Adjunctive sodium-glucose cotransporter 2 (SGLT2) inhibitors with progestins and endometrial cancer risk in benign uterine diseases and hyperplasia.

OBJECTIVE

To evaluate whether concomitant sodium-glucose cotransporter 2 inhibitor (SGLT2i) and progestin therapy is associated with the risk of incident endometrial cancer (EC) and subsequent hysterectomy among patients with endometrial hyperplasia (EH) or benign uterine pathology.

METHODS

We conducted a retrospective cohort study using the TriNetX real-world clinical database. Patients with EH, abnormal uterine bleeding, or other benign uterine pathology who received progestin therapy were identified and grouped by concomitant SGLT2i use. Propensity score matching (PSM) was performed to balance baseline characteristics between the SGLT2i + progestin and progestin-only groups. Primary outcomes were incident EC, subsequent hysterectomy, and a composite outcome of EC or hysterectomy. Subgroup analyses were performed by route of progestin administration, uterine pathology, age, and body mass index. Sensitivity analyses were conducted to address potential residual confounding.

RESULTS

A total of 486,837 eligible patients were included, including 7605 (1.6%) in the SGLT2i + P group and 479,232 (98.4%) in the P-only group. After 1:1 PSM, 7034 patients remained in each group. During 2-years of follow-up, EC occurred in 29 patients (0.4%) in the SGLT2i + P group and 65 (0.9%) in the P-only group. Compared with progestin alone, SGLT2i + progestin was associated with lower risks of incident EC (HR, 0.43; 95% CI, 0.28-0.67) and subsequent hysterectomy (HR, 0.51; 95% CI, 0.43-0.60). Findings were generally consistent across subgroups and sensitivity analyses.

CONCLUSIONS

Concomitant SGLT2i use was associated with lower risks of EC and hysterectomy among patients receiving progestin therapy for non-malignant uterine pathology. Further prospective evaluation is warranted to assess its applicability and underlying mechanisms.