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Taking glucagon-like peptide 1 (GLP-1) receptor agonists for type 2 diabetes was associated with greater reductions in colorectal cancer (CRC) risk compared with several other diabetes medication classes, a nationwide cohort study found.

Among treatment-naive patients with diabetes, a decreased risk for CRC was noted in those who started taking GLP-1 agonists compared with those on the following:

• Insulin (HR 0.56, 95% CI 0.44-0.72)
• Metformin (HR 0.75, 95% CI 0.58-0.97)
• SGLT2 inhibitors (HR 0.77, 95% CI 0.62-0.97)
• Sulfonylureas (HR 0.82, 95% CI 0.68-0.98)
• Thiazolidinediones (HR 0.82, 95% CI 0.69-0.97)

CRC risk reduction was more pronounced in patients with obesity or overweight taking GLP-1 agonists compared with the other antidiabetic agents, including insulin (HR 0.50, 95% CI 0.33-0.75) and metformin (HR 0.58, 95% CI 0.38-0.89), reported Rong Xu, PhD, of Case Western Reserve University School of Medicine in Cleveland, and co-authors in a research letter in.

It's not surprising that GLP-1 drugs would have a bigger impact in patients with a higher body mass index, commented Vinni Makin, MBBS, MD, also of Case Western Reserve but who was not involved in the study.

"We know use of GLP-1 receptor agonists has a significant weight reduction benefit in patients," he said. Obesity is a major for CRC.

However, the finding of more profound effects in overweight patients suggests "a potential protective effect against CRC partially mediated by weight loss and other mechanisms not related to weight loss," Xu's group suggested, noting that "GLP-1 RAs [receptor agonists] have pleiotropic effects on lowering plasma glucose, inducing weight loss, and modulating immune functions."

Makin also pointed to "studies to support that in certain colon cancer cells, GLP-1 receptor activation reduces cell growth and survival, increases intracellular cAMP levels and augments apoptosis by inducing irinotecan, a topoisomerase I inhibitor."

"We need large, long-term clinical trials to investigate further the relation between GLP-1 receptor agonists and future cancer risk and progression and how that efficacy might differ based on gender, age, and kind of cancer," he said.

For their 15-year retrospective study, Xu and co-authors analyzed electronic medical record data for 1.2 million patients from 59 healthcare organizations across the U.S. using the TriNetX . Included were individuals who had received their first antidiabetic prescription (at an average age of 57 years) after medical encounters for type 2 diabetes from 2005 to 2019 who had no such prior medication use and no prior CRC diagnosis.

Patients were stratified according to obesity/overweight and sex, the authors said, but limited sample sizes didn't allow for stratification by age, race, and ethnicity. Approximately 9% of the cohort were of Hispanic or Latinx ethnicity, and around 16% of the included patients were Black.

Patients were assigned to exposure and comparison cohorts and propensity score-matched 1:1 for demographics, adverse socioeconomic determinants of health, preexisting medical conditions, family and personal history of cancers and colonic polyps, lifestyle factors, and procedures such as colonoscopy.

Researchers analyzed the time between the first prescription of GLP-1 receptor agonists and other antidiabetics and the first CRC diagnosis within the 15-year follow-up. Non-GLP-1 antidiabetics assessed included insulin, metformin, alpha glucosidase inhibitors, sulfonylureas, and thiazolidinediones. For SGLT2 inhibitors and DPP-4 inhibitors, the researchers used data starting in 2013 and 2006, upon first approval of those drugs, respectively.

In the overall study population, GLP-1 agonists were associated with a lower but not statistically significant reduction in CRC risk compared with alpha-glucosidase inhibitors (HR 0.59, 95% CI 0.31-1.13) and DPP-4 inhibitors (HR 0.93, 95% CI 0.78-1.10).

In patients with overweight or obesity, the link between GLP-1 agonists treatment and reduced CRC risk was greatest for insulin and metformin but also seen to a lesser degree compared with the other antidiabetic medications with the DPP-4 inhibitors (HR 0.77, 95% CI 0.59-1.00), SGLT2 inhibitors (HR 0.68, 95% CI 0.47-0.99), sulfonylureas (HR 0.63, 95% CI 0.48-0.82), and thiazolidinediones (HR 0.73, 95% CI 0.54-0.98).

Study limitations acknowledged by the researchers included "potential unmeasured or uncontrolled confounders, self-selection, reverse causality, and the need to validate results with other data and study populations."

"Further research is warranted to investigate the effects in patients with prior antidiabetic treatments, underlying mechanisms, potential differential effects within GLP-1 RAs, and effects of GLP-1 RAs on other obesity-associated cancers," Xu and colleagues concluded.

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