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This extensive real-world retrospective cohort study found that concomitant use of sodium-glucose cotransporter 2 (SGLT2) inhibitors with progestin therapy among patients with benign uterine diseases or endometrial hyperplasia (EH) was associated with a significantly lower incidence of endometrial cancer (EC) and fewer subsequent hysterectomies compared to progestin therapy alone.
The hazard ratio for incident EC was 0.43, indicating a 57% risk reduction, and a 49% risk reduction for hysterectomy was observed during a 2-year follow-up period.
Results were consistent across subgroups stratified by progestin administration route, uterine pathology, age, and body mass index, with sensitivity analyses addressing potential confounding supporting robustness of findings.
Study Background
Endometrial cancer is a common malignancy of the female reproductive tract, often preceded by endometrial hyperplasia, a benign condition characterized by abnormal thickening of the uterine lining. Progestin therapy is the cornerstone of medical management to reverse hyperplasia and reduce cancer risk, especially for patients desiring uterine preservation.
Concurrently, sodium-glucose cotransporter 2 inhibitors (SGLT2i), originally developed for type 2 diabetes management, have demonstrated beneficial metabolic effects beyond glycemic control, including potential anti-neoplastic properties observed in various cancers.
Despite the potential, the additive effect of SGLT2i to progestin therapy on endometrial cancer risk in patients with benign uterine pathology has not been well studied.
Study Design and Methods
This study utilized the TriNetX real-world clinical database, analyzing a retrospective cohort of 486,837 patients diagnosed with EH, abnormal uterine bleeding, or other benign uterine pathologies who received progestin therapy.
Patients were categorized into two groups: those receiving concomitant SGLT2 inhibitors with progestins (SGLT2i + P group; n=7,605) and those on progestin therapy alone (P-only group; n=479,232). Propensity score matching (1:1) was performed to balance baseline confounding factors, resulting in 7,034 matched patients in each group.
Primary outcomes included incident endometrial cancer, subsequent hysterectomy, and a composite of either event during a 2-year follow-up. Subgroup analyses assessed outcomes by route of progestin administration (oral, intrauterine, injectable), underlying uterine pathology, patient age, and BMI. Sensitivity analyses addressed residual confounding.
Key Findings and Results
After matching, endometrial cancer developed in 29 patients (0.4%) in the SGLT2i + P group compared with 65 patients (0.9%) in the P-only group. This corresponded to a hazard ratio (HR) of 0.43 (95% confidence interval [CI], 0.28–0.67), indicating a 57% relative risk reduction with adjunctive SGLT2i use.
Similarly, hysterectomy was significantly less frequent in the adjunctive group (HR, 0.51; 95% CI, 0.43–0.60), and the composite outcome of EC or hysterectomy mirrored this benefit.
Subgroup analyses demonstrated consistent risk reductions regardless of progestin administration route. Notably, patients with endometrial hyperplasia showed robust favorable outcomes, as did various age and BMI strata. Sensitivity analyses confirmed the stability of findings, addressing unmeasured confounding and indication bias.
No significant safety concerns or adverse event data were reported in this observational dataset regarding the dual therapy.
Expert Commentary
This study provides compelling real-world evidence supporting the integration of SGLT2 inhibitors alongside standard progestin therapy in women with benign uterine diseases and EH to mitigate progression to endometrial cancer and reduce the need for hysterectomy.
Biologically, SGLT2 inhibitors may exert anti-proliferative effects through metabolic modulation, inhibition of cellular glucose uptake in endometrial tissue, or reduction of systemic insulin resistance, factors implicated in carcinogenesis. These mechanisms warrant further mechanistic studies.
However, limitations include its retrospective design, potential for unmeasured confounding despite propensity matching, and lack of randomized control. The relatively small proportion of patients on SGLT2i also necessitates careful interpretation regarding generalizability.
Prospective clinical trials are needed to confirm causality, optimize dosing regimens, and evaluate long-term safety and efficacy in this patient population.
Conclusion
The addition of SGLT2 inhibitors to progestin therapy in patients with benign uterine pathology and endometrial hyperplasia appears to significantly reduce the risk of developing endometrial cancer and the rate of subsequent hysterectomy. These findings point to a promising adjunct therapeutic strategy that could alter clinical management and improve outcomes for patients at risk.
Future prospective investigations should elucidate underlying mechanisms and validate these results to potentially expand clinical guidelines.
Funding and Disclosure
The study was supported by institutional research grants; no conflicts of interest were reported by the authors in the publication.
References
- Yen TT, Lu CA, Hsieh TYJ, Lee GY, Jiang C, Tanner EJ. Adjunctive sodium-glucose cotransporter 2 (SGLT2) inhibitors with progestins and endometrial cancer risk in benign uterine diseases and hyperplasia. Gynecol Oncol. 2026 Jul;211:89-97. PMID: 42385610.
- Barakat RR, Markman M. Progestins in the management of endometrial hyperplasia and carcinoma. Gynecol Oncol. 2021;161(1):202-209.
- Polyzos SA, Anastasilakis AD. Mechanistic insights into SGLT2 inhibitors for oncology: potential anti-tumor effects beyond diabetes treatment. Endocrine Reviews. 2022;43(5):736-752.
