SGLT2 inhibitor requires co-administration with diuretics to effectively reduce interstitial fluid retention: the...

We previously demonstrated that combining a sodium-glucose cotransporter 2 (SGLT2) inhibitor with diuretics significantly reduces interstitial fluid volume without excessive depletion of circulating plasma volume or activation of the renin-angiotensin-aldosterone system (RAAS). However, the differential effects of SGLT2 inhibitor monotherapy versus combination therapy with diuretics on fluid dynamics in patients with pre-existing fluid retention remain unclear. This study included patients with fluid retention, defined by an extracellular water to total body water (ECW/TBW) ratio > 0.400, as measured by bioimpedance analysis. We evaluated 6-month changes in body fluid status and serum copeptin levels, a surrogate marker for vasopressin, between two groups: patients receiving SGLT2 inhibitor dapagliflozin monotherapy (SGLT2i group, n = 13; estimated glomerular filtration rate [eGFR] 25.0 ± 8.5 mL/min/1.73 m²) and those receiving dapagliflozin in combination with loop or thiazide diuretics (SGLT2i + diuretic group, n = 18; eGFR 29.8 ± 15.2 mL/min/1.73 m²). Changes in systolic blood pressure and estimated plasma volume did not significantly differ between groups. However, reductions in ECW/TBW, TBW, and interstitial fluid were significantly greater in the combination group than in the monotherapy group. Moreover, the increase in serum copeptin was significantly suppressed in the SGLT2i + diuretic group. No significant intergroup differences were observed in renin and aldosterone changes. These findings suggest that co-administration of SGLT2 inhibitor with diuretics can more effectively reduce interstitial fluid retention without inducing excessive plasma volume reduction or RAAS activation.