SGLT2 inhibitors and nephrolithiasis risk in patients with type 2 diabetes: A cohort study and meta-analysis.

Objective: This study aimed to evaluate the relationship between sodium-glucose cotransporter 2 inhibitor (SGLT2i) use and nephrolithiasis risk.

Methods: In this real-world cohort study, we analyzed electronic health records from the TriNetX Analytics Network, which includes patients from 64 U.S. healthcare organizations. Adult patients with type 2 diabetes (T2D) who initiated SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), or glucagon-like peptide-1 receptor agonists (GLP-1RAs) between January 2015 and December 2023 were included. Comparisons were made between SGLT2is and DPP4is and between SGLT2is and GLP-1RAs. Patients were followed-up for up to 5 years. A meta-analysis was further conducted to synthesize available evidence.

Results: The cohort study included 500,000 patients (250,000 pairs) for SGLT2is vs. DPP4is comparisons and 482,284 patients (241,142 pairs) for SGLT2is vs. GLP-1Ras comparisons. The risk of nephrolithiasis was significantly lower in SGLT2i users compared with DPP4i (HR: 0.86; 95% CI: 0.83-0.90) and GLP-1RA users (HR: 0.90; 95% CI: 0.86-0.94). A meta-analysis combining our study with four additional real-world studies further supported these findings.

Conclusions: This study suggests that SGLT2is may provide benefits beyond glycemic control by reducing nephrolithiasis risk, offering an advantage when selecting glucose-lowering therapies for patients with T2D.