Effects of the sodium‐glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: A comparison study with furosemide and tolvaptan

Abstract

Aim Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic properties. We recently reported that an SGLT2 inhibitor ameliorated extracellular fluid expansion with a transient increase in urinary Na+ excretion. However, the effects of SGLT2 inhibitors on fluid distribution in comparison to conventional diuretics remain unclear. Methods Forty chronic kidney disease patients with fluid retention (average estimated glomerular filtration rate 29.2 ± 3.2 mL/min per 1.73 m2) were divided into the SGLT2 inhibitor dapagliflozin (DAPA), loop diuretic furosemide (FR) and vasopressin V2 receptor antagonist tolvaptan (TLV). The body fluid volume was measured on days 0 and 7 using a bioimpedance analysis device. Results In all three groups, body weight was significantly and similarly decreased, and urine volume numerically increased for 7 days. Bioimpedance analysis showed that the changes in intracellular water were similar, but that there were significant changes in the extracellular water (ECW) (DAPA −8.4 ± 1.7, FR −12.5 ± 1.3, TLV −7.4 ± 1.5%, P = 0.048). As a result, the change in the ratio of ECW to total body water in the DAPA group was significantly smaller than that in the FR group, but numerically larger than that in the TLV group (DAPA −1.5 ± 0.5, FR −3.6 ± 0.5, TLV −0.5 ± 0.4%, P < 0.001). Conclusion Sodium‐glucose cotransporter 2 inhibitor DAPA predominantly decreased the ECW with a mild increase in urine volume, but the change in the ECW/total body water was smaller than that in patients treated with FR, and larger than that in patients treated with TLV, suggesting that the effects of SGLT2 inhibitors on fluid distribution may differ from those of conventional diuretics.

Osmotic diuresis by SGLT2 inhibition stimulates vasopressin‐induced water reabsorption to maintain body fluid volume

“…Because SGLT2 cotransports glucose with Na + (in a 1:1 ratio) (Kanai, Lee, You, Brown, & Hediger, ; Vallon et al, ), SGLT2 inhibition decreases Na + reabsorption in the early proximal tubule and the non‐reabsorbed glucose induces an osmotic diuretic effect (Lambers Heerspink, Zeeuw, Wie, Leslie, & List, ). In accordance, human and animals studies reported that SGLT2 inhibitors can modestly increase urinary Na + excretion and urine volume (Ansary, Nakano, & Nishiyama, ; Masuda et al, ; Ohara et al, ).…”

Enhancement of the serum chloride concentration by administration of sodium–glucose cotransporter-2 inhibitor and its mechanisms and clinical significance in type 2 diabetic patients: a pilot study

“…"Chloride-regaining" diuretics, defined by the "chloride theory" [10], could have peculiar properties of preserving plasma volume and renal function [22,25,26], and the capability of draining interstitial body fluid by the serum chloride-associated enhancement of vascular "tonicity" [8,10], as mentioned above. This concept is consistent with the recent clinical observations that SGLT2i reduces interstitial congestion without deleterious effects of arterial underfilling or predominantly decreased extracellular volume [27,28].…”

“…An SGLT2i administration in T2DM/non-HF patients preserve or enhance the serum chloride concentration. Such a diuretic effect would preserve vascular volume and promote drainage of excessive extravascular fluid into the vascular space [27,28] by enhancing vascular "tonicity" [8]. Caution is advised when using an SGLT2i in patients with hypernatremia/chloremia because these diuretics might lead to an increase in serum chloride and sodium levels [42].…”

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure

“… 15 In another small observational study in patients with CKD, dapagliflozin was associated with preferential reduction in extracellular water in comparison to furosemide. 16 As a potential HF therapy, SGLT2 inhibitors could be frequently prescribed alongside loop diuretics, but there are little data on coadministration. A study of 42 healthy volunteers randomized to dapagliflozin, bumetanide, or combination therapy found that the combination of dapagliflozin and bumetanide caused a significant increase in urine volume, but not urinary sodium, compared with bumetanide alone.…”