Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat

Abstract

The chronic intrinsic diuretic and natriuretic tone of sodium-glucose cotransporter 2 (SGLT2) inhibitors is incompletely understood because their effect on body fluid volume (BFV) has not been fully evaluated and because they often increase food and fluid intake at the same time. Here we first compared the effect of the SGLT2 inhibitor ipragliflozin (Ipra, 0.01% in diet for 8 wk) and vehicle (Veh) in Spontaneously Diabetic Torii rat, a nonobese type 2 diabetic model, and nondiabetic Sprague-Dawley rats. In nondiabetic rats, Ipra increased urinary excretion of Na (UNaV) and fluid (UV) associated with increased food and fluid intake. Diabetes increased these four parameters, but Ipra had no further effect, probably because of its antihyperglycemic effect, such that glucosuria and, as a consequence, food and fluid intake were unchanged. Fluid balance and BFV, determined by bioimpedance spectroscopy, were similar among the four groups. To study the impact of food and fluid intake, nondiabetic rats were treated for 7 days with Veh, Ipra, or Ipra+pair feeding+pair drinking (Pair-Ipra). Pair-Ipra maintained a small increase in UV and UNaV versus Veh despite similar food and fluid intake. Pair-Ipra induced a negative fluid balance and decreased BFV, whereas Ipra or Veh had no significant effect compared with basal values. In conclusion, SGLT2 inhibition induces a sustained diuretic and natriuretic tone. Homeostatic mechanisms are activated to stabilize BFV, including compensatory increases in fluid and food intake.

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

“…Conceivably, because the change in ECW/TBW depends on initial sodium clearance and initial ECW/TBW in the analysis of the present study, high BNP level as a marker for the ECW/TBW ratio, might lead to a decrease ECW/TBW ratio, rather than a special effect of DAPA. Furthermore, our finding that DAPA did not change the ECW/TBW in patients with lower BNP levels thus indicates that SGLT2 inhibitors have a homeostatic mechanism for regulating the body fluid status, as we recently reported . Further studies are required to evaluate the interaction between body fluid reduction and the distribution and clinical outcomes, which is a convincing mechanism for the cardio‐renal protective effects of SGLT2 inhibitors, as shown in the EMPA‐REG OUTCOME trial and the CANVAS Program …”

“…Furthermore, our finding that DAPA did not change the ECW/TBW in patients with lower BNP levels thus indicates that SGLT2 inhibitors have a homeostatic mechanism for regulating the body fluid status, as we recently reported. 8 Further studies are required to evaluate the interaction between body fluid reduction and the distribution and clinical outcomes, which is a convincing mechanism for the cardio-renal protective effects of SGLT2 inhibitors, as shown in the EMPA-REG OUTCOME trial and the CANVAS Program. 1,2 In the present study, the SGLT2 inhibitor DAPA numerically decreased the eGFR, but FR and TLV slightly increased the eGFR from baseline.…”

“…increase in urinary fluid and Na + excretion.. 6,7 Furthermore, our recent study with a pair-feeding and drinking experiment revealed that the diuretic and natriuretic effect of SGLT2 inhibitors is not secondary to enhanced food and fluid intake. 8 Along with the diuretic effect, SGLT2 inhibitors reduce plasma volume in patients with type 2 diabetes. 9 We recently reported that an SGLT2 inhibitor, dapagliflozin (DAPA), transiently increases the urinary Na + excretion and ameliorates extracellular fluid expansion in diabetic kidney disease (DKD) patients with fluid retention.…”

Effects of ipragliflozin on glycemic control, appetite and its related hormones: A prospective, multicenter, open‐label study (SOAR‐KOBE Study)

“…In rats and other rodents, as well as humans, SGLT‐2 inhibitors have been shown to increase overall food intake in addition to increasing urinary glucose excretion, likely accounting for such attenuation of the weight‐reducing effect. However, few studies have examined the mechanism underlying this change in appetite during treatment with SGLT‐2 inhibitors. Therefore, we have here evaluated the efficacy of the SGLT‐2 inhibitor, ipragliflozin, in patients with type 2 diabetes, as well as investigated its effects on hormones related to appetite regulation.…”

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

“…Diabetic patients frequently present with electrolyte abnormalities [12]. The diuretic effects of SGLT2i may influence the serum chloride concentration, but few experimental [13][14][15] and clinical studies [16,17] have deeply evaluated the effects and mechanistic consideration of SGLT2i on the serum chloride levels. The findings of the present study indicate that SGLT2i preserves or enhances the serum chloride concentration in T2DM/ non-HF patients.…”