GLP-1 Combination Reduced Endometrial Cancer Risk by 66%, Study Finds

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs)—in combination with a progestin—reduced the risk of endometrial cancer (EC) by approximately 66%, according to researchers who published data in JAMA Network Open. The retrospective study further reveals the dynamic capabilities of GLP-1 RAs beyond diabetes and weight loss treatment.¹

“Our findings demonstrated that the combined use of GLP-1 RA plus progestins significantly reduced EC risk not only in the endometrial hyperplasia [EH] subgroup (an association supported by previous preclinical data), but also in the low-risk population (benign uterine pathology),” the authors wrote.¹

Studying GLP-1 RAs and EC Risk

GLP-1 RAs are some of the most popular drugs on the market and in clinical research. Touted for their substantial benefits for metabolic disorders, they also show potential in cancer treatment and prevention. Emerging research led the study authors to investigate whether use of GLP-1 RAs in combination with progestin therapy could reduce EC risk among patients with nonmalignant uterine conditions.¹

They designed a retrospective cohort study and collected the data of 444,820 patients from TriNetX to analyze EC and hysterectomy among adult women with EH or benign uterine pathology who received progestins between May 1, 2005, and December 31, 2022. They were stratified by body mass index (BMI), age, baseline risk level, and progestin route. The primary end point was EC incidence, with a secondary end point of incidence of subsequent hysterectomy.¹

Of the population, 18,414 patients received GLP-1 RA in combination with progestin and 426,406 received progestin alone (mean [SD] age, 43.1 [10.2] years vs 35.2 [10.9] years).¹

Four treatments were evaluated¹:

1. GLP-1 RA plus progestins versus progestins alone
2. GLP-1 RA plus progestins versus metformin progestins
3. Triple therapy (GLP-1 RA, metformin, and progestins) versus metformin plus progestins
4. Triple therapy versus progestins alone

The data showed a clinically meaningful association between GLP-1 RAs with progestins and lower EC risk (HR, 0.34 [95% CI, 0.27–0.44]), which remained consistent across subgroups, stratified by progestin route, baseline risk, BMI, and age. The authors also observed a lower EC risk with GLP-1 RAs compared with metformin plus progestins (HR, 0.30 [95% CI, 0.15–0.59]). Triple therapy demonstrated greater reductions in endometrial cancer risk compared with dual therapy (metformin plus progestins; HR, 0.37 [95% CI, 0.25–0.53]) and progestin monotherapy (HR, 0.44 [95% CI, 0.29–0.66]).¹

In addition, patients receiving GLP-1 RAs with progestins experienced lower hysterectomy rates at both 2 years (HR, 0.47 [95% CI, 0.42–0.53]) and 5 years (HR, 0.59 [95% CI, 0.54–0.64]).¹

How GLP-1 RAs May Reduce EC Risk

Prior data shows that GLP-1 RAs, when combined with a progestin, can significantly upregulate PR expression, reduce cell viability in EC organoids, and improve progestin responsiveness even in malignant neoplasms with low baseline PR levels.¹

Collectively, these findings suggest that GLP-1 RAs may mitigate progesterone resistance via upregulation of PR expression and engaging downstream signaling pathways, including PGRMC1, cyclic AMP, ERK, and c-Src.¹

“These findings suggest that GLP-1 RAs may improve endometrial outcomes not only through metabolic regulation but also by potentially modulating hormonal signaling pathways,” the authors wrote.¹

Treating EC

EC is the most common cancer of the uterus and the fourth most common cancer in women in the US. According to the American Cancer Society, almost 70,000 women will receive an EC diagnosis in 2026 alone, with an estimated mortality of over 14,000 individuals. ²

Studies report that metabolic risk factors—obesity, insulin resistance, type 2 diabetes, and unopposed estrogen—drive EC risk through endometrial proliferation and carcinogenesis. Although early-stage disease is often treatable, prevention and early detection remain critical to reducing morbidity and the need for invasive treatments like hysterectomy.^1,2

Newer therapies—such as immunotherapies and targeted therapies—demonstrate clinically meaningful improvements in therapeutic response and outcomes. In 2024, the FDA approved 3 key agents at the helm of EC treatment^3-5:

• pembrolizumab (Keytruda; Merck) in combination with carboplatin and paclitaxel, followed by pembrolizumab as a single agent, to treat primary advanced or recurrent EC;
• durvalumab (Imfinzi; AstraZeneca) in combination with carboplatin and paclitaxel, followed by durvalumab monotherapy, to treat primary advanced or recurrent endometrial cancer that is mismatch repair deficient; and
• dostarlimab-gxly (Jemperli; GSK) in combination with carboplatin and paclitaxel chemotherapy, followed by dostarlimab-gxly as a single agent, for the treatment of adult patients with primary advanced or recurrent EC

Overall, the data from the study suggest that the addition of GLP-1s to progestin therapy may play a meaningful role in reducing EC risk and the need for hysterectomy. As research advances, these findings point to a potential new avenue in EC management alongside established therapies and evolving treatment options.

REFERENCES

1. Yen T, Yi Jin Hsieh T, Lee G, et al. GLP-1 receptor agonists plus progestins and endometrial cancer risk in nonmalignant uterine diseases. JAMA Netw Open. February 10, 2026. doi:10.1001/jamanetworkopen.2025.58205

2. Key statistics for endometrial cancer. American Cancer Society. Updated January 14, 2026. Accessed February 12, 2026. https://www.cancer.org/cancer/types/endometrial-cancer/about/key-statistics.html

3. McGovern G. FDA approves pembrolizumab with chemotherapy to treat adult patients with endometrial carcinoma. Pharmacy Times. June 18, 2024. Accessed February 12, 2026. https://www.pharmacytimes.com/view/fda-approves-pembrolizumab-with-chemotherapy-to-treat-adult-patients-with-endometrial-carcinoma

4. Ferruggia K. FDA approves durvalumab plus chemotherapy to treat endometrial cancer. Pharmacy Times. June 17, 2024. Accessed February 12, 2026. https://www.pharmacytimes.com/view/fda-approves-durvalumab-plus-chemotherapy-to-treat-endometrial-cancer

5. Halpern L. FDA expands approval of dostarlimab-gxly plus chemotherapy to all adults with primary, recurrent endometrial cancer. Pharmacy Times. August 1, 2024. Accessed February 12, 2026. https://www.pharmacytimes.com/view/fda-expands-approval-of-dostarlimab-gxly-plus-chemotherapy-to-all-adults-with-primary-or-recurrent-endometrial-cancer