Sodium-Glucose Cotransporter 2 Inhibitors Prevent Nephrolithiasis in Patients with Diabetes

Key Points. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) were associated with lower nephrolithiasis risk compared with dipeptidyl peptidase-4 inhibitor and glucagon-like peptide-1 receptor agonist in patients with diabetes. Risk reduction with SGLT2i was consistent across age, glycemic control, body mass index, and renal function subgroups. Findings support potential use of SGLT2i as a preventive strategy for kidney stones in high-risk diabetic populations. Background. Nephrolithiasis (NL) is a prevalent condition associated with diabetes mellitus (DM) and obesity, yet effective pharmacologic preventive options remain limited. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), primarily used to manage type 2 DM, have shown potential lithoprotective effects. Methods. This retrospective multinational cohort study used electronic health records from the TriNetX database. Adults with DM initiating SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4is), or glucagon-like peptide-1 receptor agonists (GLP-1RAs) were included. Propensity score matching was conducted to balance baseline covariates, yielding 358,096 matched pairs (SGLT2i versus DPP4i) and 371,374 pairs (SGLT2i versus GLP-1RA). The primary outcome was incidence of NL. Results. SGLT2i use was associated with a significantly lower risk of NL compared with DPP4i (1.5% versus 1.9%; hazard ratio, 0.825; 95% confidence interval, 0.795 to 0.855; P < 0.001) and GLP-1RA (1.6% versus 2.0%; hazard ratio, 0.812; 95% confidence interval, 0.784 to 0.840; P < 0.001). Subgroup analyses showed consistent protective effects across age, hemoglobin A1c, body mass index, and renal function strata, although the association was slightly attenuated in older adults, those with suboptimal glycemic control, or impaired renal function. Conclusions. SGLT2is may reduce the risk of NL among patients with DM. Possible mechanisms include increased urinary citrate excretion, urinary alkalinization, and anti-inflammatory effects. These findings suggest that SGLT2i may reduce the risk of incident NL in diabetic populations, particularly those with additional metabolic risk factors for NL.