Mechanisms by Which Glucagon-Like-Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors Reduce Cardiovascular Risk in Adults With Type 2 Diabetes Mellitus

The growing global burden of type 2 diabetes mellitus confers significant morbidity and mortality in addition to significant cost to local health-care systems. In recent years, 2 classes of therapies have shown some promise in reducing the risk of adverse cardiovascular (CV) events: 1) glucagon-like-peptide-1 (GLP-1) receptor agonists and 2) sodium-glucose cotransporter-2 (SGLT-2) inhibitors. The mechanisms whereby these therapies reduce the risk of adverse CV outcomes are emerging. Both classes of therapies have overlapping yet distinct mechanisms of action. GLP-1 receptor agonists appear to target the incretin axis, inhibit gastric mobility pathways, modify CV risk factors through weight reduction, induce protection of ischemia/reperfusion injury and improve endothelial dysfunction. In comparison, SGLT-2 inhibitors appear to improve ventricular loading conditions, reduce sympathetic nervous system activation, reduce cardiac fibrosis, reduce renal hypoxia and renal-cardiac signalling, reduce left ventricular mass and improve cardiac energetics. In this review, we summarize the potential mechanisms whereby GLP-1 receptor agonists and SGLT-2 inhibitors improve CV outcomes in patients with type 2 diabetes and highlight evidence for their use in populations without diabetes.