中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
β受体阻断药自20世纪60年代上市以来,已被广泛应用于降低冠心病患者的心血管事件死亡风险。然而,由于不同类型的β受体阻断药对糖脂代谢的影响不同,从而影响冠心病及糖尿病患者的预后,所以在冠心病合并糖尿病时如何选择β受体阻断药至关重要。一系列的临床研究表明,以阿替洛尔等为代表的非血管舒张性β受体阻断药可能有新增糖尿病的风险,而以卡维地洛为代表的血管舒张性β受体阻断药在调节糖代谢等方面发挥着较为乐观的作用,且具有较好的安全性和耐受性。然而目前探究或报道不同类型的β受体阻断药对冠心病合并糖尿病患者的作用差异及用药选择的综述性文献较少,因此,该文将就近年来不同类型的β受体阻断药在冠心病合并糖尿病患者的临床研究,对糖脂代谢等方面的影响及临床上如何进行合理地选择使用作一综述。
尽管β受体阻断药改善冠心病患者预后的证据确凿,却少有文献报道或探究不同类型的β受体阻断药对冠心病合并糖尿病患者的作用效果差异及合理用药选择。笔者就近年来β受体阻断药在冠心病合并糖尿病患者的临床研究,对糖脂代谢等方面的影响及临床上如何合理使用综述如下。
根据对血管活性效应的不同,β受体阻断药可以分为非血管舒张性β受体阻断药和血管舒张性β受体阻断药两大类。
多为第3代β受体阻断药,又称为糖尿病友好型(DM-friendly)。该类药物除具有阻断β受体的作用外,还可通过阻断α1肾上腺素能受体(如卡维地洛、拉贝洛尔、阿尔马尔)或其他机制(如奈必洛尔、布新洛尔)等,产生外周血管扩张活性。
通过单药随访观察或与钙通道阻滞药(calcium channel blockers,CCBs),血管紧张素转化酶抑制药和血管紧张素受体阻断药(angiotensin converting enzyme inhibitors/angiotensin receptor blocker,ACEI/ARBs)等冠心病常用药物比较,研究显示非血管舒张性β受体阻断药可能存在导致糖代谢异常的不良反应。
在HAENNI等[17]研究中,在对原发性高血压患者进行为期6个月的美托洛尔治疗后,这些患者的快速血糖水平并没有明显改变,但糖化血红蛋白(HbA1C)却在基线水平上提高了5.4%(
一项纳入了12项临床试验的Meta分析比较了在高血压患者中,使用β受体阻断药的新发糖尿病风险。相比于安慰药组,治疗组患者应用阿替洛尔和普萘洛尔其新发糖尿病的风险增加了44%[
美托洛尔是目前我国冠心病患者临床使用最广泛的β受体阻断药之一[21],然而在有关血管舒张性β受体阻断药与美托洛尔或阿替洛尔进行比较的临床研究中,多数研究证实血管舒张性β受体阻断药对糖脂代谢的调节更具优势,应成为冠心病合并糖尿病患者用药的优先选择[22,23,24,25]。
研究提示,卡维地洛与美托洛尔对胰岛素敏感性的影响可能存在不同,而胰岛素敏感性的下降又与内皮功能不全和胰岛素刺激下的内皮功能变化密切相关。KVEIBORG等[26]研究了美托洛尔与卡维地洛对2型糖尿病患者内皮功能和胰岛素刺激性内皮功能的作用差异。研究中美托洛尔组的患者胰岛素刺激性的内皮功能有所下降,卡维地洛组无明显改变。该结果提示,在2型糖尿病患者中,美托洛尔会降低胰岛素敏感性,而卡维地洛治疗的患者不会改变甚至可能改善胰岛素敏感性。
2014年ARNOLD等[5]观察了TRIUMPH研究中美国24家医院心肌梗死注册的1 382例糖尿病患者,将“血糖控制不佳”(worsened glucose control)定义为HbA1C比基线水平上升超过0.1%,或使用强化糖尿病药物治疗(包括降糖药物剂量增加、种类增加、加用胰岛素或每日胰岛素用量增加20%)。研究结果显示:在多因素分析模型中,服用糖尿病友好型β受体阻断药的糖尿病患者相较非糖尿病友好型发生“血糖控制不佳”的风险降低了20%[
