Endometrial cancer incidence continues to rise in many countries, particularly among women with metabolic dysfunction, obesity, and benign uterine conditions. A new large retrospective cohort study published online in JAMA Network Open has found that adding glucagon-like peptide-1 receptor agonists (GLP-1RAs) to progestin therapy is associated with a lower risk of developing endometrial cancer among women with benign uterine pathology or endometrial hyperplasia.
GLP-1RAs, originally approved forthe management of type 2 diabetes and more recently for weight loss, have metabolic effects that include weight reduction, improved insulin sensitivity, and anti-inflammatory actions. Progestins are widely used as conservative therapy for endometrial hyperplasia or other non-malignant uterine conditions because of their ability to counteract estrogen-driven endometrial proliferation. Whether GLP-1RAs can amplify the protective effects of progestins against cancer progression has been an open question — and one that this study aimed to address using real-world clinical data.
Clinical summary box
CLINICAL SUMMARY
What was examined
The association between adding GLP-1 receptor agonists to progestin therapy and the risk of subsequent endometrial cancer in women with benign uterine pathology and endometrial hyperplasia. Comparisons included GLP-1RA + progestin versus progestin alone, versus metformin + progestin, and triple-therapy combinations.
Key findings
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Combined GLP-1RA and progestin therapy was associated with a significantly lower endometrial cancer risk compared with progestin monotherapy (HR ~0.34 after matching).
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Protective associations were consistent across subgroups defined by age, BMI, baseline risk, and progestin administration route; hysterectomy rates were also lower with combined therapy.
Clinical implications
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These observational results suggest that GLP-1RAs may enhance the cancer-risk-reducing effects of progestins in women with benign uterine disease or hyperplasia.
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Prospective clinical trials are needed to confirm causality and determine whether GLP-1RAs could be integrated into preventive or adjunctive treatment strategies.
The investigators accessed a federated electronic health records database (TriNetX) to identify women who received progestin therapy for benign uterine disease or endometrial hyperplasia between May 1, 2005 (the year GLP-1RAs were first approved by the US Food and Drug Administration), and December 31, 2022. Participants were stratified into four treatment comparisons: GLP-1RA plus progestin versus progestin only; GLP-1RA plus progestin versus metformin plus progestin; triple therapy (GLP-1RA, metformin, and progestin) versus metformin plus progestin; and triple therapy versus progestin alone. Subgroup analyses were performed within the primary comparison to assess consistency across different risk categories, routes of progestin administration, age groups, and body mass index (BMI) strata.
Featured Event
In total, 444 820 women met the inclusion criteria. Among them, 18 414 received combined GLP-1RA and progestin therapy, while 426 406 received progestins alone. After propensity score matching to balance potential confounders, the primary analysis revealed that GLP-1RA plus progestin was associated with a significantly lower incidence of endometrial cancer than progestin alone, with a hazard ratio of approximately 0.34 (95% confidence interval, 0.27–0.44). This corresponds to an estimated two-thirds reduction in observed endometrial cancer risk among patients treated with the combination compared with progestin monotherapy.
The protective association persisted across subgroups defined by progestin route (systemic vs intrauterine), baseline risk level, BMI category, and age group, suggesting robustness of the findings across a range of clinical contexts. In secondary analyses, GLP-1RA plus progestin was also associated with a lower endometrial cancer risk than metformin plus progestin; triple therapy appeared to be more strongly associated with reduced risk compared with either dual-therapy comparator. Women in the GLP-1RA plus progestin group also had lower subsequent hysterectomy rates at both 2- and 5-year follow-up intervals.
These real-world associations raise the possibility that GLP-1RAs — through effects on weight, insulin resistance, and inflammatory and growth signalling pathways — might enhance the antitumorigenic impact of progestins in the endometrium. Preclinical research has shown that GLP-1 receptor expression may interact with progesterone receptor pathways, potentially leading to reduced tumour cell viability when both agents are used together, though detailed mechanisms remain an active area of investigation.
Because the study is observational, it cannot prove causation. Residual confounding and selection biases are possible despite careful statistical adjustment. The authors underscore the need for prospective, controlled studies to establish whether GLP-1RA therapy can play a causal role in preventing endometrial cancer in women with benign uterine disease or hyperplasia.
Paper: Yen T, et al. GLP-1 Receptor Agonists Plus Progestins and Endometrial Cancer Risk in Nonmalignant Uterine Diseases. JAMA Netw Open. 2026;9(2):e2558205. Access online here.
