Metabolic Effects of Short-term GLP-1 Treatment in Insulin Resistant Heart Failure Patients

Abstract

Objectives:

We studied the metabolic effects of 48-h GLP-1 treatment in insulin resistant heart failure patients.

Methods:

In a randomized placebo-controlled double-blinded cross-over study, 11 non-diabetic HF patients with IHD received 48-h GLP-1 and placebo-infusion. We applied OGTT, hyperinsulinemic clamp, indirect calorimetry, forearm, and tracer methods.

Results:

7 insulin resistant HF (EF 28%±2) patients completed the protocol. GLP-1 decreased plasma glucose levels (p=0.048) and improved glucose tolerance. 4 patients had hypoglycemic events during GLP-1 vs. none during placebo. GLP-1 treatment tended to increase whole body protein turnover (p=0.08) but did not cause muscle wasting. No significant changes in circulating levels of insulin, glucagon, free fatty acids or insulin sensitivity were detected.

Conclusion:

GLP-1 treatment decreased glucose levels and increased glucose tolerance in insulin resistant HF patients with IHD. Hypoglycemia was common and may limit the use of GLP-1 in these patients. Insulin sensitivity, lipid-, and protein metabolism remained unchanged.

Data were collected at the examinational laboratories of Department of Endocrinology and Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark

Key words

heart failure - insulin resistance - metabolism - incretines

• References

• 1 Suskin N, McKelvie RS, Burns RJ et al. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 2000; 21: 1368-1375
• 2 Norrelund H, Wiggers H, Halbirk M et al. Abnormalities of whole body protein turnover, muscle metabolism and levels of metabolic hormones in patients with chronic heart failure. J Intern Med 2006; 260: 11-21
• 3 Anker SD, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol 2002; 85: 51-66
• 4 Anker SD, Ponikowski P, Varney S et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997; 349: 1050-1053
• 5 Kalantar-Zadeh K, Anker SD, Horwich TB et al. Nutritional and Anti-Inflammatory Interventions in Chronic Heart Failure. The American Journal of Cardiology 2008; 101: S89-S103
• 6 Nyenwe EA, Jerkins TW, Umpierrez GE et al. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism 2011; 60: 1-23
• 7 Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Molecular and Cellular Endocrinology 2009; 297: 127-136
• 8 Luque MA, Gonzalez N, Marquez L et al. Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes. J Endocrinol 2002; 173: 465-473
• 9 Parkes DG, Pittner R, Jodka C et al. Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism 2001; 50: 583-589
• 10 Creutzfeldt WO, Kleine N, Willms B et al. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care 1996; 19: 580-586
• 11 Sokos GG, Nikolaidis LA, Mankad S et al. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail 2006; 12: 694-699
• 12 Halbirk M, Nørrelund H, Møller N et al. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure. American Journal of Physiology – Heart and Circulatory Physiology 2010; 298: H1096-H1102
• 13 Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419
• 14 Bonora E, Kiechl S, Willeit J et al. Prevalence of insulin resistance in metabolic disorders: the Bruneck Study. Diabetes 1998; 47: 1643-1649
• 15 Espelund U, Hansen TK, Hojlund K et al. Fasting unmasks a strong inverse association between ghrelin and cortisol in serum: studies in obese and normal-weight subjects. J Clin Endocrinol Metab 2005; 90: 741-746
• 16 Frystyk J, Tarnow L, Hansen TK et al. Increased serum adiponectin levels in type 1 diabetic patients with microvascular complications. Diabetologia 2005; 48: 1911-1918
• 17 Guo Z, Nielsen S, Burguera B et al. Free fatty acid turnover measured using ultralow doses of [U-13C]palmitate. Journal of Lipid Research 1997; 38: 1888-1895
• 18 Nystrom T, Gutniak MK, Zhang Q et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 2004; 287: E1209-E1215
• 19 Hansen BF, Jensen P, Nepper-Christensen E et al. Effects of glucagon-like peptide-1 (7-36)amide on insulin stimulated rat skeletal muscle glucose transport. Acta Diabetologica 1998; 35: 101-103
• 20 Holst JJ. The Physiology of Glucagon-like Peptide 1. Physiol Rev 2007; 87: 1409-1439
• 21 Dunning BE, Foley JE, Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1. Diabetologia 2005; 48: 1700-1713
• 22 Ritzel R, Orskov C, Holst JJ et al. Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7-36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia 1995; 38: 720-725
• 23 Zander M, Madsbad S, Madsen JL et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359: 824-830
• 24 Shalev A, Holst JJ, Keller U. Effects of glucagon-like peptide 1 (7-36 amide) on whole-body protein metabolism in healthy man. Eur J Clin Invest 1997; 27: 10-16
• 25 Zander M, Christiansen A, Madsbad S et al. Additive Effects of Glucagon-Like Peptide 1 and Pioglitazone in Patients With Type 2 Diabetes. Diabetes Care 2004; 27: 1910-1914
• 26 Monami M, Marchionni N, Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol 2009; 160: 909-917
• 27 Kim W, Egan JM. The Role of Incretins in Glucose Homeostasis and Diabetes Treatment. Pharmacol Rev 2008; 60: 470-512
• 28 Lerche S, Soendergaard L, Rungby J et al. No increased risk of hypoglycaemic episodes during 48 h of subcutaneous glucagon-like-peptide-1 administration in fasting healthy subjects. Clin Endocrinol (Oxf) 2009; 71: 500-506
• 29 Doehner W, Rauchhaus M, Ponikowski P et al. Impaired Insulin Sensitivity as an Independent Risk Factor for Mortality in Patients With Stable Chronic Heart Failure. Journal of the American College of Cardiology 2005; 46: 1019-1026
• 30 Nikolaidis LA, Poornima I, Parikh P et al. The Effects of Combined Versus Selective Adrenergic Blockade on Left Ventricular and Systemic Hemodynamics, Myocardial Substrate Preference, and Regional Perfusion in Conscious Dogs With Dilated Cardiomyopathy. Journal of the American College of Cardiology 2006; 47: 1871-1881
• 31 Degn KB, Juhl CB, Sturis J et al. One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and alpha- and beta-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes. Diabetes 2004; 53: 1187-1194
• 32 Mari A, Sallas WM, He YL et al. Vildagliptin, a Dipeptidyl Peptidase-IV Inhibitor, Improves Model-Assessed {beta}-Cell Function in Patients with Type 2 Diabetes. Journal of Clinical Endocrinology Metabolism 2005; 90: 4888-4894