SGLT2 inhibitors preserve serum chloride in non-diabetic CKD: a propensity-matched and LASSO regression analysis

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel renoprotective agents for patients with chronic kidney disease (CKD) and have diverse effects, including on the regulation of electrolyte balance. However, their effects on serum chloride concentrations remain unclear. We conducted a retrospective single-center study of 343 CKD patients without diabetes or proteinuria who were not taking diuretics, including 202 SGLT2i users and 141 non-users, and applied propensity score (PS) matching and LASSO regression analysis. The outcomes were the change in chloride concentration with adjustment for covariates, before and after PS matching. Factors associated with these changes were identified using multivariable analysis and LASSO regression. An adjusted linear mixed effects model showed that the annual changes in chloride concentration for the non-SGLT2i and SGLT2i users were -0.39 (95% CI: -0.61 to 0.17) mEq/L/year and 0.49 (95% CI: -0.02 to 1.00) mEq/L/year, respectively [difference 0.88 (95% CI: 0.58 to 1.17) mEq/L/year] (<i>p</i> < 0.001). After PS matching, there was also a significant difference between users and non-users of SGLT2is in the mean change in chloride concentration [difference 0.44 (95% CI: 0.03 to 0.84) mEq/L/year] (<i>p</i> = 0.036). Subgroup analyses confirmed these findings. Furthermore, the use of SGLT2is had the strongest influence on the 2-year change in serum chloride concentration. To our knowledge, this is the first propensity-matched study to demonstrate a sustained chloride-preserving effect of SGLT2 inhibitors in non-diabetic CKD. In conclusion, this study identifies a previously underrecognized tubular electrolyte effect of SGLT2 inhibitors-preservation of serum chloride-which may partly explain their consistent cardioprotective effects across diverse CKD populations.