The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health: A Comprehensive Review

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and gluca-gon-like peptide-1 (GLP-1) play central roles in metabolic and cardiovascular regulation. GLP-1 receptor agonists (GLP-1RAs) are established therapies for type 2 diabetes mellitus (T2DM) and obesity because of their insulinotropic effects, weight reduction, and proven cardiovascular benefit. In contrast, GIP was historically overlooked due to reduced β-cell responsiveness in T2DM. The development of dual GIP/GLP-1 receptor agonists has reshaped this view. Tirzepatide, the first-in-class co-agonist, provides superior glycemic control and weight loss compared with selective GLP-1RAs, demonstrating synergistic actions between the two incretin pathways. This review summarizes key physiology, pathophysiology, and therapeutic evidence in incretin biology. We describe secretion patterns, receptor distributions, and distinct ac-tions of GIP and GLP-1, as well as alterations in incretin signaling in T2DM and obesity. Cardiovascular protective mechanisms are outlined, including improvements in lipid metabolism, reductions in blood pressure, enhanced endothelial nitric oxide activity, suppression of macrophage inflammation, decreased foam-cell formation, and stabiliza-tion of atherosclerotic plaques. Emerging directions—such as dual and triple ago-nists—and unresolved questions regarding long-term vascular effects of GIP and the potential for genotype-guided incretin therapy are also discussed. Collectively, these findings highlight a shift toward integrated incretin-axis modulation for metabolic and cardiovascular disease.