Renal and urothelial cancer risks with SGLT2 inhibitors vs GLP-1 receptor agonists in type 2 diabetes: a target trial emulation

BACKGROUND: 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. METHODS: 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 1 June 2014, to 31 May 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. RESULTS: 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. CONCLUSION: Based on the established cardiorenal benefits of both agents, our findings provide comparative safety and cancer risk data warranting further investigation.