Emerging Evidence Positions GLP-1 Receptor Agonists as a Novel Strategy to Reduce CRC Risk

Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Victoza, Saxenda), and tirzepatide (Zepbound, Mounjaro), among the most transformative pharmacologic advances of the past decade, are now attracting attention for a potential role far removed from their origins in blood glucose regulation and weight management: the prevention of colorectal cancer (CRC).¹

Contrary to initial concerns that these agents would increase the likelihood of developing certain cancers, such as pancreatic or thyroid, results from recent studies have largely shown no significant links between GLP-1 use and increased cancer incidence. In fact, emerging evidence indicates strong signals in favor of GLP-1 receptor agonists for reducing cancer risk in select malignancies, although the current literature is limited.

Recently, a real-world study comparing GLP-1 receptor agonists with aspirin for primary CRC prevention has bolstered interest in the broader oncologic potential of this drug class.^2,3 Though the study is the most direct evaluation of GLP-1 receptor agonists as a CRC risk reduction strategy to date, its results have also raised questions about mechanism, patient selection, and the path to prospective validation.

What are the proposed mechanisms behind the protective effect of GLP-1 agonists?

According to Colton Jones, MD, a hematology and oncology fellow at The University of Texas (UT) at San Antonio and lead study author of this real-world analysis, the biological rationale for GLP-1 receptor agonists as preventive agents in CRC draws on several converging mechanisms.

“Initial preclinical data stem from the ability of GLP-1 receptor agonists to reduce chronic inflammation in the body and also reduce obesity, which is an independent risk factor for cancer in general,” Jones explained in an exclusive interview with OncLive. “But it goes beyond that. It also improves insulin sensitivity, which is why it’s used to treat type 2 diabetes. Data have shown that better blood glucose control is associated with lower cancer risk.”

Jones continued, "What gets even more interesting is that GLP-1 receptor agonist medications work in the colon specifically, not only to reduce inflammation within the colon itself, but also to increase the abundance of protective bacteria that could prevent colon cancer. The most compelling anticancer mechanism from in vitro studies is inhibition of a key pathway involved in cancer proliferation and pathogenesis: the PI3K/AKT/mTOR pathway."

For Joel Saltzman, MD, FASCO, the most plausible mechanism centers on the established links between obesity, systemic inflammation, and cancer. “Obesity leads to inflammation, and these drugs obviously do a wonderful job reducing obesity. We’re seeing benefits in osteoarthritis, cardiovascular outcomes, and kidney protection. There’s what looks like a class effect, [but] it’s going to take years of basic science to really understand how to design these drugs best,” he said in an interview with OncLive. Saltzman is vice chair of regional oncology and staff physician at the Cleveland Clinic Taussig Cancer Center and a member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center in Cleveland, Ohio.

What evidence supports GLP-1 receptor agonist use for CRC prevention?

Data from a 2024 cohort study published in JAMA Oncology found that among more than 1.2 million drug-naive patients with type 2 diabetes, GLP-1 receptor agonist use was associated with a significant reduction in CRC risk compared with insulin use (HR, 0.56; 95% CI, 0.44-0.72), with consistent findings observed in patients both with and without overweight or obesity.⁴

“[This] landmark study…was really the first study to show that these medications could have clinical benefit in that context, and it directly informed our research,” Jones noted.

A subsequent 2024 analysis published in JAMA Network Open by the same group expanded the lens, examining GLP-1 receptor agonists vs insulin and metformin across 13 obesity-associated cancers in more than 1.6 million patients with type 2 diabetes.⁵ In this analysis, GLP-1 receptor agonist use was associated with a lower risk than insulin for 10 of the 13 cancer types, including a 46% reduction in CRC risk, though the advantage over metformin was not statistically significant for most cancer types, including CRC.

