Tirzepatide vs semaglutide for metabolic optimization in patients with cancer: A target trial emulation study.

528 Background: Tirzepatide has demonstrated superior weight, glycemic, and cardiovascular outcomes compared to placebo and semaglutide. However, patients with cancer have been systematically excluded from nearly all trials. This study evaluated the comparative effectiveness of tirzepatide vs. semaglutide across weight and metabolic markers in cancer survivors. Methods: We conducted a target trial emulation using EHR data of 14,108 adults from 49 U.S. healthcare organization. Adults diagnosed with cancer and subsequently T2DM or obesity were eligible. Patients were divided into two exclusive groups: tirzepatide or semaglutide. Primary outcomes were time to BMI < 25 kg/m² and overall survival. Exploratory outcomes included change in body weight, HbA1c, fasting glucose, lipids, triglycerides (TG), and glomerular filtration rate (eGFR) over 24 months. Patients were 1:1 propensity score matched (PSM) on baseline demographics, comorbidities, and lab values. Time-to-event outcomes were analyzed using Cox proportional hazards models; continuous outcomes were compared using t-tests on the most recent lab value within the outcome window. Subgroup analyses included age, sex, and cancer type. Results: At 24 months, patients treated with tirzepatide were associated with a significantly higher likelihood of reaching the target BMI of < 25 kg/m2 (HR 1.74, 95%CI 1.53-1.99) and improved overall survival (HR 0.65, 95%CI 0.50-0.85). Compared to semaglutide, tirzepatide yielded greater percent reductions from baseline in body weight (-8.7% vs. -5.7%), HbA1c (-12.9% vs. -8.2%), fasting glucose (-15.4% vs. -9.3%), triglycerides (-18.2% vs. -11.1%), and increase in HDL cholesterol (+3.9% vs. +2.1%). GFR declined similarly in both groups (-2.6% vs. -2.5%, p = 0.03). Subgroup analyses showed female cancer survivors (HR 1.71, 95%CI 1.52-1.93), particularly endometrial cancer survivors (HR 1.96, 95%CI 1.21-3.18), experienced the greatest weight loss benefit. Conclusions: Tirzepatide was associated with superior metabolic profile compared to semaglutide. These findings support the real-world utility of tirzepatide for metabolic optimization in oncology care and highlight the need for prospective study. Absolute change in metabolic markers at 24 months between study groups. Tirzepatide Semaglutide P-value BMI<25 HR 1.74, 1.53-1.99 <0.01 Overall Survival HR 0.65, 0.50-0.85 <0.01 Body Weight (lbs) -20.22 -13.00 <0.01 HbA1c (%) -0.94 -0.60 <0.01 Glucose (mg/dL) -22.50 -13.50 <0.01 Triglycerides (mg/dL) -30.98 -18.62 <0.01 Total Cholesterol (mg/dL) -13.36 -11.18 0.20 LDL (mg/dL) -9.97 -8.67 0.99 HDL (mg/dL) +1.74 +0.90 <0.01 GFR (mL/min/1.73m²) -1.91 -1.89 0.03 Bold indicates statistical significance.