Abstract
Diabetes mellitus (DM) is both a metabolic and chronic inflammatory disease, wherein immune dysregulation contributes to multisystem complications. Beyond glycemic control, anti-diabetic agents-Metformin (Met), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)-exert immunomodulatory effects through cytokine and chemokine modulation. This review summarizes mechanistic and experimental findings (2013-2025), showing that Met suppresses pro-inflammatory cytokines (e.g., interleukin-1 beta [IL-1β], IL-6, tumor necrosis factor-alpha [TNF-α]) and enhances anti-inflammatory mediators (e.g., IL-10, growth differentiation factor-15 [GDF-15]) via adenosine monophosphate-activated protein kinase (AMPK) activation, nuclear factor kappa-B (NF-κB) inhibition, NLR family pyrin domain containing 3 (NLRP3) inflammasome suppression, and gut microbiota modulation. These effects reduce inflammation, oxidative stress, and fibrosis in organs including the kidney, liver, brain, and retina. SGLT-2i (e.g., empagliflozin, dapagliflozin) reduce IL-1β, IL-6, IL-17, transforming growth factor-beta (TGF-β), and monocyte chemoattractant protein-1 (MCP-1), primarily in renal, cardiac, and hepatic tissues, through β-hydroxybutyrate-induced NLRP3 inhibition and mitochondrial protection. Empagliflozin also suppresses Th17 and promotes Treg responses in T2D. GLP-1 RAs (liraglutide, semaglutide) reduce IL-1β, IL-6, IL-18, and TNF-α, enhance IL-10 and stromal-derived factor-1α (SDF-1α), and decrease MCP-1, improving endothelial function and wound healing. These agents modulate TGF-β/small mothers against decapentaplegic (Smad) and AMPK pathways to attenuate fibrosis, oxidative injury, and neuronal damage. Emerging novel formulations and synergistic combinations further amplify their anti-inflammatory and metabolic benefits. This dual immunometabolic action repositions anti-diabetic agents as multifunctional modulators in precision therapy, extending their role beyond glycemic control to the long-term prevention of complications.