Emerging Role of Dual Glucagon-Like Peptide-1 (GLP-1)/Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor...

Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have emerged as a novel therapeutic class with potential relevance for cardiovascular prevention, particularly in the context of obesity and type 2 diabetes mellitus. Incretin physiology provides the biological foundation for this approach, as GLP-1 and GIP exert complementary metabolic and vascular effects. While GLP-1 receptor agonists have demonstrated well-established reductions in major adverse cardiovascular events, GIP has regained interest due to evidence suggesting preserved vascular and anti-atherosclerotic actions despite reduced insulinotropic efficacy in diabetes.  Dual receptor agonism integrates these pathways, leading to substantial improvements in cardiometabolic risk factors. Agents such as tirzepatide induce marked and sustained weight loss, with significant reductions in visceral adiposity, a key driver of cardiovascular disease. These effects are accompanied by robust improvements in glycemic control and insulin sensitivity, resulting in attenuation of glucotoxicity and lipotoxicity, both of which contribute to endothelial dysfunction and myocardial injury. Additional benefits include reductions in blood pressure, favorable modulation of lipid profiles, and suppression of systemic inflammatory markers, alongside improvements in endothelial function and vascular stiffness. Pharmacologically, dual GLP-1/GIP receptor agonists are engineered to provide balanced receptor activation, allowing superior metabolic efficacy compared with single GLP-1 receptor agonists. Clinical trial data indicate cardiovascular safety and improvements in surrogate cardiovascular endpoints, with reductions in major cardiometabolic risk factors comparable to those achieved with established incretin therapies. However, definitive evidence of incremental cardiovascular outcome benefits remains limited.