We analyzed key clinical trials, including SUSTAIN 6, PIONEER 6, STEP HFpEF, STEP HFpEF DM, and supportive studies on glucagon-like peptide receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, alongside mechanistic insights into semaglutide’s metabolic, anti-inflammatory, and decongestive effects. This evidence concerns the gene GLP1R and diabetes mellitus.