Impact of GLP-1 receptor agonists on outcomes in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab: A multicenter propensity-matched real-world analysis.

Abstract

e16180 Background: First-line treatment of advanced unresectable or metastatic hepatocellular carcinoma (HCC) is now defined by immune checkpoint inhibitor (ICI) based combinations, particularly atezolizumab plus bevacizumab. Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used in type 2 diabetes mellitus (T2DM), may favorably modulate immune and metabolic pathways, potentially enhancing ICI efficacy and improving cardiovascular safety. We evaluated the real-world impact of GLP-1RA exposure on clinical outcomes in patients with HCC treated with atezolizumab plus bevacizumab. Methods: We conducted a multicenter retrospective cohort study using the TriNetX Global Collaborative Network, a federated electronic health record database, including data from January 1, 2018, to December 31, 2025. Adult patients with HCC and T2DM initiating atezolizumab plus bevacizumab were stratified into two cohorts: those prescribed any GLP-1RA within 12 months prior to treatment initiation (GLP-1RA group) and those treated with alternative antihyperglycemic agents without GLP-1RA exposure (non-GLP-1RA group). Alternative agents included metformin, SGLT2 inhibitors, DPP-4 inhibitors, insulin, thiazolidinediones, alpha-glucosidase inhibitors, and sulfonylureas. One-to-one propensity score matching was performed to balance demographics, HCC etiology, comorbidities, laboratory parameters, and concurrent antidiabetic therapies. Outcomes were assessed over a 5-year follow-up period. The primary endpoint was overall survival (OS). Secondary endpoints included major adverse cardiovascular events (MACE), excluding patients with pre-existing events. All analyses were conducted within the TriNetX analytics platform. Results: Among 920 eligible patients, 106 (11.5%) received GLP-1RA therapy and 814 (88.5%) comprised the non-GLP-1RA cohort. After 1:1 propensity score matching, 70 patients were included in each group. GLP-1RA exposure was associated with a improvement in OS compared with the non-GLP-1RA group at 5 years (hazard ratio [HR] 0.51; 95% CI, 0.32–0.82). In the MACE analysis, which excluded patients with prior cardiovascular events (GLP-1RA, n = 45; non-GLP-1RA, n = 48), GLP-1RA therapy was associated with a lower risk of MACE at 5 years (HR 0.49; 95% CI, 0.24–0.98). Conclusions: In patients with T2DM and HCC treated with atezolizumab plus bevacizumab, prior GLP-1RA exposure was associated with significantly improved overall survival and a reduced risk of major adverse cardiovascular events compared with alternative antihyperglycemic therapies. These findings support a potential synergistic role of GLP-1RAs in this population and warrant prospective validation.