Semaglutide in Cardiovascular Disease: Integrating Mechanisms with Evidence from Major Clinical Trials

Cardiovascular disease (CVD) remains the leading cause of global morbidity and mortality, with a growing contribution from cardiometabolic disorders such as type 2 diabetes mellitus and obesity. Traditional glucose-lowering therapies have primarily focused on glycaemic control without demonstrating consistent cardiovascular benefit, leading to a paradigm shift toward therapies that target both metabolic and cardiovascular risk. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, has emerged as a promising agent with integrated effects on glycaemic regulation, body weight, vascular function, and systemic inflammation. This review synthesizes current evidence on the role of semaglutide in cardiovascular disease, integrating mechanistic insights with findings from major clinical trials. Semaglutide improves insulin secretion, suppresses glucagon release, delays gastric emptying, and promotes sustained weight reduction through central appetite regulation. Beyond metabolic effects, it enhances endothelial function, reduces oxidative stress, and exerts anti-inflammatory actions that contribute to stabilization of atherosclerotic processes. Large cardiovascular outcome trials, including SUSTAIN-6 and SELECT, demonstrate significant reductions in major adverse cardiovascular events in both diabetic and non-diabetic populations, highlighting benefits independent of glycaemic control. Additionally, emerging evidence suggests favourable effects in obesity-related heart failure and broader cardiometabolic risk profiles. Despite these benefits, challenges related to long-term outcomes, comparative effectiveness, and accessibility remain. Overall, semaglutide represents a shift toward integrated cardiometabolic therapeutics, acting across multiple pathophysiological pathways and offering potential as a disease-modifying agent in cardiovascular care.