GLP-1s Tied to Lower Cancer Risk in Patients With Obesity

Individuals with obesity without diabetes taking GLP-1 receptor agonists (RAs) may have a reduced risk for certain cancers, a new study suggests.

The target trial emulation of more than 160,000 patients found that individuals receiving the medications had a 41% lower risk for obesity-associated cancers (OACs), with an even more substantial 68% risk reduction among men.

“If confirmed in prospective studies, GLP-1 RAs may be associated with a broader clinical profile that extends beyond obesity management to include potential effects on cancer risk,” wrote lead author A.H.-C. Hsu, of Houston Methodist Neal Cancer Center, Houston, and colleagues in Annals of Oncology.

How Are GLP-1 RAs Linked to Reduced Cancer Risk?

According to the investigators, obesity is a recognized risk factor for 13 malignancies: breast, colorectal, endometrial, kidney, pancreatic, thyroid, ovarian, esophageal, gastric, liver, and gallbladder cancers, as well as multiple myeloma and meningioma. These conditions account for about 40% of cancers diagnosed in high-income countries, with incidence rising fastest among younger adults.

Preclinical work suggests GLP-1 receptor activation can suppress proliferation in cancer cells that express the receptor, although these mechanisms remain poorly understood. Observational clinical data have linked GLP-1 RAs to lower cancer risk, mainly in people with type 2 diabetes, but it has remained unclear whether the same association would hold among patients with obesity without diabetes.

How Was the New Study Designed?

The investigators first identified 229,467 adults with obesity without diabetes or a prior OAC in the TriNetX federated database. These patients were entered into a target trial emulation framework, which uses trial-like eligibility, treatment, and follow-up rules to approximate a randomized comparison from observational data.

The population was divided into two cohorts; the first comprised patients who filled at least two prescriptions for a GLP-1 RA and the second included patients who received only diet or exercise counseling. Groups were balanced using 1:1 propensity score matching, yielding 80,899 patients per group. The mean age was 47 years, and about 72% of the population were women.

The primary outcome was the cumulative incidence of OACs over 2 years. Further analyses characterized the same outcome based on sex, BMI, race, and the two most-used drugs, semaglutide and tirzepatide.

What Were the Key Findings?

GLP-1 RA use was associated with a 41% lower incidence of OACs overall (hazard ratio [HR], 0.59). The association held across most subgroups, with a more pronounced benefit among men (HR, 0.32) compared with women (HR, 0.65).

Taking tirzepatide (HR, 0.31) was also associated with a greater risk reduction than taking semaglutide (HR, 0.80); however, the investigators encouraged a cautious interpretation of these findings because the study was not designed for a head-to-head comparison between the agents.

In contrast with the above positive findings, no significant risk reduction was observed among Black patients (HR, 0.77; 95% CI, 0.58-1.03) vs a roughly 50% risk reduction among White patients (HR, 0.54; 95% CI, 0.47-0.62).

The reason for the lack of benefit among Black patients is unclear.

Among specific OACs, greatest risk reductions were reported for multiple myeloma (HR, 0.37), pancreatic cancer (HR, 0.40), endometrial cancer (HR, 0.42), and colorectal cancer (HR, 0.49).

No significant risk reductions were observed for breast cancer, ovarian cancer, or meningioma.

What Are the Clinical Implications?

The investigators emphasized that the study, being observational, is insufficient to confirm that GLP-1 RAs prevent cancer in this patient population. Still, the findings may be worth mentioning to patients considering GLP-1 RAs.

While using GLP-1 RAs specifically to lower cancer risk is “not ready for prime time yet,” the data may offer some reassurance for patients concerned about OACs who already have reason to be prescribed GLP-1 RAs, Michael D. Iglesia, MD, PhD, told Medscape Medical News.

Iglesia, who was not involved in the study, took a more cautious stance on the subgroup findings, first pointing out that women report higher rates of gastrointestinal side effects with GLP-1 RAs, so “the men in this study may have received more consistent GLP-1 RA exposure.”

Commenting on the negative findings among Black patients in the study, Iglesia, who is a medical oncologist at the UNC Lineberger Comprehensive Cancer Center pointed out that this subgroup comprised only 82 GLP-1 RA users and 106 people on diet or exercise.

“Issues related to structural inequality and access to care often affect this kind of study,” he said, adding that further work on social and structural factors is needed “before we posit any biological underpinnings for this observed difference.”

What Questions Remain?

Hsu and colleagues called for long-term prospective trials and postmarketing surveillance to track cancer outcomes among GLP-1 RA users, particularly younger patients.

Underlying mechanisms remain a key unknown, the investigators noted, as it remains unclear whether GLP-1 RAs lower cancer risk through weight loss, direct effects on cancer cells, or some combination thereof.

“Knowing the mechanism behind the association shown in this paper would be important for understanding which cancer types may be treated best with GLP-1 RAs,” Iglesia said.

The investigators and Iglesia reported having no conflicts of interest.

A version of this article first appeared on Medscape.com.