Sodium-Glucose Cotransporter 2 Inhibitors Prevent Nephrolithiasis in Patients with Diabetes: A TriNetX-Based Real-World Global Comparison.

Background: Nephrolithiasis is a prevalent condition associated with diabetes mellitus (DM) and obesity, yet effective pharmacological preventive options remain limited. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), primarily used to manage type 2 DM, have shown potential lithoprotective effects.

Methods: This retrospective multinational cohort study utilized electronic health records from the TriNetX database. Adults with DM initiating SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4i), or glucagon-like peptide-1 receptor agonists (GLP1-RA) were included. Propensity score matching was conducted to balance baseline covariates, yielding 358,096 matched pairs (SGLT2i vs. DPP4i) and 371,374 pairs (SGLT2i vs. GLP1-RA). The primary outcome was incidence of nephrolithiasis.

Results: SGLT2i use was associated with a significantly lower risk of nephrolithiasis compared to DPP4i (1.5% vs. 1.9%; HR 0.825, 95% CI: 0.795-0.855; p < 0.001) and GLP1-RA (1.6% vs. 2.0%; HR 0.812, 95% CI: 0.784-0.840; p < 0.001). Subgroup analyses showed consistent protective effects across age, HbA1c, BMI, and renal function strata, although the association was slightly attenuated in older adults, those with suboptimal glycemic control, or impaired renal function.

Conclusions: SGLT2 inhibitors may reduce the risk of nephrolithiasis 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 nephrolithiasis in diabetic populations, particularly those with additional metabolic risk factors for nephrolithiasis.