一项纳入了17项研究共2 358例心血管疾病(冠心病、高血压等)同时有应用β受体阻断药指征(合并或不合并糖尿病)患者的Meta分析结果表明,虽然美托洛尔和卡维地洛比较对血糖的影响不大,但是使用美托洛尔治疗后HbA1C显著高于卡维地洛等血管舒张性β受体阻断药,提示卡维地洛更有利于血糖控制[27]。
TEPLIAKOV等[28]研究了奈必洛尔对冠心病合并2型糖尿病患者的安全性和有效性。研究将患者随机分为胰岛素抵抗组和非胰岛素抵抗组,所有患者均接受为期8周的奈必洛尔治疗。结果表明,奈必洛尔对糖代谢和血脂代谢并无不良影响,且患者的平均血胰岛素水平降低了18.4%,胰岛素抵抗指数(以HOMA-IR模型测量)减少了11.9%。此外,研究提示1.25~5 mg·d-1的奈必洛尔可以提高运动耐量和生活质量,改善胰岛素抵抗。
GEMINI试验是一项大规模的随机、对照、双盲的临床试验,旨在评价美托洛尔和卡维地洛对控制血糖效果的差异。研究纳入了1 235例高血压合并糖尿病的患者,随访了35周,结果证实美托洛尔与卡维地洛对降压和控制心率的效果相近,但美托洛尔组患者的血糖和平均HbA1C水平却明显升高,胰岛素抵抗增加,胰岛素敏感性也无改善,患者发生微量白蛋白尿的比例较高。而卡维地洛组患者HbA1C无明显升高,胰岛素抵抗下降(以HOMA-IR模型测量),且胰岛素敏感性增加(9.1%)。此外,卡维地洛组由于血糖控制恶化而退出试验的患者更少[24]。研究提示,鉴于卡维地洛与美托洛尔改善心血管病患者临床结局的效果相近,而在糖代谢方面更具优势,因而应成为β受体阻断药使用的优先选择。
β受体阻断药能明确改善冠心病合并糖尿病患者心血管事件预后[31,32]。大量的临床研究结果表明,β受体阻断药适用于各种类型的冠心病治疗,且能减少合并糖尿病的患者中再次心肌梗死、猝死和心律失常发生率[33]。研究表明,急性心肌梗死合并糖尿病的患者使用以美托洛尔为代表的β受体阻断药能明显降低死亡率和再梗发生率[20]。
ANDERSON等[34]研究了不同类型β受体阻断药对心肌梗死(包括心肌梗死合并糖尿病)患者的死亡率、再次梗死等预后结局指标的差异。研究结果表明,使用β受体阻断药能使冠心病合并糖尿病患者明显获益,且卡维地洛与其他β受体阻断药在改善患者预后上无明显差异。
COMET试验是一项为期5年的大规模、多中心、随机对照临床试验,旨在比较卡维地洛和美托洛尔对心力衰竭患者(包括合并糖尿病患者)临床结局上的差异。研究结果提示使用β受体阻断药的两组患者临床结局和预后均能得到改善,且卡维地洛组患者相较美托洛尔组的患者全因死亡率更低[34%
国内的研究资料表明,心肌梗死合并糖尿病的患者中β受体阻断药应用具有两个特点:一是使用率低,仅为15.6%;二是美托洛尔使用率高[21]。而实际上,不同类型的β受体阻断药在药理学和血流动力学上作用各异,传统的非血管舒张性β受体阻断药可以改善心肌缺血症状,但可能掩盖低血糖症状和增加胰岛素抵抗。而以卡维地洛和奈必洛尔为代表的血管舒张性β受体阻断药心脏选择性高,同时也具有更少的代谢异常的不良反应,导致新发糖尿病的风险也更小。该类药物在糖代谢和调节胰岛素敏感性方面发挥着较为乐观的作用,且不会增高血总胆固醇和低密度脂蛋白胆固醇水平,具有较好的安全性和耐受性,因而应成为冠心病合并糖尿病患者用药的优先选择[5,40]。
迄今为止,由于第3代β受体阻断药的临床研究多为高血压或心力衰竭合并糖尿病,但是在冠心病合并糖尿病中的大规模临床研究的证据十分匮乏,因而目前临床指南推荐的证据级别仍为B级,同时也鲜有探究不同类型的β受体阻断药对冠心病合并糖尿病患者的作用差异及用药选择的综述性文献。此外,该类药物对糖脂代谢的影响和改善患者预后是否存在差别,尚有待于进一步的大规模随机对照临床研究提供证据。
综上所述,根据国内外指南推荐,基于β受体阻断药对改善冠心病合并糖尿病患者预后的显著作用,因此所有冠心病合并糖尿病的患者均应使用β受体阻断药。由于血管舒张性β受体阻断药在代谢方面的优势,因而此类药物应该成为冠心病合并糖尿病患者用药的优先选择。
The authors have declared that no competing interests exist.
