Abstract
Cardiovascular (CV) diseases (CVDs) remain a leading global health issue, causing about one-third of all deaths worldwide. Among modifiable CV risk factors (systolic blood pressure, non-HDL cholesterol, diabetes, body mass index, and smoking), diabetes is a leading one, accounting for established CVDs in 34.8% of diabetic patients, with an increasing prevalence of disease. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), like exenatide, liraglutide, albiglutide, dulaglutide, and semaglutide, initially developed for treatment of Type 2 diabetes, have shown CV benefits, and international guidelines recommend now GLP-1 RAs as preferred drugs for CV prevention in diabetic patients regardless of baseline HbA1c or metformin use. Among GLP-1 RAs, subcutaneous semaglutide has demonstrated cardio-metabolic risk factors reduction and efficacy in CV prevention. Development of oral semaglutide represents the evolution of the molecule. The PIONEER study programme confirmed the efficacy of oral semaglutide in reducing HbA1c, body weight, and cardio-metabolic risk factors as well as CV safety. Notably, independently by route of administration, semaglutide showed early CV benefits, suggesting mechanisms beyond glycaemic control or weight reduction. Semaglutide, combining potent cardio-metabolic effects with oral route, emerges as a pivotal treatment for high-risk Type 2 diabetes patients, offering comprehensive CV protection independent of HbA1c levels.