GLP-1RA plus progestin combo fends off endometrial cancer risk

Concurrent use of a glucagon-like peptide-1 receptor agonist (GLP-1RA) and progestins appears to protect against the risk of endometrial cancer in women with benign uterine pathology or endometrial hyperplasia, according to a real-world study.

Analysis of large data from the TriNetX database showed that compared with women on progestins alone, those who were taking GLP-1RA plus progestins had a 66-percent lower risk of endometrial cancer (hazard ratio [HR], 0.34, 95 percent confidence interval [CI], 0.27–0.44). This protective benefit was observed across subgroups defined by progestin route, baseline risk, BMI, and age. [JAMA Netw Open 2026;9:e2558205]

When compared with women receiving metformin plus progestins, those on GLP-1RA plus progestins also showed a substantially lower endometrial cancer risk (HR, 0.30, 95 percent CI, 0.15–0.59). Further analysis indicated that triple therapy with a GLP-1RA, metformin, and progestins was associated with a greater risk reduction relative to metformin plus progestins (HR, 0.37, 95 percent CI, 0.25–0.53) or progestin monotherapy (HR, 0.44, 95 percent CI, 0.29–0.66).

Total hysterectomy was performed with significantly less frequency among women taking GLP-1RA plus progestins vs those on progestins only at the 2-year (HR, 0.47, 95 percent CI, 0.42–0.53) and 5-year follow-up (HR, 0.59, 95 percent CI, 0.54–0.64).

Synergistic interaction

GLP-1RAs are used for the treatment of type 2 diabetes and weight loss, the investigators said.

“Beyond their metabolic effects, emerging evidence suggests that GLP-1RAs may possess broader therapeutic potential in several obesity-related malignant neoplasms, including antitumorigenic properties mediated through multiple signalling pathways in different organ systems,” they said.

The investigators noted that the findings of their study point to a possible synergetic role for GLP-1RA as an adjunct therapy in endometrial cancer prevention among patients with endometrial hyperplasia or benign uterine pathology.

“GLP-1RAs may improve endometrial outcomes not only through metabolic regulation but also by potentially modulating hormonal signalling pathways,” they added.

Study population

For the study, the investigators looked at 444,820 women (mean age 35.5 years, 55.7 percent White) with endometrial hyperplasia (high-risk group) or benign uterine pathology (low-risk group) such as abnormal uterine bleeding, submucosal leiomyoma, endometrial polyp, or simple hyperplasia.

The analysis included propensity-score matched pairs of 15,747 women each in the GLP-1RA plus progestins arm and the progestins alone arm. Endometrial cancer occurred in 0.5 percent and 1.8 percent of women in the respective arms over a mean follow-up of 1,332.5 and 1,962.5 days.

There were 3,137 pairs of women included in the GLP-1RA plus progestins vs metformin plus progestins comparison cohort, 5,769 pairs in the GLP-1RA/metformin/progestins vs metformin plus progestins comparison cohort, and 5,318 pairs in the GLP-1RA/metformin/progestins vs progestin monotherapy comparison cohort. 

“Further prospective studies and clinical trials are warranted to validate the findings, to explore optimal dosing and duration strategies, and to better elucidate the biological mechanisms of GLP1-RA,” the investigators said.