Cardiovascular Effects of GLP-1 and Glucagon Dual Receptor Agonism in Humans

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition characterised by chronic hyperglycaemia resulting from insulin resistance and impaired insulin secretion. 415 million adults live with T2DM worldwide. It is a growing global health problem, closely linked to the increasing prevalence of obesity. The numbers living with T2DM is expected to increase to 642 million by 2040 and estimates suggest up to 12% of global health expenditure will need to be spent on diabetes and its complications. Type 2 diabetes at least doubles the risk of cardiovascular disease and is associated with a 2-to-4-fold increase in mortality. Current treatments aim to normalise blood glucose, reduce the risk of microvascular and macrovascular complications and therefore lower the risk of cardiovascular disease and overall mortality. Several previously established therapies for T2DM were associated with weight gain (insulin, sulphonylureas and thiazolidinediones) or an increased risk of hypoglycaemia (insulin and sulfonylureas). A wealth of new anti-diabetic agents have emerged over the past two decades including dipeptidyl peptidase IV inhibitors, glucagon like peptide-1 (GLP-1) receptor agonists and selective sodium-glucose transporter-2 inhibitors (SGLT2i). These medications have transformed treatment pathways and prognosis for individuals with T2DM as well as obesity (GLP-1 receptor agonists), heart failure (SGLT2i) and chronic kidney disease (SGLT2i) Glucagon like peptide-1 and glucagon are two peptide hormones involved in the regulation of glucose homeostasis as well as a diverse range of pharmacological actions on the cardiovascular system. GLP-1 receptor agonists reduce cardiovascular events in adults with T2DM and obesity. From a cardiovascular perspective, GLP-1 receptor agonists increase heart rate and lower blood pressure. Glucagon is traditionally thought to act as a positive chronotrope and inotrope in humans. Dual agonist peptides at the GLP-1 and glucagon receptor are in clinical development for a range of chronic metabolic conditions including T2DM, chronic kidney disease and metabolic dysfunction-associated steatohepatitis. The cardiovascular actions of GLP-1 and glucagon receptor agonism are well studied, however less is known about their combination. This thesis reviews the discovery, background, physiology, metabolic and cardiovascular effects of these peptide hormones. The cardiovascular effects of GLP-1 and glucagon receptor dual agonism are subsequently explored through a series of systemic intravenous infusion studies, COCOA and COCONUT. The COCOA study examined the non-invasive haemodynamic effects of exenatide (a licensed GLP-1 receptor agonist), glucagon and exenatide:glucagon dual agonism in healthy male adults. Consistent with its well-known chronotropic effect, high dose glucagon acutely increased heart rate by ~11 bpm after 120 minutes (p<0.001). Low dose glucagon and exenatide infusions acutely increased heart rate by ~4 bpm after 60 minutes (p<0.001). Co-infusion led to a greater increase in heart rate by ~7 bpm (p<0.001). The COCONUT study explored the effects of GLP-1:glucagon dual receptor agonism on myocardial function and myocardial glucose uptake in overweight adults with T2DM, using 18F-FDG PET-MRI. Both infusions significantly increased myocardial glucose uptake (p<0.05). Glucagon caused a small, non-significant increase in stroke volume (+4 ml). Exenatide:glucagon co-infusion non-significantly increased left ventricular ejection fraction (+1.6%) and improved global longitudinal strain (-0.6%). Further research is required to evaluate these effects to see whether GLP-1:glucagon dual receptor agonists have a role to play in reducing cardiovascular risk and attenuating symptoms and prognosis in patients with diabetic cardiomyopathy and other conditions linked with the metabolic syndrome.