# GLP-1 Receptor Agonists Plus Progestins and Endometrial Cancer Risk in Nonmalignant Uterine Diseases

## TL;DR

Combining GLP-1 receptor agonists with progestins may reduce endometrial cancer risk in women with benign uterine conditions.

## Contribution

Combining GLP-1RAs with progestins shows a novel protective effect against endometrial cancer.

## Key findings

- Combined GLP-1RA and progestin therapy significantly lowers endometrial cancer risk compared to progestin alone.
- The protective effect of GLP-1RA plus progestin is consistent across BMI, age, and baseline risk subgroups.
- Triple therapy (GLP-1RA, metformin, and progestin) further reduces cancer risk compared to dual therapy.

## Abstract

Do GLP-1 receptor agonists enhance the effectiveness of progestins in reducing endometrial cancer (EC) risk among patients with nonmalignant uterine conditions?

In this cohort study with 444 820 participants, combined GLP-1RA with progestin was associated with a significantly lower risk of developing EC compared with progestin alone, across subgroups stratified by body mass index, age, baseline risk level, and progestin route.

These results suggest that adding GLP-1RAs to progestin therapy in women with benign uterine diseases or hyperplasia may be associated with reduced EC risk.

This cohort study compares the associations of glucagon-like peptide-1 (GLP-1) receptor agonists and of progestins with risk of endometrial cancer among US women with endometrial hyperplasia or other benign uterine pathologies.

As endometrial cancer (EC) incidence rises, particularly among individuals with obesity and metabolic disorders, effective strategies targeting hormonal and metabolic risks are needed.

To evaluate EC risk in patients with endometrial hyperplasia (EH) or benign uterine pathology treated with progestins vs combined progestins and glucagon-like peptide-1 receptor agonists (GLP-1RAs).

This cohort study used TriNetX to analyze EC and hysterectomy among adult women with EH or benign uterine pathology who received progestins between May 1, 2005 (GLP-1RA approval date), and December 31, 2022. Analyses were based on deidentified electronic health records identified via International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, and data were obtained on February 23, 2025. Four treatment comparisons were analyzed: GLP-1RA plus progestins vs progestins only; GLP-1RA plus progestins vs metformin progestins; triple therapy (GLP-1RA, metformin, and progestins) vs metformin plus progestins; triple therapy vs progestins only. Subgroup analyses GLP-1RA plus progestins vs progestins only stratified patients by progestin route, risk level, body mass index (BMI), and age.

GLP-1RAs, progestins, and/or metformin.

The primary outcome was the incidence of EC. The secondary outcome was the incidence of subsequent hysterectomy.

A total of 18 414 and 426 406 adult female patients received GLP-1RA combined with progestin and progestin alone, respectively (mean [SD] age, 43.1 [10.2] years vs 35.2 [10.9] years). GLP-1RA with progestins was associated with a significantly lower risk of EC compared with progestins only (HR, 0.34 [95% CI, 0.27-0.44]). This protective association remained consistent across subgroups, stratified by progestin route, baseline risk, BMI, and age. GLP-1RA plus progestins also showed a lower EC risk than metformin plus progestins (HR, 0.30 [95% CI, 0.15-0.59]). Triple therapy was more effective in reducing EC risk than dual (metformin plus progestins) (HR, 0.37 [95% CI, 0.25-0.53]) or progestin monotherapy (HR, 0.44 [95% CI, 0.29-0.66]). Hysterectomy rates were lower in the GLP-1RA plus progestins group at 2-year (HR, 0.47 [95% CI, 0.42-0.53]) and 5-year (HR, 0.59 [95% CI, 0.54-0.64]) follow-up.

In this cohort study of women with benign uterine pathology or endometrial hyperplasia, combined GLP-1RA and progestin was associated with reduced EC risk. Further investigation is warranted to assess its applicability and underlying mechanisms.