exenatide and Arrhythmias--Cardiac

A1C is associated with diabetes complications but does not reflect glycemic variability (GV), which may worsen outcomes by inducing inflammation, oxidative stress, and cardiac arrhythmias. We tested whether a glucagon-like peptide 1 agonist-based regimen can reduce GV and cardiometabolic risk markers while maintaining similar A1C levels in people with insulin-requiring type 2 diabetes and high cardiovascular risk.. After run-in on metformin and basal-bolus insulin (BBI), 102 participants continued metformin and basal insulin and were randomized to exenatide dosing before the two largest meals (glucacon-like peptide-1 receptor agonist and insulin [GLIPULIN group]) or continuation of rapid-acting insulin analogs (BBI group). Indices of GV by continuous glucose monitoring (CGM), hypoglycemia, weight, risk markers, and cardiac arrhythmias were assessed. The primary end point was change in glucose coefficients of variation (CV) by CGM from baseline to 26 weeks.. At randomization, the median A1C was 7.3% (57 mmol/mol) for GLIPULIN and 7.4% (56.3 mmol/mol) for BBI, and glucose CVs were 30.3 for BBI and 31.9 for GLIPULIN. At 26 weeks, A1C levels were similar (7.1% [54 mmol/mol] vs. 7.2% [55 mmol/mol]), whereas mean CV improved with GLIPULIN (-2.4 vs. 0.4, P = 0.047). Other GV indices followed similar nonsignificant patterns of improvement with GLIPULIN. There were no differences in hypoglycemic events during CGM or arrhythmias during electrocardiographic monitoring. On-trial changes in body weight (-4.8 kg vs. +0.7 kg, P < 0.001), alanine aminotransferase (P = 0.0002), and serum amyloid A (P = 0.023) favored GLIPULIN.. GLIPULIN reduced GV, weight, and some cardiometabolic risk markers while maintaining equivalent A1C levels versus BBI and might improve clinical outcomes in a larger trial.

Topics: Adult; Aged; Alanine Transaminase; Arrhythmias, Cardiac; Blood Glucose; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin, Short-Acting; Male; Meals; Metformin; Middle Aged; Peptides; Risk Factors; Serum Amyloid A Protein; Venoms

The aim of this study was to investigate the effect of exendin-4 (Ex-4) on ventricular arrhythmias and calcium sparks-mediated calcium leak in a myocardial infarction-heart failure model.We studied the influence of exendin-4 on ventricular arrhythmogenesis in a rat myocardial infarction-heart failure model. In vivo arrhythmia studies (electrocardiogram [ECG] telemetry studies), ex vivo arrhythmia studies calcium sparks tests, and analysis of total and phosphorylated ryanodine receptor (RyR) 2 and CaMK-II were carried out in sham group, myocardial infarction (MI) group, MI + Ex-4 and MI + Ex-4 + Exendin9-39 (Ex9-39) groups.ECG telemetry studies showed an antiarrhythmic effect of exendin-4 with reduction of spontaneous ventricular arrhythmias. Exendin-4 abbreviated the APD

Topics: Animals; Arrhythmias, Cardiac; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Disease Models, Animal; Electrocardiography; Exenatide; Heart Failure; Male; Rats; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum

Glucagon-like peptide-1 receptor (GLP-1R) agonists improve cardiovascular outcomes in patients with type 2 diabetes mellitus. However, systemic actions of these agents cause sympathetic activation, which is generally considered to be detrimental in cardiovascular disease. Despite significant research interest in cardiovascular biology of GLP-1, the presence of GLP-1R in ventricular cardiomyocytes remains a controversial issue, and the effects of this peptide on the electrical properties of intact ventricular myocardium are unknown. We sought to determine the effects of GLP-1R agonist exendin-4 (Ex4) on ventricular action potential duration (APD) and susceptibility to ventricular arrhythmia in the rat heart in vivo and ex vivo.. Ventricular monophasic action potentials were recorded in anaesthetized (urethane) rats in vivo and isolated perfused rat hearts during sinus rhythm and ventricular pacing.. In vivo, systemic administration of Ex4 (5 μg/kg intravenously) increased heart rate, and this effect was abolished by β-adrenoceptor blockade. Despite causing sympathetic activation, Ex4 increased APD at 90% repolarization during ventricular pacing by 7% ( P=0.044; n=6) and reversed the effect of β-adrenoceptor agonist dobutamine on APD at 90% repolarization. In isolated perfused hearts, Ex4 (3 nmol/L) increased APD at 90% repolarization by 14% ( P=0.015; n=6) with no effect on heart rate. Ex4 also reduced ventricular arrhythmia inducibility in conditions of β-adrenoceptor stimulation with isoproterenol. Ex4 effects on APD and ventricular arrhythmia susceptibility were prevented in conditions of muscarinic receptor blockade or inhibition of nitric oxide synthase.. These data demonstrate that GLP-1R activation effectively opposes the effects of β-adrenoceptor stimulation on cardiac ventricular excitability and reduces ventricular arrhythmic potential. The effect of GLP-1R activation on the ventricular myocardium is indirect, mediated by acetylcholine and nitric oxide and, therefore, can be explained by stimulation of cardiac parasympathetic (vagal) neurons.

Topics: Acetylcholine; Action Potentials; Adrenergic beta-Agonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Exenatide; Glucagon-Like Peptide-1 Receptor; Heart Rate; Heart Ventricles; Incretins; Isolated Heart Preparation; Male; Myocardial Contraction; Nitric Oxide; Rats, Sprague-Dawley; Signal Transduction; Time Factors; Ventricular Function

Topics: Animals; Arrhythmias, Cardiac; Connexin 43; Electrocardiography; Exenatide; Glucose; Heart; Hypoglycemic Agents; Insulin; Ischemic Preconditioning, Myocardial; Myocardial Reperfusion Injury; Myocardium; Peptides; Potassium; Sweetening Agents; Swine; Tachycardia, Ventricular; Venoms; Ventricular Fibrillation