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Abstract BACKGROUND: Despite recommended pharmacotherapies the use of secondary prevention therapy after myocardial infarction (MI) remains suboptimal. Patients with diabetes mellitus (DM) have worse prognosis after MI compared to patients without DM and aggressive secondary prevention pharmacotherapy in this population is therefore warranted. We examined the changes in use of evidence-based secondary prevention pharmacotherapy in patients with and without DM discharged after first MI. METHODS: All patients aged 30 years or older admitted with first MI in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations. Univariate and multivariate logistic regression models were used to identify patient characteristics associated with initiation of acetylsalicylic acid, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, -blockers, and clopidogrel within 90 days, and statins within 180 days of discharge, respectively. RESULTS: A total of 78,230 patients were included, the mean age was 68.3 years (SD 13.0), 63.5% were men and 9,797 (12.5%) had diabetes. Comparison of claimed prescriptions in the period 1997-2002 and 2003-2006 showed significant (p < 0.001) increases in claims for acetylsalicylic acid (38.9% vs. 69.7%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (38.7% vs. 50.4%), -blockers (69.2% vs. 77.9%), clopidogrel (16.7% vs. 66.3%), and statins (41.3% vs. 77.3%). During 2003-2006, patients with DM claimed significantly less acetylsalicylic acid (odds ratio [OR] 0.81 [95% confidence interval [CI] 0.74-0.88) and clopidogrel (OR 0.91 [95% CI 0.83-1.00]) than patients without DM. CONCLUSIONS: Despite sizeable increase in use of evidence-based secondary prevention pharmacotherapy after MI from 1997 to 2006, these drugs are not used in a substantial proportion of subjects and patients with DM received significantly less antiplatelet therapy than patients without DM. Increased focus on initiation of secondary prevention pharmacotherapy after MI is warranted, especially in patients with DM.
[本文引用:1]
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Discharge β-blocker prescription after myocardial infarction (MI) is recommended for all eligible patients. Numerous β-blocker choices are presently available with variable glycometabolic effects, which could be an important consideration in patients with diabetes mellitus (DM). Whether patients with DM preferentially receive β-blockers with favorable metabolic effects after MI and if this choice is associated with better glycemic control postdischarge is unknown. Among patients from 24 US hospitals enrolled in an MI registry (2005-2008), we investigated the frequency of “DM-friendly” β-blocker prescription at discharge by DM status. β-Blockers were classified as DM-friendly (eg, carvedilol and labetalol) or non–DM-friendly (eg, metoprolol and atenolol), based on their effects on glycemic control. Hierarchical, multivariable logistic regression examined the association of DM with DM-friendly β-blocker use. Among DM patients, we examined the association of DM-friendly β-blockers with worsened glycemic control at 6 months after MI. Of 4,031 MI patients, 1,382 (34%) had DM. β-Blockers were prescribed at discharge in 93% of patients. Diabetes mellitus–friendly β-blocker use was low regardless of DM status, although patients with DM were more likely to be discharged on a DM-friendly β-blocker compared with patients without DM (13.5% vs 10.3%, P = .003), an association that remained after multivariable adjustment (odds ratio 1.41, 95% CI 1.13-1.77). There was a trend toward a lower risk of worsened glucose control at 6 months in DM patients prescribed DM-friendly versus non–DM-friendly β-blockers (Relative Risk 0.80, 95% CI 0.60-1.08). Most DM patients were prescribed non–DM-friendly β-blockers—a practice that was associated with a trend toward worse glycemic control postdischarge. Although in need of further confirmation in larger studies, our findings highlight an opportunity to improve current practices of β-blockers use in patients with DM.
[本文引用:3]
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The development and subsequent clinical application of the beta-adrenergic receptor blocking drugs over the past 50 years represent one of the major advances in human pharmacotherapy. No other class of synthetic drugs has demonstrated such widespread therapeutic utility for the treatment of so many cardiovascular and noncardiovascular diseases. In addition, these drugs have proven to be molecular probes that have contributed to our understanding of disease, and on the molecular level, both the structure and the function of the 7 transmembrane G protein receptors, which mediate the actions of many different hormones, neurotransmitters, and drugs. The evolution of beta-blocker drug development has led to refinements in their pharmacodynamic actions that include agents with relative beta1-selectivity, partial agonist activity, concomitant alpha-adrenergic blockers activity, and direct vasodilator activity. In addition, long-acting and ultra-short-acting formulations of beta-blockers have also demonstrated a remarkable record of clinical safety in patients of all ages. Indeed, the beta-adrenergic blockers have provided us with a great clinical legacy for now and in years to come.
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Hypertension and type 2 diabetes mellitus (DM) are major cardiovascular risk factors, and often cluster in the same individual in the context of the metabolic syndrome. Management of hypertension in the diabetic patient is extremely important, and agents from all major antihypertensive classes are effective towards this goal. Conventional beta-blockers are associated with detrimental effects on insulin sensitivity, glycaemic control, and the incidence of type 2 DM and thus are less often used in hypertensive patients with DM. In contrast, the newer vasodilating beta-blockers appear to be free of adverse effects on the above metabolic parameters, and could be a valuable tool for hypertension treatment in patients with DM or the metabolic syndrome. This review summarizes the evidence on the effects of antihypertensive treatment with both traditional and vasodilating beta-blockers on parameters related to carbohydrate metabolism, and discuss the pathophysiological mechanisms that may be responsible.
