A groundbreaking retrospective cohort study has unveiled compelling evidence that sodium-glucose cotransporter-2 inhibitors (SGLT2i), a class of medications primarily used to manage type 2 diabetes mellitus, may dramatically improve survival outcomes in patients diagnosed with endometrial cancer. Published in the renowned journal BMC Cancer, this research signals a potential paradigm shift in adjunctive cancer therapy by intertwining oncological outcomes with metabolic regulation. The comprehensive analysis, harnessing a large-scale real-world electronic health record database from the United States TriNetX network, identifies a significant association between SGLT2i use and reduced all-cause mortality among affected individuals.
Endometrial cancer, a malignancy intimately linked with metabolic disturbances such as obesity and diabetes, poses a significant health burden globally. The pathophysiological interplay between hyperglycemia, insulin resistance, and cancer proliferation has been the subject of burgeoning scientific inquiry. Notably, SGLT2 inhibitors, beyond their established glycemic control benefits, have recently drawn interest for potential anti-cancer properties, potentially mediated through mechanisms including improved insulin sensitivity, attenuation of inflammatory pathways, and metabolic reprogramming. This retrospective cohort endeavor rigorously examines whether such pharmacological attributes translate into tangible survival advantages within a clinically relevant patient population.
The research team extracted data on 2,079 matched pairs of female patients diagnosed with endometrial cancer between 2014 and 2023, ensuring robust control of confounding variables via propensity score matching. This methodological approach balanced a spectrum of baseline characteristics encompassing demographic factors, comorbidities such as heart failure and chronic kidney disease, and concurrent medication use. The dual groups—those receiving SGLT2i therapy and those without—were then subjected to survival analyses using Kaplan–Meier estimations coupled with Cox proportional hazards models to quantify mortality risk differentials.
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Results demonstrate that patients treated with SGLT2 inhibitors exhibited a strikingly lower all-cause mortality rate, at 8.21%, compared to 20.56% in the non-SGLT2i cohort. The statistically significant hazard ratio of 0.50 (95% confidence interval 0.41–0.59; p < 0.0001) highlights a 50% reduction in mortality risk associated with SGLT2i administration. This compelling survival benefit persisted consistently across diverse subgroups stratified by age, body mass index (BMI), and prevalent comorbid states, underscoring the drug class’s broad therapeutic promise within the heterogeneous endometrial cancer patient population.
Importantly, the safety profile of SGLT2 inhibitors was scrutinized with particular attention to well-documented adverse effects such as urinary tract infections, diabetic ketoacidosis, sepsis, and acute kidney failure. Encouragingly, the study found no increase in the incidence of these serious adverse events among SGLT2i users, lending support to the feasibility of repurposing this drug class safely in oncological contexts. Such findings alleviate concerns about potential iatrogenic harm which often complicates cancer treatment regimens, thus enhancing the attractiveness of SGLT2i as adjunctive agents.
Delving deeper into the molecular biology, the link between SGLT2i and improved cancer prognosis may be rooted in their multifaceted mechanisms of action. By inhibiting renal glucose reabsorption, these drugs promote glycosuria and consequent plasma glucose reduction, impacting cancer cell metabolism that thrives in hyperglycemic environments. Preclinical studies have also highlighted SGLT2i’s capacity to modulate signaling pathways involved in cell proliferation and apoptosis, including AMPK activation and mTOR inhibition, which may collectively retard tumor growth and progression.
Furthermore, chronic inflammation and oxidative stress, pivotal contributors to tumorigenesis, may be mitigated by SGLT2i via systemic metabolic improvements. Given that obesity and T2DM create pro-inflammatory milieus facilitating oncogenesis, the metabolic recalibration induced by SGLT2 inhibition presents a plausible biological basis for the observed survival advantages. This notion is bolstered by the consistent benefit seen in patients with heart failure and chronic kidney disease, conditions intertwined with systemic metabolic dysregulation and inflammation.
The retrospective nature of this analysis, while robust in scale and methodological rigor, warrants cautious interpretation regarding causality. Nonetheless, the real-world setting of the TriNetX database enhances generalizability, capturing heterogeneous patient populations outside the confines of clinical trials. This ecological validity is critical when exploring therapeutic repurposing, ensuring findings resonate with everyday clinical practice rather than idealized experimental conditions.
Clinicians and researchers alike may find these results paradigm-shifting, as they highlight the dual roles of metabolic agents in both chronic disease management and cancer therapeutics. The data suggests that integrating SGLT2i into the treatment algorithm for patients with endometrial cancer and concurrent T2DM could confer substantial mortality benefits, persuading oncologists to contemplate cross-disciplinary therapeutic strategies that transcend traditional boundaries.
Future prospective randomized controlled trials are imperative to validate these observational findings and to explore optimal dosing regimens, timing of initiation, and potential combination therapies with cytotoxic or immunomodulatory agents. Moreover, mechanistic studies dissecting the precise molecular pathways by which SGLT2 inhibitors exert anti-neoplastic effects will be invaluable in refining patient selection and maximizing therapeutic efficacy.
The implications of this study extend beyond endometrial cancer, potentially inspiring investigation into SGLT2i’s utility across a spectrum of malignancies with metabolic underpinnings. Given the global rise in obesity and diabetes, the intersection of metabolism and cancer biology represents fertile ground for innovative treatments that leverage existing pharmacotherapies with established safety profiles.
In sum, this pioneering research provides compelling evidence that sodium-glucose cotransporter-2 inhibitors significantly reduce all-cause mortality in patients afflicted by endometrial cancer. Their multi-pronged effects targeting metabolic dysfunction, tumor biology, and systemic inflammation render them promising adjuncts in cancer care. As the oncology community strives for personalized and integrated therapies, the repurposing of SGLT2 inhibitors exemplifies the innovative potential of cross-disciplinary approaches rooted in metabolic medicine.
This study not only opens doors to improved survival outcomes but also heralds a new era where the convergence of endocrinology and oncology yields transformative benefits for patients. The seamless integration of real-world electronic health data analytics with cutting-edge molecular science underscores the evolving landscape of precision medicine, offering hope and novel strategies in the fight against cancer.
Subject of Research: Association between sodium-glucose cotransporter-2 inhibitor use and mortality in patients with endometrial cancer
Article Title: Association of sodium-glucose cotransporter-2 inhibitor use and mortality in patients with endometrial cancer: a retrospective cohort study
Article References: Wang, M., Ye, M., Lucero, M. et al. Association of sodium-glucose cotransporter-2 inhibitor use and mortality in patients with endometrial cancer: a retrospective cohort study. BMC Cancer 25, 1065 (2025). https://doi.org/10.1186/s12885-025-14453-w
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14453-w
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