Abstract
IMPORTANCE: As endometrial cancer (EC) incidence rises, particularly among individuals with obesity and metabolic disorders, effective strategies targeting hormonal and metabolic risks are needed. OBJECTIVE: 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). DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: GLP-1RAs, progestins, and/or metformin. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of EC. The secondary outcome was the incidence of subsequent hysterectomy. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.