GLP-1 RAs vs. SGLT2is: Divergent Pathways of Cardiovascular Inflammation Control in Obesity-Associated Diabetes

Diabesity, defined as the coexistence of type 2 diabetes and obesity, is a major global driver of cardiovascular disease through mechanisms of chronic low-grade meta-inflammation. Recent advances in glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated benefits that extend beyond glycemic control to encompass immunometabolic modulation. The present narrative review aimed to synthesize evidence on the anti-inflammatory pathways and cardiovascular benefits of these agents, focusing on their mechanistic overlap, divergence and clinical implications. A systematic search of PubMed, Scopus, Web of Science and Google Scholar was conducted for articles published between 2010 and 2024. Approximately 350 articles were screened, and 129 were included based on relevance to inflammation, diabesity and cardiovascular outcomes, integrating data from mechanistic studies, imaging substudies and randomized controlled trials. Evidence suggests that GLP-1 RAs primarily attenuate inflammation through gut-brain-vascular signaling, endothelial transcriptional modulation, and macrophage polarization, whereas SGLT2is exert their effects via renal-hemodynamic reset, suppression of the NLRP3 inflammasome, and reduction of epicardial adipose tissue. Both classes consistently lower levels of systemic cytokines such as IL-6 and hsCRP and improve endothelial function, collectively mitigating cardiometabolic risk. However, major outcome trials were not designed with inflammation as a primary endpoint, and no head-to-head studies have directly compared these agents for inflammatory outcomes. Critical research gaps include the need for standardized biomarker panels, advanced imaging modalities, and evaluation of combination therapy. Future research should focus on precision medicine approaches incorporating phenotyping, biomarker stratification and long-term inflammation-focused trials to optimize personalized treatment strategies for patients with diabesity.