480 Background: The Warburg effect has long been recognized as a key driver of cancer cell metabolism. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) reduce cellular glucose uptake, thereby limiting the substrate for this pathway. We evaluated the incidence of renal cell carcinoma (RCC) among SGLT2i users, using dipeptidyl peptidase-4 inhibitor (DPP4i) users as a controls. Among patients with RCC, we further compared survival outcomes between users of these two drug classes. Methods: In this retrospective study, de-identified patient data was pooled from over 72 healthcare networks across the US using the TriNetX database. Adult patients ( > 18 years old) were propensity-score matched for age at index event, sex, race and ethnicity in all stages of this study. In the first stage, patients with type 2 diabetes (ICD 10 E.11) with no history of urological cancers (C64, C65, C66, C67, C68) were divided into cohorts based on the use of SGLT2i (ATC A10BK) or DPP-4i (ATC A10BH) within the past 3 years. Metformin use (RxNorm 6809) was excluded from all groups to avoid confounding. They were further matched for factors increasing risk of RCC: hypertension, acute kidney failure or chronic kidney disease, tobacco use, chronic viral hepatitis, calculus of kidney and ureters, BMI, serum creatinine, and HbA1c. A total of 71,442 patients in each group were compared for association with RCC (C64) incidence. In the second stage, patients with RCC and no prior urological malignancy were divided into SGLT2i and DPP4i users based on use within the past 3 years and matched for comorbidities (hypertension, ischemic heart disease, atherosclerosis, cerebrovascular diseases, type 2 diabetes, acute kidney failure or chronic kidney disease, diseases of the liver, chronic lower respiratory diseases), TNM staging and labs (serum creatinine, hemoglobin, total bilirubin, total protein, serum LDL, triglycerides, NT-pro BNP, ejection fraction, HbA1c, BMI). After propensity-score matching, 1,159 patients per group were compared for death as an outcome, and Kaplan–Meier (KM) analysis was used to estimate survival probability. Results: SGLT2i users had a lower incidence of renal cell carcinoma over 3 years when compared to DPP4i users (RR: 0.746, 95% CI 0.655 - 0.849, p < 0.0001). SGLT2i users with RCC had a lower risk of mortality when compared to DPP4i users (RR: 0.64, 95% CI 0.507 - 0.808, p = 0.0001). On KM analysis, SGLT2i users had a 83.209% survival probability (compared to 74.47% in control) at the end of time window, with median survival not being reached at most recent follow up in both groups. Conclusions: Prior studies have reported high levels of SGLT2 expression on RCC cells. This could explain the above findings, as well as make RCC a suitable target for cancer risk modification using SGLT2 inhibition. Further prospective studies are needed to validate this.
Kumar et al. (Sun,) studied this question.