SGLT2 inhibitors may increase creatinine clearance: data mining utilizing the FDA Adverse Event Report System database and pharmacokinetic study with rats

Introduction: Augmented renal clearance is a condition in which creatinine clearance exceeds 130 ml/min/1.73 m². The present study aimed to identify drugs that increase creatinine clearance. Methods: We initially investigated drugs associated with an upsurge in the reporting frequencies of “creatinine renal clearance increased” (CRCI) and “glomerular filtration rate increased” (GFRI) using the FDA Adverse Event Reporting System (FAERS) database. Effect of the drugs on renal clearance of creatinine and lithium was examined using rats. Results: The database contained 625 reports on CRCI and GFRI. Among the primary suspect drugs identified, empagliflozin had the highest number of reports (29), followed by canagliflozin (27), emtricitabine/tenofovir (21), and sacubitril/valsartan (21). Dapagliflozin had 16 reports. Reporting odds ratios (95% confidence intervals) for empagliflozin, canagliflozin, and dapagliflozin were 29.7 (20.5–43.1), 28.6 (19.5–42.1), and 19.7 (12.0–32.3), respectively. In rats infused with phlorizin, a typical inhibitor of sodium-glucose cotransporters (SGLTs), increases were observed in fractional glucose excretion, creatinine clearance, and the renal clearance of lithium. The plasma concentration of creatinine remained unchanged, while that of lithium decreased. Renal glucose excretion in rats administered phlorizin correlated with creatinine clearance (r = 0.859). Conclusion: These results suggest that SGLT2 inhibitors may increase renal clearance of creatinine or drugs.