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Sedentary life style and high calorie dietary habits are prominent leading cause of metabolic syndrome in modern world. plays a central role in occurrence of various diseases like , and , which lead to resistance and like (CVDs) mediated by oxidative stress. The mortality rate due to CVDs is on the rise in developing countries. resistance (IR) leads to micro or macro , peripheral arterial dysfunction, hampered blood flow, , as well as the cardiomyocyte and the endothelial dysfunctions, thus increasing risk factors for coronary artery blockage, and suggesting that there is a strong association between IR and CVDs. The plausible linkages between these two pathophysiological conditions are altered levels of such as IR- and PGC-1 that hamper -mediated as well as other functions of in the cardiomyocytes and the endothelial of the heart. Reduced , -2 and elevated levels of NADP(H)-dependent oxidases produced by activated M1 macrophages of the adipose tissue and elevated levels of circulating are also cause of CVD in mellitus condition. sensitizers, blockers, scavengers are used as therapeutics in the amelioration of CVD. It evidently becomes important to unravel the mechanisms of the association between IR and CVDs in order to formulate novel efficient drugs to treat patients suffering from resistance-mediated . The possible associations between resistance and are reviewed here.
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Abstract Anti-adrenergic therapy has been widely accepted as an important therapeutic intervention in patients with chronic heart failure. However, there has been continuing controversy regarding the risks and clinical significance of metabolic effects of different anti-adrenergic drugs. This review summarizes what has been learned from clinical trial evidence regarding the benefits of anti-adrenergic drugs in diabetic patients with chronic heart failure.
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Abstract beta-Adrenoceptor antagonists (beta-blockers) have historically been considered an effective and safe option for first-line treatment of hypertension. However, very recently, it has been proposed that beta-blockers should no longer be considered suitable for first-line therapy in the patient with uncomplicated hypertension because of unfavourable morbidity and mortality data. New evidence from recent clinical studies of nebivolol, a third-generation highly selective beta(1)-blocker with additional endothelial nitric oxide (NO)-mediated vasodilating activity, confirms previous findings that this drug differs from other beta-blockers. The combined mechanisms of beta-adrenoceptor antagonism and NO-mediated vasodilation may potentiate the blood pressure-lowering effect of this agent, and confer a broader favourable metabolic profile, which may be clinically relevant for hypertensive patients. The antioxidant properties of nebivolol and its neutral or even favourable effects on both carbohydrate and lipid metabolism are well documented. These properties consistently differentiate nebivolol from nonvasodilating beta-blockers such as atenolol, metoprolol or bisoprolol. Therapeutic indications for beta-blockers include a wide range of co-morbidities found in hypertensive patients, including ischaemic heart disease, tachyarrhythmias and heart failure. Given that the majority of hypertensive patients require more than one drug to control blood pressure, the multiple mechanisms of action and favourable metabolic profile of nebivolol could make it an alternative therapeutic option for hypertensive patients requiring beta-adrenoceptor therapy.
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ABSTRACT In contrast to classical beta-adrenoreceptor antagonists, nebivolol and carvedilol possess endothelium-dependent vasorelaxant properties. It has been proposed that nebivolol and carvedilol activate microvascular endothelium into producing NO by the release of extracellular ATP and subsequent stimulation of endothelial P(2) receptors. Here we tested this hypothesis in the coronary circulation of the isolated guinea pig heart. We analyzed the role of NO in the coronary vasodilatation induced by nebivolol and carvedilol as well as a possible involvement of extracellular ATP in these responses. Nebivolol and carvedilol (3-30 x 10(-6) M) induced a concentration-dependent coronary vasodilatation that was inhibited by NO-synthase inhibitor, L-NAME (10(-4) M). In contrast to nebivolol and carvedilol, neither atenolol nor labetalol acted as a coronary vasodilator. Vasodilatation induced by nebivolol and carvedilol was affected neither by the P(1) receptor antagonist, 8-sulfophenyl theophylline (8-SPT, 10(-5) M), nor by the P(2) receptor antagonist, suramin (10(-5) M). On the other hand, ATP-induced coronary vasodilatation (0.3-10 x 10(-6) M) was strongly inhibited by L-NAME (10(-4) M), partially inhibited by 8-SPT (10(-5) M), while suramin (10(-5) M) had a minor effect. In conclusion, in the isolated guinea pig heart nebivolol and carvedilol, but not their classical counterparts (atenolol, labelatol), act as NO-dependent coronary vasodilators. It seems unlikely that this response is mediated by the release of extracellular ATP.
