A study by Jones et al offers a provocative contribution to the landscape of colorectal cancerprevention by directly comparing two pharmacologic strategies with markedly different historical roles in prevention (see sidebar on page 47).1 Aspirin has long served as the benchmark for primary prevention of colorectal cancer, supported by decades of epidemiologic data and randomized clinical trials, but its clinical utility is constrained by concerns about bleeding risk.
In contrast, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged primarily as metabolic therapies, with growing interest in their antiinflammatory and antiproliferative mechanisms. By presenting a real-world, head-to-head comparison of these agents, this analysis advances the field into comparative effectiveness.
… The high cost and nontrivial side-effect profile of GLP-1RAs, even relative to aspirin, suggest that their greatest potential value may lie in targeted prevention among higher-risk individuals who already meet clinical indications for therapy. Viewed in this context, GLP-1RAs emerge as a promising yet still unproven strategy for colorectal cancer prevention.— ANDREW T. CHAN, MD, MPH
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Leveraging a database of more than 150 million patients, the authors observed 26% relative reduction in colorectal cancer incidence among GLP-1RA users, which was consistent across multiple sensitivity analyses and subgroups, including age, body mass index (BMI), and glycemic status. These findings align with several prior observational studies reporting an association between GLP-1RA use and reduced colorectal cancer risk, lending coherence to an emerging epidemiologic signal.2 The particularly strong association observed among individuals with elevated A1C levels further supports a biologically plausible link between metabolic dysregulation, insulin signaling, and colorectal tumorigenesis. Additionally, the surprising agent-specific signal observed with semaglutide raises the possibility of heterogeneity within the GLP-1RA class.
Understanding the Preventive Potential of the Two Therapies
However, there are several important caveats to these findings. First, the body of evidence supporting the preventive potential of the two therapies differs substantially. Aspirin’s preventive benefit is supported by a robust body of evidence from both observational studies and randomized clinical trials demonstrating reductions in colorectal adenomas, cancer incidence, and cancer mortality.3 In contrast, evidence supporting a protective role for GLP-1RAs remains entirely observational. Moreover, short-term randomized trials of GLP-1RAs designed primarily to evaluate metabolic outcomes have not consistently demonstrated reductions in colorectal cancer incidence, likely reflecting limited follow-up, low event rates, and the absence of cancer-specific endpoints.4
Second, comparing cancer-preventive effectiveness between agents with fundamentally different primary indications introduces substantial challenges related to confounding by indication. Despite rigorous propensity score matching, it is difficult to fully account for unmeasured differences in health behaviors, health-care utilization, metabolic trajectories, and clinician prescribing patterns that distinguish GLP-1RA users from aspirin users.
Third, it remains unclear whether the observed association reflects a direct anticancer effect of GLP-1 signaling or is mediated primarily through weight loss and improvements in adiposity-related inflammation, given that colorectal cancer is a well-established obesity-associated malignancy.5 Although benefit was observed across BMI strata, these analyses cannot disentangle weight-dependent from weight-independent mechanisms.
Although prospective randomized trials are essential to establish causality, such studies will be exceptionally challenging to conduct. Demonstrating a reduction in colorectal cancer incidence would require very large populations, prolonged follow-up, and careful management of crossover and adherence, whereas blinding would be difficult given the distinctive metabolic and gastrointestinal effects of GLP-1RAs.
Developing Clinical Trials That Inform Definitive Clinical Guidance
These practical constraints argue for a more creative, staged approach to evidence generation. Biomarker-driven, proof-of-principle trials using intermediate endpoints, such as colorectal adenomas, mucosal proliferation indices, inflammatory markers, or microbiome and metabolic signatures, may be necessary before embarking on large-scale prevention trials.
Finally, the high cost and nontrivial side-effect profile of GLP-1RAs, even relative to aspirin, suggest that their greatest potential value may lie in targeted prevention among higher-risk individuals who already meet clinical indications for therapy. Viewed in this context, GLP-1RAs emerge as a promising yet still unproven strategy for colorectal cancer prevention.
Together, these findings highlight the need for innovative, pragmatic trial designs to bridge the gap between observational evidence and the level of evidence required to inform definitive clinical guidance. ν
DISCLOSURE: Dr. Chan has no financial conflicts of interest to declare related to the topic of this commentary. He has received consulting income from Pfizer and Boehringer Ingelheim for topics unrelated to this commentary.
