Background <p>A combination of Glucagon-Like Peptide-1 Receptor Agonist (GLP-1 RA) and a Sodium-Glucose co-transporter-2 Inhibitor (SGLT2i) has demonstrated complementary benefits. This analysis aimed to compare combination therapy (GLP-1 RA and SGLT2i) with SGLT2i alone, both on top of standard HF care, in patients with baseline HF.</p> Methods <p>Systematic searches (PubMed, ScienceDirect, Scopus) and citation searching were performed on February 17, 2026. Original studies directly compared combination therapy and SGLT2i alone in patients with pre-existing HF diagnosis were included. Primary endpoints were all-cause mortality, all-cause hospitalization, and worsening heart failure (WHF). NOS was used for quality assessment. R (v.4.4.1) was used for random-effect meta-analysis. Certainty of evidence was evaluated using the GRADE framework.</p> Results <p>Eight cohorts (<i>n</i> = 75,833 patients) were included. Combination therapy resulted in a lower risk of all-cause mortality [RR: 0.62; 95% CI: 0.47–0.83; <i>p</i> = 0.0014], all-cause hospitalization [RR: 0.89; 95% CI: 0.84–0.96; <i>p</i> = 0.0012], and WHF [RR: 0.74; 95% CI: 0.64–0.87; <i>p</i> = 0.0001] during 1-year follow-up. Combination therapy was associated with significantly improved LVEF [MD: 3.83%; 95% CI: 0.44–7.22; <i>p</i> = 0.0397] and reduced acute kidney injury risk [HR: 0.70; 95% CI: 0.65–0.74] without any significant increase in adverse events (including hypoglycemia, gastrointestinal side effects, pancreatitis, and urinary tract infections). GRADE assessment yielded moderate evidence for three primary endpoints.</p> Conclusions <p>In patients with established HF, combination of GLP-1 RA and SGLT2i therapy was associated with significant reductions in mortality, hospitalization, and WHF, without significant adverse events. Further randomized trials are urgently warranted to confirm such outcomes.</p> Registration <p>PROSPERO identifier no. CRD420261320840.</p> Graphical abstract <p></p>