Microsoft word - carvedilol-metabolicsyndrome.docx

Memo: Carvedilol for Blood Pressure Control in Metabolic Syndrome and
Type 2 Diabetes
The compensatory hyperinsulinemia associated with metabolic syndrome and type2 diabetes provides an activating stimulus to brain sympathetic centers (which evidently maintain their sensitivity to insulin), leading to a chronic up-regulation of sympathetic tone.1, 2 This is a key cause of the blood pressure elevation typically seen in these syndromes. An increase in sympathetic tone promotes increases in heart rate, cardiac inotropy, renin secretion, renal sodium retention, and vascular resistance - all of which interact to elevate blood pressure.2 (Hyperinsulinemia also acts directly on the kidney – which likewise maintains its insulin responsiveness in metabolic syndrome – to promote sodium reabsorption.3) Moreover, the increase in global mortality associated with an increased resting heart rate suggests that chronic elevation of sympathetic activity increases risk not only for cardiovascular events and heart failure but for cancer mortality as well, likely reflecting the presence of beta2 receptors on many pre-neoplastic and neoplastic tissues.4-9 Hence, increased sympathetic tone may be a key mediator of the increased cardiovascular and cancer risk associated with metabolic syndrome and type 2 diabetes.10, 11 For this reason, the vasodilating beta-blocker carvedilol, which inhibits alpha1 as well as beta1 and beta2 adrenergic receptors, has the potential to strike to the root of the contribution of metabolic syndrome to hypertension, and to lessen the adverse impact of this syndrome on overall health and survival. Studies of carvedilol in metabolic syndrome and type 2 diabetes indicate that it is an effective and reasonably well tolerated agent for blood pressure control.12-14 The randomized, double-blind GEMINI trial, targeting hypertensive type 2 diabetics already receiving renin-angiotensin system inhibitors, found that, as contrasted to the non-vasodilating beta blocker metoprolol, (a beta1-selective agent which does not inhibit alpha1 receptors), carvedilol tends to have a favorable impact on insulin sensitivity, glycemic control, and lipid values; moreover, its use is associated with fewer diabetic symptoms, lower risk for weight gain, and a lesser tendency for normoalbuminuria to progress to microalbuminuria, .15-18 These findings suggest that alpha1 stimulation promotes and exacerbates metabolic syndrome – as further demonstrated by the favorable metabolic impact of pure alpha1 antagonists such as doxazosin.19 Carvedilol also has the further merit of direct antioxidant activity20-23 – of interest in light of the prominent contribution of oxidative stress to the complications of metabolic syndrome and diabetes. These considerations do not gainsay the utility of other pharmaceutical strategies – angiotensin and calcium antagonists, diuretics – for controlling blood pressure in patients with metabolic syndrome or type 2 diabetes; telemisartan, an AT1 receptors antagonist, is of particular interest in this regard in light of its partial PPARgamma agonism.24 Many patients will require combination regimens for optimal blood pressure control. However, there is reason to suspect that antihypertensive protocols which include carvedilol may have a better impact on long term health outcomes in such patients – a proposition that hopefully will be tested in future research. (1) Landsberg L. Insulin and the sympathetic nervous system in the pathophysiology of hypertension. (2) Facchini FS, Stoohs RA, Reaven GM. Enhanced sympathetic nervous system activity. The linchpin between insulin resistance, hyperinsulinemia, and heart rate. Am J Hypertens 1996 October;9(10 Pt 1):1013-7. (3) Reaven GM. The kidney: an unwilling accomplice in syndrome X. Am J Kidney Dis 1997 (4) Persky V, Dyer AR, Leonas J et al. Heart rate: a risk factor for cancer? Am J Epidemiol 1981 (5) Thomas F, Guize L, Bean K, Benetos A. Pulse pressure and heart rate: independent risk factors for cancer? J Clin Epidemiol 2001 July;54(7):735-40. (6) Jouven X, Escolano S, Celermajer D et al. Heart rate and risk of cancer death in healthy men. (7) Perez-Sayans M, Somoza-Martin JM, Barros-Angueira F, Diz PG, Gandara Rey JM, Garcia- Garcia A. Beta-adrenergic receptors in cancer: therapeutic implications. Oncol Res 2010;19(1):45-54. (8) Schuller HM, Al-Wadei HA. Beta-adrenergic signaling in the development and progression of pulmonary and pancreatic adenocarcinoma. Curr Cancer Ther Rev 2012 May 1;8(2):116-27. (9) Tang J, Li Z, Lu L, Cho CH. beta-Adrenergic system, a backstage manipulator regulating tumour progression and drug target in cancer therapy. Semin Cancer Biol 2013 December;23(6PB):533-42. (10) Mottillo S, Filion KB, Genest J et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010 September 28;56(14):1113-32. (11) Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D. Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care 2012 November;35(11):2402-11. (12) Fardoun RZ. Carvedilol versus cardioselective beta-blockers for the treatment of hypertension in patients with type 2 diabetes mellitus. Pharmacotherapy 2006 October;26(10):1491-500. (13) Carella AM, Antonucci G, Conte M, Di PM, Giancola A, Antonucci E. Antihypertensive treatment with beta-blockers in the metabolic syndrome: a review. Curr Diabetes Rev 2010 July;6(4):215-21. (14) Leonetti G, Egan CG. Use of carvedilol in hypertension: an update. Vasc Health Risk Manag (15) Bakris GL, Fonseca V, Katholi RE et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA 2004 November 10;292(18):2227-36. (16) Bakris GL, Fonseca V, Katholi RE et al. Differential effects of beta-blockers on albuminuria in patients with type 2 diabetes. Hypertension 2005 December;46(6):1309-15. (17) McGill JB, Bakris GL, Fonseca V et al. beta-blocker use and diabetes symptom score: results from the GEMINI study. Diabetes Obes Metab 2007 May;9(3):408-17. (18) Messerli FH, Bell DS, Fonseca V et al. Body weight changes with beta-blocker use: results from GEMINI. Am J Med 2007 July;120(7):610-5. (19) Glanz M, Garber AJ, Mancia G, Levenstein M. Meta-analysis of studies using selective alpha1- blockers in patients with hypertension and type 2 diabetes. Int J Clin Pract 2001 December;55(10):694-701. (20) Yue TL, Cheng HY, Lysko PG et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992 October;263(1):92-8. (21) Maggi E, Marchesi E, Covini D, Negro C, Perani G, Bellomo G. Protective effects of carvedilol, a vasodilating beta-adrenoceptor blocker, against in vivo low density lipoprotein oxidation in essential hypertension. J Cardiovasc Pharmacol 1996 April;27(4):532-8. (22) Moser M, Frishman W. Results of therapy with carvedilol, a beta-blocker vasodilator with antioxidant properties, in hypertensive patients. Am J Hypertens 1998 January;11(1 Pt 2):15S-22S. (23) DiNicolantonio JJ, Hackam DG. Carvedilol: a third-generation beta-blocker should be a first- choice beta-blocker. Expert Rev Cardiovasc Ther 2012 January;10(1):13-25. (24) Suksomboon N, Poolsup N, Prasit T. Systematic review of the effect of telmisartan on insulin sensitivity in hypertensive patients with insulin resistance or diabetes. J Clin Pharm Ther 2012 June;37(3):319-27.

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