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Abstract OBJECTIVE: To compare the effects of the ACE inhibitor perindopril and the beta-blocker carvedilol on blood pressure and endothelial functions in NIDDM patients with hypertension. RESEARCH DESIGN AND METHODS: We conducted a double-blind randomized trial in 26 patients with NIDDM and mild hypertension. A 4-week run-in placebo period preceded the active 12-week treatment with perindopril (4-8 mg daily) or carvedilol (25-50 mg daily). Endothelial functions were assessed by evaluating the hemodynamic (mean blood pressure, leg blood flow) and rheological (platelet aggregation, blood viscosity, and blood filterability) responses to an intravenous bolus of 3 g L-arginine, the natural precursor of nitric oxide. RESULTS: Both perindopril and carvedilol significantly reduced mean blood pressure (P < 0.001) and increased leg blood flow (P < 0.05) to the same extent; blood filterability remained unchanged in both perindopril- and carvedilol-treated groups. Carvedilol reduced platelet aggregation and blood viscosity significantly (P < 0.05) but perindopril did not. Before treatment, the hemodynamic and rheologic responses to L-arginine were significantly lower in patients (P < 0.05-0.01) than in 20 nondiabetic nonhypertensive control subjects. After 12 weeks of treatment, both drugs normalized the hemodynamic responses to L-arginine. Platelet aggregation response to L-arginine was ameliorated by carvedilol and remained unchanged in the perindopril group. CONCLUSIONS: At the doses used, both drugs effectively reduce blood pressure and normalize the hemodynamic responses to L-arginine. The implications of the ameliorated endothelial function for the poor cardiovascular outlook of the NIDDM hypertensive patient need further assessment.
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Most studies assessing the effects of beta-blockers were carried out with traditional, beta(1)-selective beta-blockers, such as metoprolol and atenolol. Pathophysiologic and pharmacologic studies have documented that not all beta-blockers are created equal. In particular, the pharmacologic and clinical profiles of the newer, vasodilating beta-blockers, such as carvedilol, have been shown to differ from those of the traditional beta-blockers. These differences, although relevant in the younger patient with hypertension, are particularly important in elderly patients in whom traditional beta-blockers may not be as effective or as well tolerated as the newer vasodilating agents.
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β-Adrenoceptor blocking agents (β-blockers) have been established as therapeutics for treatment of patients with hypertension, ischemic heart diseases, chronic heart failure, arrhythmias, and glaucoma. However, their clinical use is limited because some patients are adversely affected by their side effects. The discovery of cardioselective (β 1-selective) blockers has overcome some of the problems. Current retrospective studies have revealed that vasodilating β-blockers (so-called β-blockers of the third generation) have advantages over the conventional type of β-blockers in terms of minimizing the adverse effects and improving the disease-derived dysfunction, thus enhancing the quality of life variables. Some of the possible advantages include improvement of insulin resistance, decrease in low-density lipoprotein cholesterol in association with increase in high-density lipoprotein cholesterol, attenuation of bronchial asthma attack and respiratory dysfunction, alleviation of coronary vasospasm provocation, peripheral circulatory disturbances, and erectile dysfunction, and better patient compliance. Release of nitric oxide, antioxidant action, β 2-adrenoceptor activation, Ca 2+ entry blockade, and other mechanisms underlying the vasodilating action may be responsible for the beneficial therapeutic effects of these agents.
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To obtain further insight into the mechanism underlying the vasodilator effect of nebivolol. Since oxidative inactivation of nitric oxide (NO) is regarded as an important cause of its decreased biological activity, we studied (1) the effect of nebivolol on some oxidative parameters in essential hypertensive patients; (2) the effect of plasma of nebivolol-treated patients on reactive oxygen species production and NO availability in endothelial cells. A total of 20 healthy subjects and 20 matched essential hypertensive patients treated with atenolol or nebivolol according to a double-blind, randomized design participated in the study. We measured low-density lipoprotein (LDL) and plasma hydroperoxides, 8-isoprostanes, oxidized LDL, susceptibility of LDL to oxidation (lag phase) and LDL vitamin E and the effect of plasma of nebivolol- and atenolol-treated patients on reactive oxygen species production and NO availability in endothelial cells exposed to oxidative stress. In hypertensive patients, nebivolol and atenolol significantly reduced blood pressure values after 4 weeks of treatment. Plasma and LDL hydroperoxides, plasma 8-isoprostanes, plasma ox-LDL and LDL lag phase were significantly improved only in the patients receiving nebivolol compared with the atenolol group. Similarly there was a reduction of reactive oxygen species (ROS) and O2*- concentration in endothelial cells exposed to oxidative stress after incubation of the cells with plasma of the patients enrolled in the trial only in the patients receiving nebivolol compared to atenolol group. Furthermore, the reduction of basal and stimulated NO induced by oxidative stress in endothelial cells was significantly lower in the patients receiving nebivolol compared to atenolol group. The findings of the present study indicate that nebivolol, through its antioxidant properties, increases NO also by decreasing its oxidative inactivation.
