Effects of Carvedilol Versus Metoprolol on Endothelial Function and Oxidative Stress in Patients With Type 2 Diabetes Mellitus

AJH 2007; 20:777–783 Diabetes Effects of Carvedilol Versus Metoprolol on Endothelial Function and Oxidative Stress in Patients With Type 2 Diabetes Mellitus Alan J. Bank, Aaron S. Kelly, Andrea M. Thelen, Daniel R. Kaiser, and J. Michael Gonzalez-Campoy Background: Data suggest that carvedilol possesses antioxidant properties that might provide vascular protection. We sought to compare the effects of carvedilol and metoprolol tartrate on endothelial function and oxidative stress in a head-to-head trial. Methods: Thirty-four patients with type 2 diabetes mellitus (T2DM) and hypertension were randomized to receive either carvedilol (n ⫽ 16) or metoprolol (n ⫽ 18) in addition to their current antihypertensive medications for 5 months. The following variables were measured preand posttreatment: blood pressure, fasting glucose and insulin, insulin resistance by homeostasis-model assessment, hemoglobin A1c, lipids, C-reactive protein (CRP), 8-isoprostane, asymmetric dimethylarginine, oxidized LDL cholesterol, ultrasound assessment of brachial-artery flow-mediated dilation (FMD), nitroglycerin-induced endothelium-independent dilation (EID), brachial and carotid artery distension, distensibility and compliance, and carotid artery intima–media thickness (cIMT). Results: Both carvedilol and metoprolol treatment resulted in significant and similar decreases in systolic (P ⬍ .05) and diastolic (P ⬍ .0001) blood pressure. Compared with metoprolol, carvedilol significantly improved FMD (P ⬍ .001). No differences between groups were noted for any of the glycemic or lipid variables except for HDL cholesterol, which significantly decreased (P ⬍ .05) in the metoprolol group compared with the carvedilol group. No differences were observed between groups for CRP, the markers of oxidative stress, EID, arterial stiffness, or cIMT. Conclusions: Compared with metoprolol, carvedilol significantly improves endothelial function in patients with T2DM. Changes in glycemic control and oxidative stress do not seem to explain the observed improvements in FMD, which suggests that other mechanisms may be involved. Am J Hypertens 2007;20:777–783 © 2007 American Journal of Hypertension, Ltd. Key Words: ␤-blocker, type 2 diabetes mellitus, endothelial function, oxidative stress. eta-adrenergic receptor antagonists (␤-blockers) were shown to be an effective therapy for hypertension, ischemic heart disease, and heart failure. Patients with type 2 diabetes mellitus (T2DM) often have cardiovascular comorbidities that could benefit from ␤-blocker therapy; however, clinicians are often reluctant to utilize this drug class because of reports of worsening glycemic control.1,2 The newer, so-called third-generation ␤-blockers may not have these negative glycemic effects. In a randomized controlled trial, carvedilol was shown to B have no effect on levels of hemoglobin A1c (HbA1c), whereas treatment with metoprolol resulted in significant increases in this marker of chronic glucose control.3 These differences are likely related to the unique receptor-blocking actions of these drugs. Carvedilol is a nonselective ␤-receptor antagonist (blocking both ␤1 and ␤2 receptors) with ␣1-receptor blocking properties, whereas metoprolol is a selective ␤1-receptor antagonist. Type 2 diabetes mellitus is a coronary-risk equivalent and is associated with hypertension and severe endothelial Received December 11, 2006. First decision January 1, 2007. Accepted January 25, 2007. From the Department of Research (AJB, ASK, AMT), St. Paul Heart Clinic, St. Paul; Departments of Medicine (AJB, DRK) and Pediatrics (ASK), School of Medicine, University of Minnesota, Minneapolis; and Minnesota Center for Obesity, Metabolism and Endocrinology (JMG-C), Eagan, Minnesota. Supported by a grant from GlaxoSmithKline, King of Prussia, PA. Clinical trials registration: This study was registered at www. clinicaltrials.gov (ID no. NCT00123604). Conflict of interest statement: A.J.B. receives research grant support from GlaxoSmithKline. A.S.K. receives research grant support from GlaxoSmithKline and is a member of the speaker’s bureau for Takeda Pharmaceuticals North America. J.M.G.-C. is a member of the speaker’s bureau for Pfizer, Merck, and GlaxoSmithKline. The final decisions regarding the present study’s concept, design, conduct, data analysis, and manuscript preparation were performed solely by the authors. Address correspondence and reprint requests to Dr. Alan J. Bank, 225 Smith Ave. N., Suite 400, St. Paul, MN 55102; e-mail: abank@stphc. com © 2007 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc. 0895-7061/07/$32.00 doi:10.1016/j.amjhyper.2007.01.019 778 CARVEDILOL AND ENDOTHELIAL FUNCTION IN TYPE 2 DIABETES dysfunction. Therefore, it is important to identify treatments that, in addition to their intended cardiovascular hemodynamic effect, may also improve endothelial health. Studies of ␤-blockers are inconclusive regarding their effects on endothelial function, with some studies showing some benefit,4 – 6 and others demonstrating no effect.7,8 There is evidence to suggest that two of the third-generation ␤-blockers, carvedilol and nebivolol, contain vasodilating properties that are likely mediated through an increased bioavailability of nitric oxide (NO).9,10 Both T2DM11 and hypertension12 are associated with elevated levels of oxidative stress. Reactive oxygen species uncouple the synthesis of NO and lead to its inactivation, ultimately decreasing NO bioavailability in the vasculature. Therefore, oxidative stress may be one mechanism responsible for endothelial dysfunction in patients with T2DM and hypertension. Data suggest that carvedilol has antioxidant properties,13–18 which may provide vascular protection by improving NO bioavailability and therefore endothelial function. No studies to date have examined the effects of carvedilol treatment on endothelial function and oxidative stress in hypertensive patients with T2DM. Therefore, we compared the vascular and antioxidant effects of carvedilol and metoprolol tartrate in a head-tohead trial in patients with T2DM and hypertension. Methods Patient Population Thirty-four patients with clinically diagnosed T2DM and hypertension were randomized to receive either carvedilol or metoprolol tartrate in addition to current antihypertensive medications. Patients were recruited from local Minneapolis and St. Paul medical clinics and via newspaper advertisements. Verbal and written informed consent was obtained from each subject, and the protocol was approved by the Western Institutional Review Board (Olympia, WA). All procedures were conducted in accordance with local institutional and Health Insurance Portability and Accountability Act (HIPAA) guidelines. Study Design This was a randomized, double-blind, parallel-group trial that compared the vascular and antioxidant effects of headto-head therapy with either carvedilol or metoprolol in addition to current antih (...truncated)