REFERENCES
1. Jones C, Obomanu E, Neely A, et al: GLP-1 receptor agonist vs aspirin for primary prevention of colorectal cancer: Evidence from a real-world head-to-head comparison. Abstract 18. 2026 ASCO Gastrointestinal Cancers Symposium. Presented January 10, 2026.
2. Wang L, Wang W, Kaelber DC, et al: GLP-1 receptor agonists and colorectal cancer risk in drug-naive patients with type 2 diabetes, with and without overweight/obesity. JAMA Oncol 10:256-258, 2024.
3. Drew DA, Chan AT: Aspirin in the prevention of colorectal neoplasia. Annu Rev Med 72:415-430, 2021.
4. Ko A, Chang YC, Bahar F, et al: Risk for cancer with glucagon-like peptide-1 receptor agonists and dual agonists. Ann Intern Med 179:216-229, 2026.
5. Du M, Drew DA, Goncalves MD, et al: Early-onset colorectal cancer as an emerging disease of metabolic dysregulation. Nat Rev Endocrinol 21:686-702, 2025.
Dr. Chan is Chief, Clinical and Translational Epidemiology Unit at Massachusetts General Hospital and the Daniel K. Podolsky Professor of Medicine at Harvard Medical School.
GLP-1 Receptor Agonists vs Aspirin in Colorectal Cancer Risk Reduction
Editor’s Note: The following study was originally reported in the April 25, 2026, issue of The ASCO Post. To provide context for the commentary by Andrew T. Chan, MD, MPH, we are including the following summary of the original report and findings.
At the 2026 ASCO Gastrointestinal Cancers Symposium, Jones et al reported findings from a large real-world comparative analysis suggesting that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may be associated with a lower risk of developing colorectal cancer compared with aspirin when used for primary prevention.1 The findings are of interest given the longstanding investigation of aspirin for colorectal cancer prevention, as well as the growing use of GLP-1RAs for diabetes and obesity management.
Using deidentified data from TriNetX, a global network of health-care organizations, investigators identified 281,656 participants and matched users of GLP-1RAs and aspirin in equal cohorts of 140,828 patients, each based on similar demographic characteristics. The mean age of participants was 58 years; 69% were female; 67% were White, 12% were Black, and 2.3% were Asian. The primary endpoint was incidence of colorectal cancer. The index date was defined as the first documented prescription or administration of either therapy, with follow-up beginning 6 months after treatment initiation. Sensitivity analyses were performed at 12 and 36 months. Median follow-up was 2,153 days for GLP-1RA users and 1,743 days for aspirin users. Subgroup analyses examined factors including age, body mass index (BMI), diabetes status, tobacco history, atherosclerotic disease, and individual GLP-1RA agents.
Investigators found that individuals who received GLP-1RAs were 36% less likely to be diagnosed with colorectal cancer compared with those who received aspirin. Among participants whose health or family history placed them at elevated risk for colorectal cancer, GLP-1RA use was associated with an approximately 43% lower risk of developing the disease compared with aspirin use.
Additional analyses suggested that GLP-1RAs were associated with reduced colorectal cancer risk among individuals who initiated treatment before age 45 and that the observed benefit appeared independent of obesity or diabetes status. However, a reduction in risk was not observed among participants with a history of tobacco use or atherosclerotic disease. When individual agents were analyzed separately, semaglutide, liraglutide, and dulaglutide were each associated with significant reductions in colorectal cancer risk, whereas tirzepatide and exenatide did not demonstrate statistically significant effects in this analysis.
Safety analyses showed that acute kidney injury, stomach ulcers, and gastrointestinal bleeding were less common in the GLP-1RA cohort than in the aspirin cohort, whereas diarrhea and abdominal pain occurred more frequently with GLP-1RAs; nausea and vomiting were reported in both groups. Although investigators noted that the absolute benefit for an individual patient was modest, they concluded that the observed reduction in colorectal cancer risk, combined with the safety profile of GLP-1RAs, may have meaningful public health implications and warrants prospective validation in randomized clinical trials.
DISCLOSURE: For full disclosures of all study authors, visit https://www.asco.org/abstracts-presentations/255085/abstract
REFERENCE
1. Jones C, Obomanu E, Neely A, et al: GLP-1 receptor agonist vs aspirin for primary prevention of colorectal cancer: Evidence from a real-world head-to-head comparison. Abstract 18. 2026 ASCO Gastrointestinal Cancers Symposium. Presented January 10, 2026.
