Type 2 diabetes mellitus (T2DM) is closely linked to increased cardiovascular risk through mechanisms involving oxidative stress, adverse cardiac remodeling, and endothelial dysfunction. While glucose-lowering therapies improve glycemic control, their mechanistic cardiovascular effects remain incompletely understood. A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with comprehensive searches performed in PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials through February 2025. Eligible studies included randomized controlled trials and prospective mechanistic investigations enrolling adults with T2DM, with or without established cardiovascular disease or heart failure. Mechanistic endpoints encompassed echocardiographic indices, cardiac magnetic resonance (CMR), vascular function, biomarkers of oxidative stress and inflammation, and metabolic parameters. Risk of bias was assessed using the Cochrane RoB 2 tool. A total of 449 records were identified, of which 127 were excluded, leaving nine studies for inclusion. Trials evaluating sodium-glucose cotransporter 2 (SGLT2) inhibitors consistently demonstrated improvements in left ventricular remodeling, oxidative stress markers, and functional capacity, with some studies showing preserved mitochondrial respiration and favorable shifts in hemodynamic parameters. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were associated with improvements in atrial strain, arterial stiffness, and diastolic function, albeit with modest effects on systolic performance. Dipeptidyl peptidase-4 (DPP-4) inhibitors showed evidence of plaque stabilization without a significant impact on overall plaque burden. Metformin, in long-term follow-up, did not significantly reduce cardiac stress biomarkers. Overall, most studies were at low risk of bias, though post-hoc analyses and open-label designs introduced some methodological concerns. Glucose-lowering therapies exert heterogeneous mechanistic cardiovascular effects in T2DM, with the most consistent cardioprotective signatures observed for SGLT2 inhibitors and, to a lesser extent, GLP-1 receptor agonists. These findings highlight distinct biological pathways through which antidiabetic therapies may confer cardiovascular benefit, underscoring the need for further mechanistic trials with standardized endpoints to bridge the gap between glycemic management and cardiovascular outcomes.
