Effects of Beta-Blocker Titration on Glucose Homeostasis in Heart Failure.
BACKGROUND: Abnormal glucose metabolism and insulin resistance have been associated with heart failure incidence, severity, and mortality. Metabolic parameters such as hepatic glucose production may be altered by beta-adrenoceptor antagonists in patients with heart failure. OBJECTIVE: This study evaluated the effects of metoprolol or carvedilol up-titration on fasting glucose, insulin resistance and beta(2)-mediated glucose production in patients with chronic heart failure. METHODS: This was a prospective, randomized, active comparator study in 15 patients with AHA/ACC Stage C systolic dysfunction HF stable on medical therapy. Participants were randomized to metoprolol 25mg daily or carvedilol 3.125mg twice daily. Metoprolol was titrated to a target of 200mg daily, and carvedilol was titrated to 25mg twice daily over 8weeks. Insulin resistance as assessed by the homeostatic model, and terbutaline-induced glucose production (AUC(0-180)), were assessed at baseline and at 4 subsequent beta-blocker titration visits over 8 weeks. RESULTS: In all 15 patients, terbutaline-induced glucose AUC(0-180) decreased (p=0.0006) as beta-blocker doses increased. A significant reduction in glucose AUC(0-180) compared to baseline was only noted in patients taking metoprolol at 100mg daily (-2424.6 [95% CI -372.6 to -4478.4] mg/dL*min) and 200mg daily (-2437.2 [95% CI -15.1 to -4604.4] mg/dL*min), and not observed in those taking carvedilol. After beta-blocker titration, fasting glucose concentrations for the metoprolol and carvedilol groups were 86.9 (95% CI 89.8-101.6) mg/dL and 95.7 (95% CI 89.8-101.6) mg/dL, respectively (p=0.0273), adjusted for baseline values. There was no significant difference between metoprolol and carvedilol on insulin resistance. CONCLUSION: Increasing doses of beta-blockers are associated with decreased in beta2-mediated glucose production in heart failure. Metoprolol, but not carvedilol, decreases hepatic glucose production at commonly used heart failure doses.
Vardeny
Orly
O
Assistant Professor, University of Wisconsin School of Pharmacy, Madison, WI.
Zebrack
James
J
Gilbert
Edward M
EM
Cheang
Kai I
KI
Eur Heart J. 1994 Nov;15(11):1528-32
7835369
Cardiovasc Res. 2006 Jan;69(1):128-39
16225854
Heart. 2007 Aug;93(8):968-73
17237130
Lancet. 1995 Jul 8;346(8967):120-1
7603193
J Clin Endocrinol Metab. 1980 Apr;50(4):680-4
6988452
J Clin Invest. 1980 Mar;65(3):682-9
6243675
Circulation. 1999 Dec 7;100(23):2312-8
10587334
JAMA. 2005 Jul 20;294(3):334-41
16030278
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4948-53
15069206
Eur Heart J. 2000 Aug;21(16):1368-75
10952826
J Clin Pharm Ther. 2003 Jun;28(3):179-86
12795776
J Hypertens. 1996 Apr;14(4):489-94
8761899
JAMA. 2004 Nov 10;292(18):2227-36
15536109
J Cardiovasc Pharmacol. 2000;35(7 Suppl 4):S9-14
11346220
N Engl J Med. 1991 Aug 1;325(5):293-302
2057034
N Engl J Med. 1987 Jun 4;316(23):1429-35
2883575
J Am Coll Cardiol. 2005 Sep 20;46(6):1019-26
16168285
Br J Pharmacol. 1999 Jul;127(5):1099-104
10455254
Diabetes Metab. 1997 Jun;23(3):213-8
9233998
J Clin Pharmacol. 1990 Feb;30(S2):S98-102
2155948
J Am Coll Cardiol. 2005 Dec 6;46(11):2054-60
16325042
J Am Coll Cardiol. 1997 Aug;30(2):527-32
9247528