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| [17] |
Abstract In a randomized double-blind crossover study in 42 patients with essential hypertension, the metabolic effects of a beta-adrenergic blocker with a pronounced beta 2-agonistic effect, dilevalol 400 mg x 1, were compared with those of metoprolol succinate 200 mg x 1. The effects of glucose metabolism were evaluated by the hyperinsulinemic euglycemic clamp technique and an intravenous glucose tolerance test (IVGTT). Insulin-mediated glucose disposal (M) and the insulin sensitivity index (M/I) increased by 19% (P = .011) and 10% (P = .27), respectively, during dilevalol treatment, but decreased by 10% (P = .15) and 22% (P = .0025), respectively, during metoprolol treatment, giving rise to significant differences between the two treatment regimens. Compared with dilevalol-treated patients, those treated with metoprolol showed increased plasma insulin values at the end of the IVGTT, but there was no difference in plasma glucose concentrations or glucose tolerance. Hemoglobin A1c (HbA1c) levels increased by 5.4% (P = .04) in the metoprolol group. Serum cholesterol, total serum and very-low-density lipoprotein (VLDL) triglycerides, and serum urate levels decreased significantly (by 6%, 22%, 29%, and 14%, respectively) during dilevalol treatment, and there was a significant difference between the effects of the two drugs on total, VLDL, and low-density lipoprotein (LDL) triglyceride and serum urate levels. These data demonstrate that a beta-blocker with a partial beta 2-agonist action differs in its metabolic effect profile from a selective beta 1-blocker and may offer advantages by improving glucose and lipid metabolism.
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| [18] |
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| [19] |
Abstract Beta blockers used for the treatment of hypertension may be associated with increased risk for new-onset diabetes mellitus (DM). A search of Medline, PubMed, and EMBASE was conducted for randomized controlled trials of patients taking beta blockers as first-line therapy for hypertension with data on new-onset DM and follow-up for > or =1 year. Twelve studies evaluating 94,492 patients fulfilled the inclusion criteria. Beta-blocker therapy resulted in a 22% increased risk for new-onset DM (relative risk 1.22, 95% confidence interval [CI] 1.12 to 1.33) compared with nondiuretic antihypertensive agents. A higher baseline fasting glucose level (odds ratio [OR] 1.01, 95% CI 1.00 to 1.02, p = 0.004) and greater systolic (OR 1.05, 95% CI 1.05 to 1.08, p = 0.001) and diastolic (OR 1.06, 95% CI 1.01 to 1.10, p = 0.011) blood pressure differences between the 2 treatment modalities were significant univariate predictors of new-onset DM. Multivariate meta-regression analysis showed that a higher baseline body mass index (OR 1.17, 95% CI 1.01 to 1.33, p = 0.034) was a significant predictor of new-onset DM. The risk for DM was greater with atenolol, in the elderly, and in studies in which beta blockers were less efficacious antihypertensive agents and increased exponentially with increased duration on beta blockers. For the secondary end points, beta blockers resulted in a 15% increased risk for stroke, with no benefit for the end point of death or myocardial infarction. In conclusion, beta blockers are associated with an increased risk for new-onset DM, with no benefit for the end point of death or myocardial infarction and with a 15% increased risk for stroke compared with other agents. This risk was greater in patients with higher baseline body mass indexes and higher baseline fasting glucose levels and in studies in which beta blockers were less efficacious antihypertensive agents compared with other treatments.
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| [20] |
Whether diabetic patients may benefit, compared with non-diabetic patients, from beta-blocker therapy following acute myocardial infarction was examined in a large multicentre cohort of 2024 patients, including 340 diabetics, 281 of whom survived hospitalization. One-year mortality following discharge was 17% for diabetics compared with 10% for non-diabetics (P less than 0.001). However, diabetics discharged on beta-blockers had a 1-year mortality of only 10%, compared with 23% for diabetics not on beta-blockers. In non-diabetics, mortality rates were 7% and 13% for those taking and not taking beta-blockers, respectively. Bias in patient selection for beta-blocker therapy might be responsible for the trends exhibited in our population since patients were not randomized to treatment. In diabetics, evidence of pulmonary congestion on X-ray was more prevalent than in non-diabetics; this appeared to be true both for patients taking beta-blockers and for those not taking beta-blockers. However, even in diabetics without evidence of pulmonary congestion on X-ray, 1-year mortality was 7% vs 17% for those with and without beta-blocker therapy, respectively (P less than 0.04). In multivariate analysis, beta-blocker use was an independent predictor of 1-year cardiac survival following hospital discharge for all diabetics, even those without evidence for pulmonary congestion on X-ray, but not for non-diabetics. These data suggest a beneficial effect, but a definitive answer regarding the benefit of beta-blockade in diabetic patients after acute myocardial infarction would require a prospective, randomized study.
