oxyntomodulin and Myocardial-Infarction

Glucagon-like peptide 1 receptor (GLP-1R) agonists are increasingly being used as treatment for type 2 diabetes. Since the U.S. Food and Drug Administration published recommendations about the cardiovascular safety of new antidiabetes therapies for treating type 2 diabetes in 2008, the results of two outstanding clinical trials using GLP-1R agonists addressing this issue (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation [LEADER] and Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6]) have been published. Both studies found beneficial effects in terms of reducing the rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, their results regarding the progression of diabetic retinopathy (DR) were neutral with liraglutide (LEADER) or worse when compared with placebo in the case of semaglutide (SUSTAIN-6). These results are surprising because of the beneficial effects of GLP-1R analogs reported in experimental models of DR. In this Perspective, an overview of the mechanisms by which GLP-1R activation exerts its effects in preventing or arresting experimental DR is given. In addition, we consider the possible reasons for the negative results regarding the progression of DR in the SUSTAIN-6 study, as well as the gaps that still need to be covered to further clarify this important issue in the management of type 2 diabetes.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Disease Models, Animal; Disease Progression; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Liraglutide; Molecular Targeted Therapy; Myocardial Infarction; Stroke; Treatment Outcome

Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A. This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.. Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA. Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.. Eli Lilly and Company.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Male; Middle Aged; Myocardial Infarction; Recombinant Fusion Proteins; Stroke

Glucose-insulin-potassium infusions are beneficial in uncomplicated patients with acute myocardial infarction (AMI) but are of unproven efficacy in AMI with left ventricular (LV) dysfunction because of volume requirements associated with glucose infusion. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties that stimulate glucose uptake without the requirements for concomitant glucose infusion.. We investigated the safety and efficacy of a 72-hour infusion of GLP-1 (1.5 pmol/kg per minute) added to background therapy in 10 patients with AMI and LV ejection fraction (EF) <40% after successful primary angioplasty compared with 11 control patients. Echocardiograms were obtained after reperfusion and after the completion of the GLP-1 infusion. Baseline demographics and background therapy were similar, and both groups had severe LV dysfunction at baseline (LVEF=29+/-2%). GLP-1 significantly improved LVEF (from 29+/-2% to 39+/-2%, P<0.01), global wall motion score indexes (1.94+/-0.11-->1.63+/-0.09, P<0.01), and regional wall motion score indexes (2.53+/-0.08-->2.02+/-0.11, P<0.01) compared with control subjects. The benefits of GLP-1 were independent of AMI location or history of diabetes. GLP-1 was well tolerated, with only transient gastrointestinal effects.. When added to standard therapy, GLP-1 infusion improved regional and global LV function in patients with AMI and severe systolic dysfunction after successful primary angioplasty.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Blood Glucose; Combined Modality Therapy; Diabetes Complications; Female; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Humans; Male; Middle Aged; Myocardial Infarction; Peptide Fragments; Pilot Projects; Safety; Stroke Volume; Treatment Outcome; Ventricular Function, Left

Glucagon-like peptide-1 (7-36) amide (GLP-1) has been studied as a treatment option in diabetic patients. We investigated the effect of recombinant GLP-1 infusion on hemodynamic parameters, myocardial metabolism, and infarct size during normoxic conditions as well as during ischemia and reperfusion using an open-chest porcine heart model. In the presence of rGLP-1, interstitial levels of pyruvate and lactate decreased during ischemia and reperfusion both in ischemic and non-ischemic tissue. Moreover, rGLP-1 infusion resulted in increased plasma insulin levels and decreased blood glucose levels. Neither hemodynamic variables nor the consequent infarct size were influenced by rGLP-1 infusion. We conclude that rGLP-1 altered myocardial glucose utilization during ischemia and reperfusion. It did not exert any untoward hemodynamic effects.

Topics: Animals; Area Under Curve; Blood Glucose; Cardiovascular System; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Ischemia; Lactic Acid; Microdialysis; Myocardial Infarction; Myocardium; Peptide Fragments; Protein Precursors; Pyruvic Acid; Reperfusion Injury; Swine; Time Factors