COMBINED therapy with GLP 1 receptor agonists and progestins is associated with a significantly lower risk of endometrial cancer in women with benign uterine disease or endometrial hyperplasia, according to a large cohort study of 444,820 participants.
Cohort Analysis Highlights Protective Effect
The study analysed electronic health records from adult women treated with progestins between May 2005 and December 2022, using the TriNetX database. Of 18,414 patients receiving GLP 1 receptor agonists plus progestins and 426,406 patients receiving progestin monotherapy, the combination therapy was associated with a markedly lower risk of endometrial cancer (hazard ratio: 0.34; 95% CI: 0.27–0.44). This protective effect was consistent across subgroups stratified by progestin route, baseline risk, body mass index, and age, suggesting broad applicability among diverse patient populations. The analysis also included comparisons with metformin plus progestins, demonstrating that GLP 1 receptor agonist therapy remained superior in reducing cancer risk (hazard ratio: 0.30; 95% CI: 0.15–0.59).
Triple Therapy with GLP 1 Receptor Agonist Offers Additional Benefit
Patients receiving triple therapy with GLP 1 receptor agonists, metformin, and progestins showed even greater risk reduction compared with dual therapy with metformin and progestins (hazard ratio: 0.37; 95% CI: 0.25–0.53) or progestin alone (hazard ratio: 0.44; 95% CI: 0.29–0.66). These findings indicate that integrating GLP 1 receptor agonists into hormonal management strategies may optimise endometrial protection, particularly in patients with metabolic risk factors.
Reduced Hysterectomy Rates and Clinical Implications
In addition to lowering cancer incidence, GLP 1 receptor agonist and progestin therapy was associated with lower rates of subsequent hysterectomy at both 2 years (hazard ratio: 0.47; 95% CI: 0.42–0.53) and 5 years (hazard ratio: 0.59; 95% CI: 0.54–0.64). These results suggest that combining GLP 1 receptor agonists with progestins could reduce the need for surgical intervention while mitigating endometrial cancer risk. Further research is warranted to explore underlying mechanisms, long term safety, and clinical applicability in routine practice.
The study provides compelling evidence that GLP 1 receptor agonists enhance the protective effect of progestins in women with benign uterine pathology or hyperplasia, offering a promising approach for personalised risk reduction.
Reference
Yen T-T et al. GLP-1 receptor agonists plus progestins and endometrial cancer risk in nonmalignant uterine diseases. JAMA Netw Open. 2026;9;(2):e2558205.
