Modern antidiabetic therapy by sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and dipeptidyl peptidase 4 inhibitors against cardiovascular diseases

Diabetes and related metabolic diseases have a high prevalence with increasing incidence and create a significant socioeconomic burden by their contribution to global mortality and disability-adjusted life years. According to data from the Global Burden of Disease Study, high fasting plasma glucose and high total cholesterol rank third and fourth in the list of global health risk factors, just behind high blood pressure and smoking. Diabetes adversely affects endothelial and cardiac function, thereby contributing significantly to the development and progression of cardiovascular diseases, which represents the leading health risk factors and causes of death worldwide. Oxidative stress and inflammation play a key role in the pathophysiology underlying diabetes mellitus and the associated cardiometabolic complications, such as metabolic dysfunction-associated fatty liver disease, hypertension, atherosclerosis, myocardial ischemia/reperfusion, and heart failure. Here, we highlight the beneficial effects of the modern antidiabetic drug classes of dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors on overall and cardiovascular mortality of diabetic individuals, with particular emphasis on their effects on oxidative stress, inflammation, and endothelial dysfunction. We discuss the mechanisms of action and pleiotropic beneficial effects and compare them with standard diabetic and cardiovascular therapy. SIGNIFICANCE STATEMENT: Modern antidiabetic drugs confer organ protection that goes beyond simple glucose-lowering. SGLT2 inhibitors and incretin-based drugs possess direct reno-, vasculo-, and cardioprotective effects that are based on potent antioxidant and anti-inflammatory properties. Other pleiotropic effects comprise improved lipid handling and weight loss, prevention of thrombosis and ischemic heart damage, and beneficial regulation of nitric oxide signaling and epigenetic and microbiotic pathways.