Additionally, in November 2025, results of an analysis that used data from the University of California (UC) Health Data Warehouse were published in Cancer Investigation. Researchers analyzed real-world outcomes in 6871 patients with colon cancer across all UC Health facilities. They found that those taking GLP-1 receptor agonists had a 5-year mortality rate of 15.5% compared with 37.1% in those not taking them.⁶ This translated to 62% lower odds of 5-year mortality (OR, 0.38; 95% CI, 0.21-0.64), which persisted after adjustment for age, body mass index (BMI), disease severity, and other confounders. The benefit was most pronounced in patients with a BMI greater than 35, suggesting that attenuation of obesity-related metabolic dysregulation may be a key driver, though the authors emphasized that the findings warrant prospective testing.

What was the rationale for comparing GLP-1s with aspirin in CRC?

For years, aspirin occupied a prominent, if contested, place in CRC chemoprevention guidelines. However, the United States Preventive Services Task Force removed its category B recommendation for aspirin in CRC primary prevention after data from a study evaluating aspirin failed to demonstrate a CRC prevention benefit and instead showed a meaningful risk of major bleeding events. As a result, the field has been left without an established pharmacologic preventive standard.⁷

"The purpose of our study was to compare GLP-1 receptor agonists to what was then the standard of care for colon cancer prevention, which was aspirin,” Jones explained. “This has never been done before…in a head-to-head fashion.”

The resulting retrospective, real-world, head-to-head comparison used deidentified data from TriNetX, a global network of health care organizations representing approximately 150 million patients across 106 health systems.^2,3 Patients aged 18 to 90 years were enrolled in the study between January 1, 2000, and January 1, 2024. A 6-month lead-in period post index date was incorporated into the study methodology to ensure that the results reflected primary prevention rather than detection of preexisting undiagnosed cancers. After propensity score matching for demographics and clinical characteristics, the analysis included 281,656 participants (GLP-1, n = 140,828; aspirin, n = 140,828).

What were the top-line findings from this real-world study?

Data shared at the American Society of Clinical Oncology 2026 Gastrointestinal Cancer Symposium (ASCO GI) revealed that CRC occurred in 0.130% of patients taking GLP-1 receptor agonists (n = 140,758) vs 0.176% of those taking aspirin (n = 140,692), corresponding to an absolute risk reduction of 0.0455%.^2,3 Furthermore, at a median follow-up of 6 years, GLP-1 receptor agonist use was associated with a 35.7% lower risk of CRC overall (HR, 0.643; 95% CI, 0.531-0.778). In the propensity score-matched analysis, this corresponded to an HR of 0.643 (95% CI, 0.531-0.778) for the overall population.

Among patients defined as high-risk based on health or family history, those taking GLP-1 receptor agonists were 42.1% less likely to develop CRC than those taking aspirin (HR, 0.579; 95% CI, 0.401-0.837). Risk reduction with GLP-1 receptor agonists was also observed across all age groups: Patients aged 18 to 44 years, 45 to 64 years, and 65 years and older experienced a 41.7% (HR, 0.583; 95% CI, 0.349-0.974), 21.0%(HR, 0.790; 95% CI, 0.623-1.003), and 27.1% (HR, 0.729; 95% CI, 0.500-1.064) reduction in risk, respectively. This finding carries particular weight given the well-documented rise in early-onset CRC, Jones noted. “The most recent data show that it is the No. 1 cause of cancer-related deaths in people [younger] than 50 years of age, especially in men,” he said. “CRC screening guidelines are not in effect for people [younger] than 45, so the question that it raises is: How do we protect people under 45 who are developing CRC? This research…shows a potential benefit with GLP-1 receptor agonists in that age group, which could really transform CRC screening and prevention in young people.”

Perhaps more surprising was the finding that risk reduction was seen regardless of whether patients had obesity or diabetes. Patients without diabetes achieved a 41.2% reduction in risk (HR, 0.588; 95% CI, 0.471-0.734) with GLP-1s; in patients with diabetes, the risk reduction was 41.2% (HR, 0.588; 95% CI, 0.471-0.734). This indicates that the benefit with GLP-1 receptor agonists may be independent of diabetes and obesity status, Jones said.

“The fact that [GLP-1 receptor agonists] worked regardless of whether patients had obesity or diabetes is interesting; I would have hypothesized that it would have been more pronounced in the obesity population,” added Saltzman, who was also a discussant of the study during its presentation at ASCO GI. “[However,] these types of studies are always difficult to interpret because it’s just a large database that we’re mining.”

