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 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% confidence intervals (CIs) were reported. Subgroup analyses by sex, age, thiazide co-use, and baseline cardiovascular risk were done.

Results: 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 DPP4i: 0.65 versus 1.12 events per 100 person-years, HR 0.54 (95% CI, 0.50-0.57), incidence rate difference (IRD) of -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 -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 -2.26 (95% CI, -1.77 to -2.76). Near-null associations were found for osteoarthritis encounters. Results were consistent across subgroups.

Conclusion: 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.