Grant Number:	1R01CA305920-01A1 Interpret this number
Primary Investigator:	Feliciano, Elizabeth
Organization:	Kaiser Foundation Research Institute
Project Title:	Real-World Impact of Incretin Mimetics on Cancer Risk Using Targeted Learning
Fiscal Year:	2026

Abstract: Obesity and type 2 diabetes mellitus (T2DM) are major global health challenges that significantly increase the risk of various cancers, including obesity-related cancers like colorectal cancer. Incretin mimetics, particularly GLP-1 receptor agonists (RAs), have emerged as effective treatments for T2DM and obesity, with demonstrated benefits in weight loss and metabolic health. The recent surge in the use of these medications, particularly for weight management in individuals without T2DM, has raised questions about their long-term effects on cancer risk. While initial studies have shown mixed results regarding the association between incretin mimetics and cancer risk, most have suffered from methodological limitations including lack of data on adherence and time-dependent confounding necessary to conduct per-protocol analyses. Thus, there is a critical need for robust, real-world data to clarify the effects of sustained use of these agents on cancer. This study will utilize a target trial emulation approach combining causal inference methods with machine learning to evaluate the effects of sustained incretin mimetic use on cancer risk, using observational data from Kaiser Permanente’s extensive healthcare database. In addition to intention-to-treat, we will conduct per- protocol analyses that emulate target trials with perfect adherence and no loss to follow-up, enabled by detailed longitudinal data on medication use, adherence, weight, glycemic control, and cancer screening, as well as evaluating alternative protocols requiring at least 1 year of use to assess legacy effects from a minimum exposure duration, reflecting real-world adherence patterns where patients often discontinue treatment after initiation. We will assess over 4.7 million patients aged 40 and older living with obesity and/or T2DM, who are candidates for incretin mimetic therapy and at risk for invasive cancers. To provide rigorous evidence on the long-term consequences of incretin mimetic use for cancer risk in real-world populations, we will evaluate the effects of sustained incretin mimetic use on: (1) metabolic risk factors such as weight, blood pressure, and lipid levels; (2) risk of advanced colorectal adenomas (precursors to colorectal cancer); and (3) incidence of invasive cancers and obesity-related cancers, with exploratory analyses focused on specific cancer sites. This research will inform cancer prevention guidelines and contribute to evidence-based clinical practices. Additionally, it will provide insights into patient characteristics that predict sustained medication use, which will be crucial for tailoring future interventions aimed at reducing cancer risks.





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