Risk of Nephrolithiasis Associated With SGLT2 Inhibitors Versus DPP4 Inhibitors Among Patients With Type 2 Diabetes: A Target Trial Emulation Study

OBJECTIVE We aim to compare the risk of nephrolithiasis among type 2 diabetes patients who initiated sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl-peptidase-4 inhibitors (DPP4is), individually within stone never- and ever-formers. RESEARCH DESIGN AND METHODS Using the 2010–2021 Korea National Health Insurance Service database, we conducted a population-based cohort study, comparing initiators of SGLT2is versus DPP4is. The primary outcome was incident nephrolithiasis. Osteoarthritis encounters served as a negative control outcome. After 1:1 propensity score (PS) matching in stone never- and ever-formers, pooled and individual hazard ratios (HRs), incidence rate difference (IRD), and 95% CIs were reported. Subgroup analyses by sex, age, thiazide co-use, and baseline cardiovascular risk were done. RESULTS The 17,006 PS-matched pairs of SGLT2i and DPP4i initiators were pooled from stone never- (105,378 pairs) and ever-formers (11,628 pairs). Over a mean of 654 days, the risk of nephrolithiasis was lower in SGLT2i initiators than in DPP4i: 0.65 vs. 1.12 events per 100 person-years, HR 0.54 (95% CI, 0.50–0.57), IRD −0.46 (95% CI,−0.21 to −0.52). Among never-formers, the HR was 0.43 (95% CI, 0.39–0.48) and IRD was −0.32 (95% CI,−0.27 to −0.36). Among ever-formers, the HR was 0.64 (95% CI, 0.59–0.69) and IRD was −2.26 (95% CI,−1.77 to −2.76). Near-null associations were found for osteoarthritis encounters. Results were consistent across subgroups. CONCLUSIONS We found a lower risk of nephrolithiasis associated with SGLT2is versus DPP4is in stone never- and ever-formers. Despite a greater relative risk reduction in the former, the absolute risk reduction was greater in the latter.