glucagon-like-peptide-1-(7-36)amide and Heart-Failure

During myocardial infarction (MI), a variety of mechanisms contribute to activation of cell death processes in cardiomyocytes, which determines the final MI size, subsequent mortality, and post-MI remodeling. The deleterious mechanisms activated during the ischemia and reperfusion phases in MI include oxygen deprival, decreased availability of nutrients and survival factors, accumulation of waste products, generation of oxygen free radicals, calcium overload, neutrophil infiltration in the ischemic area, depletion of energy stores, and opening of the mitochondrial permeability transition pore, all of them contributing to activation of apoptosis and necrosis in cardiomyocytes. Glucagon-like peptide-1 [GLP-1 (7-36) amide] has gained relevance in recent years for metabolic treatment of patients with type 2 diabetes mellitus. Cytoprotection of different cell types, including cardiomyocytes, is among the pleiotropic actions reported for GLP-1. This paper reviews the most relevant experimental studies that have contributed to a better understanding of the molecular mechanisms and intracellular pathways involved in cardioprotection induced by GLP-1 and analyzes in depth its potential role as a therapeutic target both in the ischemic and reperfused myocardium and in other conditions that are associated with myocardial remodeling and heart failure.

Topics: Animals; Cardiotonic Agents; Cell Survival; Cells, Cultured; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Enteroendocrine Cells; Enzyme Activation; Glucagon-Like Peptide 1; Heart Failure; Heart Function Tests; Humans; Hypoglycemic Agents; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocytes, Cardiac; Peptide Fragments; Protein Kinases; Signal Transduction

The aim of the present study was to assess the risk of overall mortality, coronary artery disease (CAD), and congestive heart failure (CHF) in patients with type 2 diabetes mellitus (T2DM) treated with metformin (MF) and an additional antidiabetic agent.. A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record (EHR) system to identify 13,185 adult patients (>18 years) with T2DM from January 2008 to June 2013 and received a prescription for MF in combination with a sulfonylurea (SU; n = 9419), thiazolidinedione (TZD; n = 1846), dipeptidyl peptidase-4 inhibitor (DPP-4i; n = 1487), or a glucagon-like peptide-1 receptor agonist (GLP-1a; n = 433). Multivariate Cox models with propensity analysis were used to compare cohorts, with MF+SU serving as the comparator group.. The mean (±SD) age was 60.6 ± 12.6 years, with 54.6% male and 75.8% Caucasians. The median follow-up was 4 years. There were 1077 deaths, 1733 CAD events, and 528 CHF events in 55,100 person-years of follow-up. A higher risk of CHF was observed with MF+DPP-4i use (hazard ratio [HR] 1.104; 95% confidence interval [CI] 1.04-1.17; P = 0.001). A trend towards improved overall survival for users of MF+TZD (HR 0.86; 95% CI 0.74-1.0; P = 0.05) and MF+GLP-1a (HR 0.569; 95% CI 0.30-1.07; P = 0.08) was observed. No significant differences in the risk of CAD were identified.. Consistent with recent studies, our results raise concern for an increased risk of CHF with use of DPP-4i.

Topics: Aged; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Heart Failure; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Multivariate Analysis; Outcome Assessment, Health Care; Peptide Fragments; Proportional Hazards Models; Retrospective Studies; Risk Factors; Sulfonylurea Compounds; Survival Rate; Thiazolidinediones

We previously demonstrated that older beagles have impaired whole body and myocardial insulin responsiveness (MIR), and that glucagon-like peptide-1 (GLP-1 [7-36] amide) improves MIR in young beagles with dilated cardiomyopathy (DCM). Here, we sought to determine if aging alone predisposes to an accelerated course of DCM, and if GLP-1 [7-36] amide would restore MIR and impact the course of DCM in older beagles.. Eight young beagles (Young-Control) and sixteen old beagles underwent chronic left ventricle (LV) instrumentation. Seven old beagles were treated with GLP-1 (7-36) amide (2.5 pmol/kg/min) for 2 weeks prior to instrumentation and for 35 days thereafter (Old + GLP-1), while other 9 served as control (Old-Control). All dogs underwent baseline metabolic determinations and LV biopsy for mitochondria isolation prior to the development of DCM induced by rapid pacing (240 min-1). Hemodynamic measurements were performed routinely as heart failure progressed.. At baseline, all old beagles had elevated non-esterifed fatty acids (NEFA), and impaired MIR. GLP-1 reduced plasma NEFA (Old-Control: 853 ± 34; Old + GLP-1: 531 ± 33 μmol/L, p < 0.02), improved MIR (Old-Control: 289 ± 54; Old + GLP-1: 512 ± 44 mg/min/100 mg, p < 0.05), and increased uncoupling protein-3 (UCP-3) expression in isolated mitochondria. Compared to the Young-Control, the Old-Controls experienced an accelerated course of DCM (7 days versus 29 days, p < 0.005) and excess mortality, while the Old + GLP-1 experienced increased latency to the onset of DCM (7 days versus 23 days, p < 0.005) and reduced mortality.. Aging is associated with myocardial insulin resistance, which predispose to an accelerated course of DCM. GLP-1 treatment is associated with increased MIR and protection against an accelerated course of DCM in older beagles.

Topics: Aging; Animals; Cardiotonic Agents; Disease Progression; Dogs; Glucagon-Like Peptide 1; Heart Failure; Infusions, Intravenous; Insulin Resistance; Myocardium; Peptide Fragments; Random Allocation