS), ox- idative stress, and adipokines, which play a fundamental role in vascular pathophysiology [19]. Diabetes and hypertension also share common pathways, such as the SNS, RAAS, oxi- Insulin Sensitivity and Glucose Metabolism dative stress, adipokines, insulin resistance, and peroxisome in Hypertensive Patients proliferator-activated receptors, which interact and influence each other. Insulin is an important hormone that plays a crucial role in the Different classes of antihypertensive drugs exert differen- regulation of glucose, lipid metabolism, and energy storage. It tial effects on metabolic status and glucose homeostasis [1]. is an anabolic hormone with complex vascular actions that Calcium-channel blockers do not adversely affect glucose me- might be beneficial or deleterious to the arterial wall [11]. tabolism, angiotensin receptor blockers (ARBs) and Theprotectiveeffects,suchasvasodilation,aremediatedby angiotensin-converting enzyme inhibitors (ACE-i) improve NO-dependent mechanisms in the endothelium, while the del- glucose metabolism, whereas conventional nonvasodilatory eterious effects of insulin, such as vasoconstriction, prolifera- beta-blockers and diuretics are associated with impaired glu- tion of vascular smooth muscle cells, and proinflammatory cose metabolism. activity, are mediated through the mitogen-activated protein kinase (MAPK) pathway [11]. In clinical conditions with in- sulin resistance, the insulin-stimulated NO pathway is selec- Hypertension in Patients with Metabolic Syndrome tively impaired and the MAPK pathway is overactivated [12, 13]. This results in an increase in proinflammatory mediators, Metabolic syndrome is a cluster of metabolic risk factors that sodium and water retention, vasoconstriction, and finally, el- include abdominal obesity, dyslipidemia, elevated plasma glu- evation of BP. Insulin-mediated glucose uptake is linked with cose, hypertension, and insulin resistance. The definition of NO-dependent vasodilation, since they share similar signaling metabolic syndrome by the Evaluation and Treatment of High pathways [14]. Blood Cholesterol in Adults (ATP III) is widely accepted [20]. Hypertension is often associated with impaired glucose According to these guidelines, metabolic syndrome can be metabolism and insulin sensitivity. There is a plethora of pub- defined as a condition in which 3 or more of the following lished data relating hypertension and insulin resistance, a com- risk factors are present: BP ≥130/85 mmHg (or drug treatment bination that often leads to an increased risk of diabetes type 2 for hypertension), high-density lipoprotein cholesterol (HDL) and cardiovascular disease. Angiotensin, which may be <1.0 mmol/L (40 mg/dL) in men or <1.3 mmol/L (50 mg/dL) Curr Hypertens Rep (2017) 19: 22 Page 3 of