Cardiovascular Effects of GLP-1 Metabolite Beyond Classical GLP-1 Receptor Signaling in Type 2 Diabetes Mellitus: A Narrative Review

Type 2 diabetes mellitus (T2DM) is a serious health issue worldwide. Patients with this disease face a much higher risk of heart disease and early death. High blood glucose also insulin resistance damages the endothelium and change the structure of blood vessels, atherosclerosis, heart attack, stroke, retinopathy, and ischemia become more likely. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that protects the heart but it does not last long in the blood. Dipeptidyl peptidase-4 (DPP-4) breaks it down into GLP-1 (9-36) within about one to two minutes. This narrative review summaries the molecular pathways through which GLP-1 and its metabolites protect the heart in T2DM beyond DPP-4 cleavage. The literature was search through PubMed, ScienceDirect, and Google Scholar up to early 2026 using the keywords “GLP-1”, “cardiac complication”, “cardiovascular”, “endothelial dysfunction”, “insulin resistance”, and “type 2 diabetes mellitus”. Normally, GLP-1 activates GLP-1r to enhance myocardial glucose uptake and vascular protection. Newer studies show that GLP-1 (9-36) amide also has cardiovascular effects, and that these effects do not need the GLP-1 receptor. It preserves cardioprotective activity by inducing cGMP/PKG-mediated vasodilatation and by limiting oxidative damage to endothelial cells, even when functional GLP-1R is absent. In short, protection seems to come from two routes: one that works through GLP-1R and one that works without it.