TOPLINE:

Among women with endometrial hyperplasia or benign uterine pathology, the addition of a GLP-1 receptor agonist (RA) to progestin therapy was associated with a two-thirds lower risk for endometrial cancer than either progestins alone or progestins plus metformin.

METHODOLOGY:

• Progestins are standard therapy for endometrial hyperplasia and abnormal uterine bleeding, and studies have shown that GLP-1 RAs combined with progestins markedly reduce cell viability of progesterone receptor-positive tumors. However, there are limited data on whether this combination vs progestins alone or combined with other metabolic therapies reduces the risk for endometrial cancer in patients with precancerous or benign uterine disease.
• Researchers used de-identified electronic health records from the TriNetX Global Collaborative Network to analyze data from 444,820 women (mean age, 35.5 years) with endometrial hyperplasia or benign uterine pathology who received progestins between May 2005 and December 2022; some participants received a GLP-1, metformin, or both in addition to progestins.
• Overall, 18,414 patients received a GLP-1 plus progestins and 426,406 received progestins only; after 1:1 propensity score matching, each matched group comprised 15,747 patients. Additional analyses involved patients who received progestins plus metformin or triple therapy with progestins, a GLP-1, and metformin.
• The primary outcome was the incidence of endometrial cancer, and the secondary outcome was the incidence of hysterectomy.

TAKEAWAY:

• After matching, endometrial cancer developed in 84 of 15,634 (0.5%) patients vs 284 of 15,747 (1.8%) patients in the GLP-1 plus progestin group vs progestin-only group. The combination therapy was associated with a 66% lower risk for endometrial cancer (hazard ratio [HR], 0.34).
• The protective association remained consistent across subgroups stratified by the route of progestin administration (levonorgestrel-releasing intrauterine devices: HR, 0.40; oral progestins: HR, 0.35), baseline risk (endometrial hyperplasia: HR, 0.49; benign pathology: HR, 0.34), BMI (≥ 30: HR, 0.27; < 30: HR, 0.28), and age (≥ 51 years: HR, 0.55; < 51 years: HR, 0.43).
• Combined use of a GLP-1 and progestin was also associated with a lower risk for endometrial cancer than progestins plus metformin (HR, 0.30). Similarly, triple therapy was associated with a reduced risk compared with dual therapy with progestins and metformin (HR, 0.37) or with progestin monotherapy (HR, 0.44).
• Hysterectomy rates were lower in the GLP-1 plus progestin group at both the 2-year (HR, 0.47) and 5-year (HR, 0.59) follow-up.

IN PRACTICE:

The results show that “adding GLP-1 RAs to progestin therapy was associated with lower endometrial cancer risk,” the authors of the study wrote. “Further prospective studies and clinical trials are warranted to validate these findings, to explore optimal dosing and duration strategies, and to better elucidate the biological mechanisms of GLP-1 RA.”

SOURCE:

The study, led by Ting-Tai Yen, MD, Texas Tech University Health Sciences Center El Paso, was published online in JAMA Network Open.

LIMITATIONS:

The retrospective nature of the study and reliance on diagnostic and procedural coding from health records may have introduced misclassification bias. Histologic confirmation of disease regression or progression was not available. Unmeasured confounders such as medication adherence and durations, lifestyle factors, or socioeconomic status may have influenced the results. Causal inference could not be established.

DISCLOSURES:

The authors did not disclose funding information. One author reported receiving speaker fees from AstraZeneca unrelated to this work. No other disclosures were reported.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.