Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP-1a), commonly used for type 2 diabetes and obesity, have shown potential anti-cancer effects in preclinical models. However, their impact on outcomes in patients with estrogen receptor-positive (ER+) metastatic breast cancer (MBC) remains unclear. This study evaluates the association between GLP-1a use and survival and (2) ER+ MBC patients treated with aromatase inhibitors without GLP-1a or metformin. Cohorts were matched 1:1 using propensity scores based on demographics, comorbidities including type 2 diabetes mellitus and Obesity; and concurrent medications, including endocrine therapies (letrozole, anastrozole, exemestane) and other systemic treatments such as CDK4/6 inhibitors, mTOR inhibitors, and HER2-targeted agents. Kaplan-Meier survival analyses were performed for overall survival and adverse outcomes over a 2-year follow-up. Results: After propensity score matching, each cohort included 1,793 patients. GLP-1a use was associated with significantly improved 2-year overall survival (HR 0.612, 95% CI: 0.484-0.773, p0.001). Risk of hospitalization was also lower in the GLP-1a group (HR 0.559, 95% CI: 0.412-0.759, p0.001). GLP-1a use was associated with reduced risk of Anemia (HR 0.769, 95% CI: 0.601-0.983, p=0.035), Thrombocytopenia (HR 0.682, 95% CI: 0.487-0.955, p=0.025) and Severe sepsis (HR 0.633, 95% CI: 0.411-0.975, p=0.037). No significant differences were observed for Neutropenia (HR 0.712, 95% CI: 0.501-1.012, p=0.057), Nausea/vomiting (HR 1.204, 95% CI: 0.958-1.512, p=0.111), Outpatient visits (HR 0.795, 95% CI: 0.159-3.970, p=0.779), Heart failure (HR 1.150, 95% CI: 0.818-1.616, p=0.421), Cardiomyopathy (HR 0.777, 95% CI: 0.460-1.312, p=0.344), Diarrhea (HR 0.998, 95% CI: 0.773-1.288, p=0.987), HFrEF (HR 0.881, 95% CI: 0.505-1.537, p=0.656), Pneumonia (HR 0.925, 95% CI: 0.680-1.258, p=0.620), Peripheral neuropathy (HR 0.893, 95% CI: 0.677-1.178, p=0.423). Conclusions: This large retrospective cohort analysis provides evidence suggesting that GLP-1a use in patients with ER+ metastatic breast cancer may offer survival benefits beyond their established metabolic indications. The association between GLP-1a use and improved two-year overall survival, as well as reduced hospitalizations and lower incidence of several treatment-related adverse events, is clinically significant and suggests a possible dual role for GLP-1a in addressing both metabolic and oncologic challenges in this population. Importantly, GLP-1a therapy was not associated with increased gastrointestinal or cardiac toxicity, reinforcing its safety profile when used alongside standard endocrine and targeted cancer therapies. These findings align with emerging data that metabolic interventions can impact tumor biology and patient outcomes, and they highlight the value of a multidisciplinary approach that addresses both oncologic and comorbid metabolic conditions. Future prospective studies and randomized clinical trials are needed to validate these results and further elucidate the underlying biological mechanisms by which GLP-1a may exert anti-tumor effects in ER+ MBC. This study signifies the evolving landscape of cancer care, where holistic, patient-centered strategies are increasingly recognized as essential for optimal outcomes. Citation Format: F. Khan, M. Zafar, B. Singeltary. Impact of Glucagon-like peptide-1 receptor agonists Use on Survival and Metabolic Outcomes in Metastatic Estrogen Receptor Positive Breast Cancer: A Real-World Cohort Study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-12.
Khan et al. (Tue,) studied this question.
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