Adding GLP-1RA to Progestin Therapy may reduce Endometrial Cancer Risk among women with benign uterine pathology: JAMA

The frequency of EC persists in rising, especially among women with obesity and other metabolic syndromes. Hormonal imbalance and metabolic dysregulation have been identified as core contributors to the development of EC. While progestins have been regularly utilized for EH and other benign uterine disorders, counteracting estrogen-induced endometrial hyperplasia, recent data indicate the potential of other metabolic drugs, such as GLP-1RAs, to influence cancer risk. The purpose of this study is to assess the efficacy of combined progestin/GLP-1RA therapy in attenuating EC incidence.

This cohort study used the TriNetX research network for the analysis of de-identified EHRs. Women with EH or benign uterine pathology treated with progestins after May 1, 2005—the approval date of GLP-1RAs—and December 31, 2022, were included in the study. Data were accessed until February 23, 2025.

Four treatment comparisons were examined:

• GLP-1RA plus progestins vs progestins alone

• GLP-1RA plus progestins vs metformin plus progestins

• Triple therapy (GLP-1RA, metformin, and progestins) vs metformin plus progestins

• Triple therapy vs progestins alone

Subgroup analyses for the comparison of GLP-1RA and progestin, apart from progestin alone, also included progestin routes of administration, baseline risk level of endometrial cancer, body mass index, and age as stratification variables. The secondary outcomes included the detection of endometrial cancer and hysterectomy.

Key findings

In this TriNetX cohort study:

• 18,414 women received GLP-1RA plus progestins

• 426,406 women received progestins alone

• Mean age: 43.1 vs 35.2 years

Primary outcome – Endometrial cancer risk:

• GLP-1RA + progestins vs progestins alone: HR 0.34 (95% CI, 0.27–0.44)

• GLP-1RA + progestins vs metformin + progestins: HR 0.30 (95% CI, 0.15–0.59)

• Triple therapy vs metformin + progestins: HR 0.37 (95% CI, 0.25–0.53)

• Triple therapy vs progestins alone: HR 0.44 (95% CI, 0.29–0.66)

Secondary outcome – Hysterectomy risk:

• 2-year follow-up: HR 0.47 (95% CI, 0.42–0.53)

• 5-year follow-up: HR 0.59 (95% CI, 0.54–0.64)

Protective associations were consistent across BMI, age, risk category, and progestin route.

In women with endometrial hyperplasia or benign pathology of the uterus, the combination of GLP-1 RA and progestin was found to result in significantly reduced risks of endometrial cancer and lower rates of hysterectomy compared to progestin alone. The potential for a new strategy of prevention of endometrial cancer by using a combination of metabolic-targeting agents and hormonal agents is suggested by the results of the risk reduction of endometrial cancer.

Reference:

Yen T, Hsieh TYJ, Lee G, Toy EP, Wei JC, Tanner EJ. GLP-1 Receptor Agonists Plus Progestins and Endometrial Cancer Risk in Nonmalignant Uterine Diseases. JAMA Netw Open. 2026;9(2):e2558205. doi:10.1001/jamanetworkopen.2025.58205