Comparative analysis of tirzepatide versus metformin and insulin in type 2 diabetes patients across the 13 most common cancers.

10508 Background: Emerging glucose-lowering therapies may influence cancer risk in patients with type 2 diabetes mellitus (T2DM). While several GLP-1 receptor agonists have been evaluated, data on tirzepatide, a dual GLP-1/GIP agonist with established cardiometabolic benefits, remain limited. We assessed the comparative risk of incident cancers and all-cause mortality among T2DM patients treated with tirzepatide versus metformin or insulin. Methods: We conducted a retrospective cohort study using TriNetX, a U.S.-based federated electronic health record network. Adults with T2DM initiating tirzepatide, metformin, or insulin between February 28, 2020 and February 28, 2025, without prior cancer, were included. Propensity score matching (1:1, greedy nearest-neighbor) balanced demographics, BMI, HbA1c, diabetes duration, and comorbidities. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the 13 most common incident cancers and all-cause mortality. Results: After 1:1 propensity score matching, baseline demographic, metabolic, diabetes-related, psychosocial, and medication characteristics were well balanced between groups, with minimal residual differences across age, sex, race/ethnicity, HbA1c, obesity severity, diabetes complications, and concomitant glucose-lowering therapies. In the tirzepatide versus insulin comparison, tirzepatide use was associated with significantly lower risks of multiple solid and hematologic malignancies, including lung, pancreatic, liver, colorectal, kidney, and endometrial cancers, as well as non-Hodgkin lymphoma (all log-rank p < 0.01), with no significant differences observed for prostate, thyroid, melanoma, bladder cancer, or leukemia. In the tirzepatide versus metformin comparison, tirzepatide was associated with significantly lower risks of lung cancer (HR 0.086, 95% CI 0.020-0.373; p < 0.001), pancreatic cancer (HR 0.124, 95% CI 0.015-1.039; p = 0.022), and breast cancer (HR 0.462, 95% CI 0.254-0.840; p = 0.009), while risks of other malignancies were not significantly different between groups. Across both matched cohorts, tirzepatide was consistently associated with markedly lower all-cause mortality compared with insulin and metformin, with absolute risk reductions of 4.8% and 0.6%, respectively (both p < 0.001). Conclusions: Among patients with type 2 diabetes, tirzepatide was associated with consistently lower all-cause mortality and reduced incidence of multiple cancers compared with insulin and metformin in a large, propensity-matched real-world analysis. These findings highlight tirzepatide as a glucose-lowering therapy with a potentially favorable oncologic risk profile, warranting prospective validation and mechanistic investigation.