incretins and Arrhythmias--Cardiac

Recent cardiovascular outcome trials of incretin-based therapies (IBT) in type 2 diabetes have not demonstrated either benefit or harm in terms of major adverse cardiovascular events (MACE). Earlier meta-analyses showed conflicting results but were limited in methodology. We aimed to perform an updated meta-analysis of all available incretin therapies on the incidence of MACE plus arrhythmia and heart failure.. We identified studies published through November 2014 by searching electronic databases and reference lists. We included RCTs in which the intervention group received incretin-based therapies and the control group received placebo or standard treatment; enrolled >100 participants in each group; interventions lasted >24 weeks; and reported data on one or more primary major adverse cardiovascular events endpoints plus terms for arrhythmia and heart failure. We used the Peto method for each CV event for individual IBT treatment.. In this meta-analysis of 100 RCTs involving 54,758 incretin-based therapies users and 48,175 controls, exenatide was associated with increased risk of arrhythmia (OR 2.83; 95% CI, 1.06-7.57); saxagliptin was associated with an increased risk of heart failure (OR 1.23; 95% CI, 1.03-1.46), and sitagliptin was associated with a significantly decreased risk of all cause death compared to active controls (OR 0.39, 95% CI 0.18-0.82).. In type 2 diabetes, exenatide may increase the risk of arrhythmia, and sitagliptin may reduce the risk of all cause death; however, the subgroup of patients most likely to experience harm or benefit is unclear. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Arrhythmias, Cardiac; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Humans; Incretins; Prognosis; Randomized Controlled Trials as Topic

To evaluate clinical outcomes in patients with diabetes, treated by cardiac resynchronization therapy with a defibrillator (CRT-d), and glucagon-like peptide 1 receptor agonists (GLP-1 RA) in addition to conventional hypoglycemic therapy vs. CRTd patients under conventional hypoglycemic drugs.. Patients with diabetes treated by CRTd experienced an amelioration of functional New York Association Heart class, reduction of hospital admissions, and mortality, in a percentage about 60%. However, about 40% of CRTd patients with diabetes experience a worse prognosis.. We investigated the 12-months prognosis of CRTd patients with diabetes, previously treated with hypoglycemic drugs therapy (n 271) vs. a matched cohort of CRTd patients with diabetes treated with GLP-1 RA in addition to conventional hypoglycemic therapy (n 288).. At follow up CRTd patients with diabetes treated by GLP-1 RA therapy vs. CRTd patients with diabetes that did not receive GLP-1 RA therapy, experienced a significant reduction of NYHA class (p value < 0.05), associated to higher values of 6 min walking test (p value < 0.05), and higher rate of CRTd responders (p value < 0.05). GLP-1 RA patients vs. controls at follow up end experienced lower AF events (p value < 0.05), lower VT events (p value < 0.05), lower rate of hospitalization for heart failure worsening (p value < 0.05), and higher rate of CRTd responders (p value < 0.05). To date, GLP-1 RA therapy may predict a reduction of AF events (HR 0.603, CI [0.411-0.884]), VT events (HR 0.964, CI [0.963-0.992]), and hospitalization for heart failure worsening (HR 0.119, CI [0.028-0.508]), and a higher CRT responders rate (HR 3.707, CI [1.226-14.570]).. GLP-1 RA drugs in addition to conventional hypoglycemic therapy may significantly reduce systemic inflammation and circulating BNP levels in CRTd patients with diabetes, leading to a significant improvement of LVEF and of the 6 min walking test, and to a reduction of the arrhythmic burden. Consequently, GLP-1 RA drugs in addition to conventional hypoglycemic therapy may reduce hospital admissions for heart failure worsening, by increasing CRTd responders rate. Trial registration NCT03282136. Registered 9 December 2017 "retrospectively registered".

Topics: Aged; Arrhythmias, Cardiac; Biomarkers; Blood Glucose; Cardiac Resynchronization Therapy; Cardiac Resynchronization Therapy Devices; Defibrillators, Implantable; Diabetes Mellitus, Type 2; Disease Progression; Electric Countershock; Female; Glucagon-Like Peptide-1 Receptor; Heart Failure; Humans; Hypoglycemic Agents; Incretins; Italy; Male; Middle Aged; Patient Readmission; Prospective Studies; Recovery of Function; Risk Factors; Time Factors; Treatment Outcome; Ventricular Function, Left

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