This target trial emulation compared renal and urothelial cancer risks between SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes, addressing an important safety question for these widely prescribed cardiometabolic agents.
The cardiovascular and renal benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) are well established among patients with type 2 diabetes (T2D). However, comparative evidence regarding cancer risk remains limited.
We compared the risk of renal cell carcinoma (RCC) and urothelial cell carcinoma (UCC), two malignancies with rising incidence and poor prognosis, in patients with T2D initiating SGLT2i vs GLP-1 RA. A new-user comparative cohort study with a target trial emulation framework was conducted using the TriNetX database from June 1, 2014, to May 31, 2024. We included adults with T2D who initiated SGLT2i and those who initiated GLP-1 RA. Patients were matched 1:1 using propensity scores based on age, sex, race, socioeconomic status, lifestyle factors, medical utilization, comorbidities, medications, and laboratory measurements. Outcomes were incident RCC and UCC, analyzed with Kaplan-Meier plots and Cox regression.
There were 294 664 patients in each group after matching, with 278 760 female individuals (47.3%), a mean age of 59.3 years, 377 312 White individuals (64.0%), 117 542 African American or Black individuals (20.0%), and 29 750 Asian individuals (5.1%). Over a mean follow-up of 44.2 months, SGLT2i use was associated with a lower incidence of RCC (1.07 vs 1.26 per 1000 patient-years; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.79-0.92) and UCC (0.89 vs 1.05 per 1000 patient-years; HR, 0.85; 95% CI, 0.78-0.92) than GLP-1 RA use. Subgroup analyses stratified by demographics and comorbidities showed consistent results.
Based on the established cardiorenal benefits of both agents, our findings provide comparative safety and cancer risk data warranting further investigation.
