Abstract PS2-02-24: Comparative Effects of Semaglutide vs Tirzepatide on Weight Change and Cardiovascular Risk in Breast Cancer Survivors

Abstract Background: Obesity and cardiometabolic dysfunction are common in breast cancer survivors and linked to higher treatment toxicity, cardiovascular morbidity, and worse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including semaglutide and Tirzepatide, show cardiometabolic benefits in non-cancer populations, but their impact in breast cancer survivors remains unclear. This study compared the effects of semaglutide and Tirzepatide versus metformin on weight trajectory and major adverse cardiovascular events (MACE) in a real-world oncology cohort. Methods: We conducted a retrospective cohort study using the TriNetX Analytics Research Network, a federated, de-identified electronic health record database. Female breast cancer patients with obesity and/or type 2 diabetes mellitus who were prescribed semaglutide (n=3,009) or Tirzepatide (n=1,652) from January 1, 2018, to June 1, 2025, were identified and matched 1:1 to metformin users without GLP-1 RA exposure using propensity scores. Baseline characteristics included demographics, comorbidities, cancer therapies, and cardiometabolic risk factors. Matching was performed using age, sex, race, BMI, hemoglobin A1c, and comorbidities. Outcomes included weight change at 12 and 24 months, and incidence of MACE, defined as myocardial infarction, stroke, or cardiovascular death. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Results: At 12 and 24 months, both semaglutide and Tirzepatide groups demonstrated significantly greater weight loss compared to matched metformin users (Table 1). Semaglutide was associated with a significant reduction in MACE versus metformin (HR 0.78, p=0.032), including MI (HR 0.68, p=0.045), with favorable trends in cardiovascular death (HR 0.75, p=0.07) and stroke (HR 0.81, p=0.18). Tirzepatide demonstrated more pronounced cardioprotective effects, reducing MACE (HR 0.63, p=0.001), MI (HR 0.52, p=0.004), and cardiovascular death (HR 0.61, p=0.033), with a trend toward stroke reduction (HR 0.72, p=0.09). Conclusions: In this real-world analysis of breast cancer patients with cardiometabolic comorbidities, both semaglutide and Tirzepatide led to clinically meaningful and sustained weight loss at 12 and 24 months and reduced cardiovascular risk, with Tirzepatide showing the greatest benefit. Our findings underscore the potential of GLP-1 receptor agonists to improve cardiometabolic health, a key modifiable risk factor in breast cancer survivors, by enhancing weight and cardiovascular outcomes. These results support the role of GLP-1 receptor agonists as adjuncts to lifestyle interventions in survivorship care. Prospective trials in breast oncology populations are needed to confirm these findings and guide the integration of strategies for cardiovascular, metabolic, and cancer risk reduction. Citation Format: J. Hundal, D. Parekh, A. Harisingani, A. Abushamma, Omer Ashruf, J. Sukumar. Comparative Effects of Semaglutide vs Tirzepatide on Weight Change and Cardiovascular Risk in Breast Cancer Survivors [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 PS2-02-24.