<![CDATA[Background: Heart failure (HF) affects over 64 million individuals globally and is associated with high morbidity and mortality, particularly in patients with type 2 diabetes mellitus (T2DM). Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are emerging therapies with reported cardiovascular benefits. However, their comparative efficacy in HF-specific outcomes remains unclear. This systematic review aimed to assess and compare the safety and efficacy of SGLT2 inhibitors and GLP-1 RAs in patients with HF. Methods: We systematically searched PubMed, EMBASE, and Scopus up to 1 May 2025 for randomized controlled trials (RCTs) evaluating SGLT2 inhibitors or GLP-1 RAs in adults with HF. Primary outcomes included all-cause and cardiovascular mortality; secondary outcomes included HF hospitalization and major adverse cardiovascular events (MACE). Risk of bias was assessed using the Cochrane RoB 2 tool and certainty of evidence with the GRADE approach. Result: Fourteen RCTs comprising 30,867 patients (52.2% female; 63.2% with T2DM) were included. SGLT2 inhibitors significantly reduced cardiovascular mortality (RR: 0.85, 95% CI: 0.78–0.93, p < 0.001, I² = 14%), all-cause mortality (RR: 0.88, 95% CI: 0.81–0.95, p = 0.002, I² = 21%), and HF hospitalizations (RR: 0.72, 95% CI: 0.67–0.77, p < 0.001, I² = 0%). GLP-1 RAs did not demonstrate significant effects on these outcomes. Overall risk of bias was low to moderate; GRADE certainty ranged from moderate to high. Conclusions: SGLT2 inhibitors provide consistent reductions in mortality and hospitalization in HF patients across glycemic statuses. GLP-1 RAs showed limited benefit in HF-specific outcomes, supporting the preferential use of SGLT2 inhibitors in HF treatment strategies.]]>
