Objective <p>Evidence on the impact of GLP-1 RAs on HF hospitalization (HHF) and mortality has been inconsistent across clinical trials in patients with diabetes. We investigated the association between GLP-1 RAs and these outcomes in a real-world setting. </p> Methods <p>We selected individuals aged 45&#xa0;years and older already treated with metformin living in Lombardy, Italy, and then split them into two groups if they initiated GLP-1 RAs or other antidiabetic drugs, between 2019 and 2021.</p> <p>A multivariable Cox proportional hazard regression model was performed to assess the association of GLP-1 RAs on HHF and all-cause death as hazard ratios (HRs) with 95% CI compared to the Other ADs group, stratifying by history of HF. The role of GLP-1 RAs was also investigated using the Inverse Probability Treatment Weighting (IPTW) and in the subgroup analyses.</p> Results <p>In total, 9795 patients in the GLP-1 RAs group (302 with HF; 9493 without) and 6018 in the Other ADs group (405 with HF; 5613 without) were included in the analysis.</p> <p>GLP-1 RAs use was significantly associated with a lower risk of HHF in patients with a history of HF (HR 0.65; CI 95% 0.426–0.987) and in those without (HR 0.52; CI 95% 0.371–0.733). A lower risk for all-cause death was also observed in GLP-1 RAs users (with HF: HR 0.45; CI 95% 0.320–0.638; without HF: HR 0.44; CI 95% 0.383–0.514). The results of the IPTW and subgroup analyses confirmed those of the main analysis.</p> Conclusion <p>Our findings showed a benefit of GLP-1 RAs on HHF and all-cause death in patients with diabetes regardless of HF history. Although, our study presents several limitations, if confirmed through dedicated randomized trial, this could further expand the role of GLP-1RAs in cardiovascular prevention”.</p> Graphical abstract <p></p>