Early plasma volume and interstitial fluid responses to SGLT2 inhibitor, loop diuretics, and their combination in chronic kidney disease

The combined use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and loop diuretics may reduce interstitial fluid (IF) retention without excessive plasma volume depletion; however, short-term effects compared with loop diuretic monotherapy remain unclear. This prospective, open-label observational study compared 7-day changes in body fluid status among patients with chronic kidney disease receiving loop diuretics alone (Loop group), SGLT2i alone (SGLT2i group), or SGLT2i plus loop diuretics (SGLT2i+Loop group). Body fluid status was assessed at baseline and day 7. In unadjusted analyses, percent change in estimated plasma volume (ePV) differed among groups (analysis of variance, *p* = 0.0076) and was lower in the SGLT2i+Loop group than in the Loop group (mean difference, -3.56%; 95% confidence interval, -6.22 to -0.90; *p* = 0.0059). However, this difference was not significant after adjustment for baseline imbalances and loop diuretic use. Percent change in IF differed overall ( *p* = 0.0030) but did not differ between the SGLT2i+Loop and Loop groups in unadjusted or adjusted analyses. In group-specific analyses, baseline ePV was inversely correlated with percent change in ePV in the SGLT2i+Loop group (r = -0.4185, *p* = 0.0418), but exploratory interaction analyses showed no significant treatment-group difference in this association. Thus, early ePV and IF responses were comparable between loop diuretic monotherapy and combination therapy after adjustment. This finding supports the hypothesis that baseline intravascular volume status may be linked to early plasma volume responses to combination therapy, a relationship that warrants testing in larger prospective studies.