Conversely, GLP-1 receptor agonists did not demonstrate a significant reduction in CRC risk among patients who used tobacco or who had atherosclerosis. “[The data] seem to confirm that the benefit is more tailored toward obesity, chronic inflammation, or chronic inflammatory processes, and not so much atherosclerotic disease,” Jones explained.

Not all GLP-1 receptor agonists performed uniformly. Among individual agents, statistically significant benefit was observed for semaglutide (36.9%; HR, 0.631; 95% CI, 0.492-0.810), liraglutide (56.4%; HR, 0.436; 95% CI, 0.220-0.861), and dulaglutide (Trulicity; 52.9%; HR, 0.471; 95% CI, 0.358-0.618). Tirzepatide and exenatide (Byetta) did not demonstrate significant CRC risk reduction, though the investigators noted smaller sample sizes for those agents.

Regarding the comparative safety profiles of GLP-1 receptor agonists vs aspirin, acute kidney injury occurred in 1.15% of patients taking GLP-1 receptor agonists compared with 2.8% of those taking aspirin (HR, 0.369; 95% CI, 0.348-0.391; P = .0001). Gastric ulcers occurred in 0.50% vs 0.55% of patients in these 2 groups, respectively (HR, 0.815; 95% CI, 0.735-0.904; P = .038), and gastrointestinal bleeding occurred in 2.1% vs 2.0% (HR, 0.852; 95% CI, 0.809-0.898; P = .018). In the GLP-1 group, patients had a slightly higher incidence of nausea and vomiting (10.5% vs 9.7%; HR, 0.980; 95% CI, 0.957-1.004; P = .0001), diarrhea (6.8% vs 5.4%; HR, 1.131; 95% CI, 1.096-1.166; P = .0001) and abdominal pain (19.0% vs 16.3%; HR, 1.055; 95% CI, 1.036-1.075; P = .0001).

“What’s so fascinating about this is that we have a drug like aspirin that is known to reduce the incidence of colon cancer, and this drug class appears to be working better 36% of the time in large data sets,” Saltzman reflected. “It’s a signal that we should start looking at this.”

What are the limitations and remaining questions surrounding GLP-1 use in CRC?

Both Jones and Saltzman were explicit about the observational nature of these findings and the caution required when interpreting data.

“This is a retrospective study, and on the hierarchy of evidence, it doesn’t compare to a randomized clinical trial,” Jones emphasized. “We can only determine association from this retrospective study.” Saltzman echoed this framing, noting that the lack of randomization means that certain confounders, including why patients were prescribed aspirin, whether GLP-1s were accessible to patients, and whether underlying conditions such as atherosclerosis or tobacco use influenced treatment selection and cancer risk, could not be fully controlled.

The nonuniformity of effect across GLP-1 agents also raises questions that current data cannot resolve. “Not every GLP-1 [receptor agonist] is the same,” Saltzman noted. “Some of them are being designed more for diabetes. Some of the ones in the pipeline are being designed to preserve muscle mass as [patients] start losing weight. What are the benefits of one GLP-1 [receptor agonist] vs the other? Is one better for heart prevention? Is one better for colon cancer prevention? These kinds of questions will take years of dedicated study to answer.”

When will GLP-1 receptor agonists be ready for prime time in CRC prevention?

In the near term, both experts agreed that these findings should not alter prescribing practice for GLP-1 receptor agonists as a CRC prevention strategy in the absence of prospective validation; however, they do provide reassurance for oncologists beginning to field questions about the safety of GLP-1 receptor agonists during routine appointments.

“A question I get in clinic fairly frequently is, ‘Is it safe for me to go on a GLP-1 inhibitor?’” Saltzman said. “If [a patient is] finishing adjuvant chemotherapy…I’m already thinking about the other things they should be doing. I’m not offering it as treatment for their colon cancer…but I believe it’s a perfectly natural thing to say we now have at least preliminary signals that it may actually help prevent colon cancer. As a medical oncologist, this is reassurance that it’s OK for my patients to consider this if they have another clear indication for this drug.”

