Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have been shown to provide extra-glycemic advantages, such as cardiovascular and renal protection, in the treatment of type 2 diabetic mellitus (T2DM). Recent data points to the possibility that gut microbiota modification may contribute to their beneficial impact. This review examines changes in microbial composition, metabolite synthesis (such as short-chain fatty acids (SCFA), bile acids, and endotoxins), and their systemic implications by integrating clinical and preclinical data on the interactions between various drug types and the gut microbiota. GLP-1RAs may favor certain taxa that synthesize SCFA and Akkermansia muciniphila. This may improve insulin sensitivity and lower inflammation. Likewise, SGLT-2is may favor a eubiotic state, which is associated with better renal and metabolic outcomes. We also discuss the use of baseline microbial profiles to predict therapy responses in a microbiota-informed precision medicine approach. Larger human investigations are required to explore causality and therapeutic efficacy, as mechanistic insights are still limited despite early encouraging findings. This narrative review synthesizes both clinical and preclinical data identified through PubMed, Scopus, Web of Science, Embase, and Google Scholar up to May 2025. Personalized holistic T2DM therapy plans that integrate both host and microbial pathways may be made possible by gut microbiota studies.