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| [21] |
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| [22] |
Beta blocker treatment may worsen glucose metabolism.To study the development of new onset diabetes in a large cohort of patients with heart failure treated with either metoprolol or carvedilol.Prospective and retrospective analysis of a controlled clinical trial.Multinational multicentre study.3029 patients with chronic heart failure.Randomly assigned treatment with carvedilol (n = 1511, target dose 50 mg daily) or metoprolol tartrate (n = 1518, target dose 100 mg daily).Diabetic events (diabetic coma, peripheral gangrene, diabetic foot, decreased glucose tolerance or hyperglycaemia) and new onset diabetes (clinical diagnosis, repeated high random glucose level or glucose lowering drugs) were assessed in 2298 patients without diabetes at baseline. Diabetic events occurred in 122/1151 (10.6%) patients in the carvedilol group and 149/1147 (13.0%) patients in the metoprolol group (hazard ratio (HR) = 0.78; 95% confidence interval (CI) 0.61 to 0.99; p = 0.039). New onset diabetes was diagnosed in 119/1151 (10.3%) v 145/1147 (12.6%) cases in the carvedilol and metoprolol treatment groups (HR = 0.78, CI 0.61 to 0.997; p = 0.048), respectively. Patients with diabetes at baseline had an increased mortality compared with non-diabetic subjects (45.3% v 33.9%; HR = 1.45, CI 1.28 to 1.65). Both diabetic and non-diabetic subjects at baseline had a similar reduction in mortality with carvedilol compared with metoprolol (RR = 0.85; CI 0.69 to 1.06 and RR = 0.82; CI 0.71 to 0.94, respectively).A high prevalence and incidence of diabetes is found in patients with heart failure over a course of 5 years. New onset diabetes is more likely to occur during treatment with metoprolol than during treatment with carvedilol.
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| [23] |
CONTEXT: Vasoconstricting beta-blocker use is associated with a reduction in HDL cholesterol, higher triglyceride, total cholesterol and LDL cholesterol levels, whereas carvedilol, a vasodilating beta-blocker, has not been associated with these effects. OBJECTIVE: To compare in a randomized, double-blind study, the effects of the beta 1-blocker metoprolol tartrate with the combined alpha 1, beta-blocker carvedilol on serum lipid concentrations. METHODS: A prospective randomized, double-blind, parallel-group trial compared the effects of carvedilol and metoprolol on total cholesterol, triglycerides, calculated LDL, HDL and non-HDL cholesterol levels at baseline and after 5 months of therapy as a secondary objective in the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensive (GEMINI) study. In this study, 1235 participants with type 2 diabetes and hypertension who were receiving renin-angiotensin system blockers were randomized either to carvedilol, receiving 6.25-25 mgtwice daily, or to metoprolol tartrate, receiving 50-200 mg twice daily. If needed, hydrochlorothiazide and a dihydropyridine calcium channel blocker were added to achieve blood pressure goals. RESULTS: In the metoprolol tartrate group, triglycerides and non-HDL cholesterol increased and both the LDL and the HDL cholesterol levels decreased. In the carvedilol group, total LDL and HDL cholesterol decreased, non-HDL cholesterol was unchanged and triglycerides increased. Comparing the carvedilol and metoprolol tartrate groups, there was no statistically significant difference in LDL and HDL cholesterol levels, but there was a significantly greater decreases with carvedilol in total cholesterol [-2.9%, 95% confidence interval (CI) -4.60 to -1.15, p < 0.001], triglycerides (-9.8%, 95% CI -13.7, -5.75%, p < 0.001) and non-HDL cholesterol (-4.03%, 95% CI -6.3 to -1.8, p < 0.0006). At the end of the study, significantly more participants in the metoprolol tartrate gro
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| [24] |
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| [25] |
This study sought to determine if metoprolol succinate ER (MET), and nebivolol (NEB), a β1-AR with increased bioavailability of nitric oxide (NO), would have differing effects on plasma asymmetric dimethylarginine concentration in hypertensives. It was hypothesized that NEB, a β1-AR antagonist and β3-AR agonist with NO-releasing properties, and MET, only a β1-AR antagonist, would have different effects on plasma asymmetric dimethylarginine (ADMA) concentration. Forty-one hypertensive subjects randomly received either 50 mg of MET (n = 19) or 5 mg of NEB (n = 22) for 4 weeks followed by 100 mg MET and 10 mg NEB for 4 weeks. ADMA and insulin-like growth factor-1 (IGF-1) were measured by enzyme-linked immunosorbent assay kit; endothelial progenitor cells were estimated using fluorescein-labeled monoclonal antibody to KDR and CD133 receptors; arterial augmentation index was measured by radial tonometry. Baseline systolic/diastolic blood pressure was 155.1 ± 18.7/85.3 ± 12.5 mm Hg for MET subjects and 157.6 ± 20.7/87.1 ± 14.0 mm Hg for NEB subjects. Baseline ADMA was 0.32 ± 0.123 μmol/L in the MET group and 0.4035 ± 0.1378 in the NEB group. ADMA increased 44.78% and 72% in the MET group at weeks 4 and 8 (
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| [26] |
Aim Studies of beta blockade in patients with type 2 diabetes have shown inferiority of metoprolol treatment compared to carvedilol on indices of insulin resistance. The aim of this study was to examine the effect of metoprolol versus carvedilol on endothelial function and insulin-stimulated endothelial function in patients with type 2 diabetes. Method 24 patients with type 2 diabetes were randomized to receive either 200 mg metoprolol succinate or 50 mg carvedilol daily. Endothelium-dependent vasodilation was assessed by using venous occlusion plethysmography with increasing doses of intra-arterial infusions of the agonist serotonin. Insulin-stimulated endothelial function was assessed after co-infusion of insulin for sixty minutes. Vaso-reactivity studies were done before and after the two-month treatment period. Results Insulin-stimulated endothelial function was deteriorated after treatment with metoprolol, the percentage change in forearm blood-flow was 60.19% - 17.89 (at the highest serotonin dosages) before treatment and -33.80% - 23.38 after treatment (p = 0.007). Treatment with carvedilol did not change insulin-stimulated endothelial function. Endothelium-dependent vasodilation without insulin was not changed in either of the two treatment groups. Conclusion This study shows that vascular insulin sensitivity was preserved during treatment with carvedilol while blunted during treatment with metoprolol in patients with type 2 diabetes. Trial registration Current Controlled Trials NCT00497003