Jones emphasized the importance of individualization. “When I’m prescribing a medication, I individualize it for my patients. I might have a patient with diabetes for whom the GLP-1 [receptor agonist] can treat the diabetes and could potentially reduce the risk of colon cancer. Conversely, I might have a patient who is morbidly obese with a family history of colon cancer; I would consider putting her on a GLP-1 receptor agonist, not only to help with the weight but also to potentially reduce her risk,” he said.

Certain contraindications, such as thyroid malignancy, particularly multiple endocrine neoplasia syndromes, must be respected, he added. Patients with chronic pancreatitis or baseline nausea and vomiting are also poor candidates. Saltzman raised reduced bowel motility as an additional consideration, noting that colonoscopy preparation protocols currently recommend holding GLP-1 agents for approximately 1 week prior to the procedure.

What is the path forward for this drug class?

“If these findings are validated and GLP-1 receptor agonists are found to reduce colon cancer risk, this could potentially impact millions of people around the world,” Jones emphasized. “The sooner [these data] are validated, the better.”

Jones and colleagues at UT San Antonio are already pursuing this direction, with ongoing investigations of GLP-1 receptor agonists alone and potential evaluations of these agents in combination with systemic therapies. This signal extends well beyond CRC; accordingly, the group has submitted several abstracts to the 2026 ASCO Annual Meeting covering GLP-1 receptor agonist use in prevention across multiple malignancies, including pancreatic cancer and leukemias, one of which was accepted for an oral podium presentation.

Meanwhile, broader class-level data continue to accumulate. A meta-analysis of retrospective cohort studies showed a consistent association between GLP-1 receptor agonist use and reduced CRC risk, though limitations, including limited granularity for individual agents and concerns about publication bias, have been noted.⁸ Preclinical investigations into whether GLP-1 receptor agonists could prevent polyp-to-cancer progression, inhibit tumor cell proliferation, or be combined with existing therapies may yield more mechanistic insights. Clinical trials are also needed to more clearly elucidate whether GLP-1 receptor agonists could directly improve cancer survival.

“There’s too much to learn,” Saltzman concluded. "“These drugs are here to stay. They’re going to be used a lot, and we’re going to have to learn a lot more about them."

References

1. Wilbon SS, Kolonin MG. GLP1 receptor agonists-effects beyond obesity and diabetes. Cells. 2023;13(1):65. doi:10.3390/cells13010065
2. Jones CF, 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. J Clin Oncol. 2026;44(suppl 2):18. doi:10.1200/JCO.2026.44.2_suppl.18
3. American Association for Cancer Research. GLP-1s spur greater reduction in colorectal cancer risk than aspirin. Cancer Discov. 2026;16(3):OF1. doi:10.1158/2159-8290.CD-NW2026-0002
4. Wang L, Wang W, Kaelber DC, Xu R, Berger NA. GLP-1 receptor agonists and colorectal cancer risk in drug-naive patients with type 2 diabetes, with and without overweight/obesity. JAMA Oncol. 2024;10(2):256-258. doi:10.1001/jamaoncol.2023.5573
5. Wang L, Xu R, Kaelber DC, Berger NA. Glucagon-like peptide 1 receptor agonists and 13 obesity-associated cancers in patients with type 2 diabetes. JAMA Netw Open. 2024;7(7):e2421305. doi:10.1001/jamanetworkopen.2024.21305
6. Cuomo RE. The influence of GLP-1 receptor agonists on five-year mortality in colon cancer patients. Cancer Investig. 2025;43(10):982-991. doi:10.1080/07357907.2025.2585512
7. Guirguis-Blake JM, Evans CV, Perdue LA, Bean SI, Senger CA. Aspirin use to prevent cardiovascular disease and colorectal cancer: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2022;327(16):1585-1597. doi:10.1001/jama.2022.3337
8. Zhong Y, Wu T, Khan NU. Association between GLP-1 receptor agonists as a class and colorectal cancer risk: a meta-analysis of retrospective cohort studies. BMC Gastroenterol. 2025;25(1):614. doi:10.1186/s12876-025-04211-4