| Summary: | Abstract Background Chloride is a key electrolyte that regulates the body fluid distribution. Accordingly, manipulating chloride kinetics by selecting a suitable diuretic could be an attractive strategy for correcting body fluid dysregulation. Therefore, this study examined the effects and contributing factors of a sodium–glucose cotransporter-2 inhibitor (SGLT2i) on the serum chloride concentration in type 2 diabetic (T2DM) patients without heart failure (HF). Methods This study was a retrospective single-center observational study that enrolled 10 T2DM/non-HF outpatients for whom the SGLT2i empagliflozin (daily oral dose of 10 mg) was prescribed. Among these 10 patients, 6 underwent detailed clinical testing that included hormonal and metabolic blood tests. Results Empagliflozin treatment for 1–2 months decreased body weight (− 2.69 ± 1.9 kg; p = 0.002) and HbA1c (− 0.88 ± 0.55%; p = 0.0007). The hemoglobin (+ 0.27 ± 0.36 g/dL; p = 0.04) and hematocrit (+ 1.34 ± 1.38%; p = 0.014) values increased, but the serum creatinine concentration remained unchanged. The serum chloride concentration increased from 104 ± 3.23 to 106 ± 2.80 mEq/L (p = 0.004), but the sodium and potassium concentrations did not change. The spot urinary sodium concentration decreased from 159 ± 43 to 98 ± 35 mEq/L (p < 0.02) and the spot urinary chloride tended to decrease (from 162 ± 59 to 104 ± 36 mEq/L, p < 0.08). Both renin and aldosterone tended to be activated (5/6, 83%). The strong organic acid metabolite concentrations of serum acetoacetate (from 42 ± 25 to 100 ± 45 μmol/L, p < 0.02) and total ketone bodies (from 112 ± 64 to 300 ± 177 μmol/L, p < 0.04) increased, but the actual HCO3 − concentration decreased (from 27 ± 2.5 to 24 ± 1.6 mEq/L, p < 0.008). Conclusions The present study demonstrated that SGLT2i enhances the serum chloride concentration in T2DM patients and suggests that the effect is mediated by the possible following mechanisms: (1) enhanced reabsorption of urinary chloride by aldosterone activation due to blood pressure lowering and blood vessel contraction effects, (2) reciprocal increase in the serum chloride concentration by reducing the serum HCO3 − concentration via a buffering effect of strong organic acid metabolites, and (3) reduced NaHCO3 reabsorption and concurrently enhanced chloride reabsorption in the urinary tubules by inhibiting Na+–H+ exchanger 3 in the renal proximal tubules. Thus, the diuretic SGLT2i induces excessive extravascular fluid to drain into the vascular space by the enhanced vascular “tonicity” caused by the elevated serum chloride concentration.
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