Carvedilol vs. metoprolol: A comparison of effects on endothelial function and oxidative stress in response to acute hyperglycemia in patients with type 2 diabetes and hypertension

Kathleen Colleran, Lina Aguirre, Mark R. Burge

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Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, USA.

DOI: 10.4236/jdm.2012.21024                

Abstract

Introduction: The GEMINI trial compared the effects of treatment with metoprolol versus carvedilol in patients with type 2 diabetes. Carvedilol demonstrated a more favorable effect on factors associated with the metabolic syndrome than metoprolol. We hypothesize that carvedilol will have additional beneficial effects on markers of inflammation, oxidative stress, and endothelial function than metoprolol. Methods: Twenty subjects were randomized to either carvedilol or metoprolol. Study procedures including assessment of metabolic parameters and endothelial function, while fasting and after a 75 g oral glucose tolerance were conducted at baseline and following 5 months of treatment. Results: Following 5 months of treatment, PAI-1 increased significantly from baseline in the metoprolol group. There were no changes in PAI-1 in the carvedilol group. While not reaching statistical significance, there was a trend toward worsening insulin resistance with metoprolol treatment compared to carvedilol treatment. Flow mediated vasodilation increased in both groups following the 2-hr OGGT during the baseline study. After five months of treatment, there was a non-significant increase in flow-mediated vasodilation under both fasting and post OGTT conditions in the carvedilol group compared to baseline. Conversely, there was no change in fasting flow mediated vasodilation in the metoprolol group. Additionally, metoprolol treatment blunted the increase in flow mediated vasodilation following OGGT compared to baseline (p < 0.05). Conclusion: Treatment with metoprolol was associated with adverse metabolic effects including increases in PAI-1 and trends toward worsening insulin resistance and endothelial function compared to treatment with carvedilol.

Keywords

Diabetes; Hypertension; Endothelial Dysfunction; Carvedilol; Metoprolol; Insulin Resistance

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Stamler, J., Vaccaro, O., Neaton, J.D. and Wentworth, D. (1993) For the multiple risk factor intervention trial research group. Diabetes, other risk factors, and the 12-year cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care, 16, 434-444. doi:10.2337/diacare.16.2.434
[2]	Song, S.H. and Brown, P.M. (2004) Coronary heart disease risk assessment in diabetes mellitus: Comparison of UKPDS risk engine with framingham risk assessment function and its clinical implications. Diabetic Medicine, 21, 238-245. doi:10.1111/j.1464-5491.2004.01116.x
[3]	Taylor, E.N., Hu, F.B. and Curhan, G.C. (2006) Antihypertensives medications and the risk of incident type 2 diabetes. Diabetes Care, 29, 1065-1070. doi:10.2337/dc05-2366
[4]	Kullo, I.J., Gau, G.T. and Tajik, A.J. (2000) Novel risk factors for atherosclerosis. Mayo Clinic Proceedings, 75, 369-380. doi:10.4065/75.4.369
[5]	Colagiuri, S., Cull, C.A. and Holman, R.R. (2002). Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes? UK prospective diabetes study 61. Diabetes Care, 25, 1410-1417. doi:10.2337/diacare.25.8.1410
[6]	Kawamura, M., Heinecke, J.W. and Chait, A. (1994). Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway. The Journal of Clinical Investigation, 94, 771-778. doi:10.1172/JCI117396
[7]	Cerriello, A. (1997) Acute hyperglycaemia and oxidative stress generation. Diabetic Medicine, 14, S45-S49. doi:10.1002/(SICI)1096-9136(199708)14:3+3.3.CO;2-I
[8]	Cerriello, A., Bortolotti, N., Crescentini, A., Motz, E., Lizzio, S., Russo, A., Ezsol, Z., Tonutti, L. and Taboda, C. (1998) Antioxidant defenses are reduced during the oral glucose tolerance test in normal and non-insulin-dependent diabetic subjects. 1998. European Journal of Clinical Investigation, 28, 329-333. doi:10.1046/j.1365-2362.1998.00295.x
[9]	Bakris, G.L., Fonseca, V., Katholi, R.E., McGill, J.B., Messerli, F.H., Phillips, R.A., Raskin, P., Wright, J.T., Oakes, R., Lukas, M.A., Anderson, K.M. and Bell, D.S. (2004) Metabolic effects of carvedilolvsmetoprolol in patients with type 2 diabetes mellitus and hypertension. A randomized controlled trial. Journal of the American Medical Association (JAMA), 292, 2227-2236. doi:10.1001/jama.292.18.2227
[10]	Bank, A.J., Kelly, A.S., Thelen, A.M., Kaiser, D.R. and Gonzalez-Campoy, M.J. (2007) Effects of carvedilol versus metoprolol on endothelial function and oxidative stress in patients with type 2 diabetes. American Journal of Hypertension (AJH), 20, 777-783.
[11]	Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F. and Turner, R.C. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia, 28, 412-419. doi:10.1007/BF00280883
[12]	Perez, A., Leotta, D.F., Sullivan, J.H., et al. (2006) Flow mediated dilation of the brachial artery: An investigation of methods requiring further standardization. BMC Cardiovascular Disorders, 7, 11-19. doi:10.1186/1471-2261-7-11
[13]	Vaughan, D.E. (1998) Plasminogen activator inhibitor—1: A common denominator in CVD. Journal Investigative Medicine, 46, 370-376.
[14]	Huber, K., Christ, G., Wojta, J. and Gulba, D. (2001) Plasminogen activator inhibitor—Type 1 in CVD. Status Report 2001. Thrombosis Research, 103, S7-S19. doi:10.1016/S0049-3848(01)00293-6
[15]	Feuerstein, G., Yue, T.L., Ma, X. and Ruffolo, R.R. (1998) Novel mechanisms in the treatment of heart failure: Inhibition of oxygen radicals and apoptosis by carvedilol. Progress in Cardiovascular Diseases, 412, 17-24. doi:10.1016/S0033-0620(98)80027-3
[16]	Yue, T.L., McKenna, P.J., Gu, J.L., Cheng, H.Y., Ruffolo, R.R. and Feuerstein, G. (1994) Carvedilol, a new vasodilating b adrenoreceptor blocker antihypertensive drug, protects endothelial cells from damage initiated by xanthine-xanthine oxidase and neutrophils. Cardiovascular Research, 28, 400-406. doi:10.1093/cvr/28.3.400
[17]	Lysko, P.G., Webb, C.L., GU, J.L., Ohlstein, E.H., Ruffolo, R.R. and Yue, T.L. (2000) A comparison of carvedilol and metoprolol antioxidant activities in vitro. Journal of Cardiovascular Pharmacology, 36, 277-281. doi:10.1097/00005344-200008000-00020
[18]	Guiuliano, D., Acampora, R., Marfella, R., et al. (1997) Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin dependent diabetes mellitus and hypertension. Annals of Internal Medicine, 126, 955-959.
[19]	Matsuda, Y., Akita, H., Terashima, M., Shiga, N., Kanazawa, K. and Yokoyama, M. (2000) Carvedilol improves endothelium-dependent dilatation in patients with coronary artery disease. American Heart Journal, 140, 753-759.
[20]	Bank, A., Kelly, A., Thelen, D. and Gonzalez-Campoy, M. (2007) Effectsof carvedilol versus metoprolol on endothelial function and oxidative stress in patients with type 2 diabetes mellitus. American Journal of Hypertension, 20, 777-783. doi:10.1016/j.amjhyper.2007.01.019