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| [27] |
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| [28] |
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| [29] |
Background: Nebivolol is a third-generation -blocker, with highest 1 selectivity and nitric-oxide-derived vasodilatation. It also exhibits antiproliferative and antioxidant property that has beneficial metabolic profile compared to second-generation blockers like atenolol. This study was planned to study the comparative effects of nebivolol and atenolol on metabolic parameters in patients with essential hypertension.<br> Materials and Methods: A prospective, randomized, parallel, open-label clinical study was carried out on patients with essential hypertension. The patients were randomly assigned to receive tablet atenolol (Group A) and nebivolol (Group B) for a period of 24 weeks. Investigations were carried out at baseline and at the end of study period, that is, 24 weeks. Out of 69 patients, 60 completed the study and the data was analyzed using student's t-test. P < 0.05 was considered statistically significant.<br> Results: Atenolol and nebivolol both showed significant (P < 0.001) antihypertensive action after 24 weeks. Mean blood sugar and lipid profile were found to be significantly (P < 0.001) elevated after 24 weeks of treatment with atenolol but not with nebivolol. Heart rate was significantly (P < 0.001) decreased in both groups at 24 weeks.<br>Conclusion: In view of metabolic adverse effects of atenolol, nebivolol is the better choice whenever -blockers have to be used in essential hypertension.
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| [30] |
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| [31] |
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| [32] |
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| [33] |
Abstract From two large scale studies in patients with suspected acute myocardial infarction we report the outcome in diabetics after treatment with either metoprolol or placebo. In the G枚teborg Metoprolol Trial mortality at 3 months was reduced by metoprolol from 17.9% to 7.5% and late infarction was reduced from 16.4% to 3.8%. In the MIAMI Trial, mortality was decreased by metoprolol from 11.3% to 5.7% and the occurrence of late infarction was decreased from 4.5% to 3.1% during 15-day follow-up. Compared with the overall results, the effect of metoprolol on mortality appears particularly impressive in diabetics.
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| [34] |
AbstractObjectives: To study differences in the clinical efficacy of various brands of β-blocker in secondary prevention after a myocardial infarction (MI). Methods: All patients hospitalized with a first MI between 1995 and 2002 who were still alive 30 days after discharge and had had at least one prescription for a β-blocker filled were identified by individual-level linkage of nationwide registries of hospitalizations and drugs dispensed from pharmacies. A total of 32,259 MI patients were included in the study. Multivariable Cox proportional hazard models were used to analyze the risks of death and recurrent MI related to treatment with different β-blockers. Results: The risks for death and recurrent MI were similar in patients using different β-blockers, except that mortality from all causes among patients with a prescription for sotalol was higher. Subgroup analyses of high-risk patients with diabetes or congestive heart failure and of patients using comparable dosages of β-blockers did not show effects on the risk of death or recurrent MI. Conclusion: Except for sotalol, the different types of β-blocker had similar clinical efficacy in reducing mortality and the recurrence of MI. The equivalent efficacy remained when high-risk patients were analyzed separately.
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| [35] |
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| [36] |
We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study.BackgroundFull adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment.MethodsThree thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina.ResultsThe effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086).ConclusionsCarvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.
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| [37] |
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DOI:10.2337/dc16-S011
URL
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| [39] |
DOI:10.2337/dc16-S003
URL
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| [40] |
β-Blockers are a standard of care in many clinical settings such as , and patients at risk for a coronary event. However, not all β-blockers are the same and they vary in properties such as lipophilicity, metabolic profile, receptor inhibition, hemodynamics, tolerability and /anti-inflammatory effects. It has been unclear whether these differences affect outcomes or if one β-blocker should be preferred over another. This review will summarize the properties of , atenolol and , as well as comparative experimental and clinical trials between these agents. We will provide compelling evidence of why should be a first-line β-blocker and why it offers many advantages over the β1-selective β-blockers.
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