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

Area of Science:

• Gynecology
• Endocrinology
• Oncology

Background:

• Endometrial cancer (EC) incidence is increasing, especially in individuals with obesity and metabolic disorders.
• There is a need for effective strategies to manage hormonal and metabolic risks associated with EC.
• Endometrial hyperplasia (EH) and benign uterine pathology are common conditions requiring treatment.

Purpose of the Study:

• To evaluate the risk of EC in patients with EH or benign uterine pathology treated with progestins compared to those receiving combined progestins and glucagon-like peptide-1 receptor agonists (GLP-1RAs).

Main Methods:

• A cohort study utilizing the TriNetX platform analyzed deidentified electronic health records from adult women diagnosed with EH or benign uterine pathology between May 2005 and December 2022.
• The study compared EC incidence and hysterectomy rates among four treatment groups: GLP-1RA plus progestins vs. progestins only; GLP-1RA plus progestins vs. metformin plus progestins; triple therapy (GLP-1RA, metformin, progestins) vs. metformin plus progestins; and triple therapy vs. progestins only.
• Subgroup analyses stratified patients by progestin route, risk level, BMI, and age to assess the consistency of findings.

Main Results:

• A total of 18,414 patients received GLP-1RA with progestin, and 426,406 received progestin alone.
• Combined GLP-1RA and progestin therapy was associated with a significantly lower risk of EC compared to progestin monotherapy (HR, 0.34; 95% CI, 0.27-0.44), with consistent findings across subgroups.
• GLP-1RA plus progestins also demonstrated a lower EC risk than metformin plus progestins (HR, 0.30; 95% CI, 0.15-0.59), and triple therapy was more effective than dual or progestin monotherapy.
• Hysterectomy rates were lower in the GLP-1RA plus progestins group at both 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:

• In this cohort of women with benign uterine pathology or EH, the combination of GLP-1RAs and progestins was linked to a reduced risk of endometrial cancer.
• The findings suggest that this combination therapy may be a valuable strategy for managing EC risk in this patient population.
• Further research is warranted to explore the clinical applicability and underlying mechanisms of this protective association.