#651 The effects of empagliflozin on fluid and eletrolyte balance

Abstract Background and Aims Sodium glucose cotransporter 2 inhibitors (SGLT2i) exert cardiovascular and renal benefits in type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), potentially mediated in part by natriuresis and changes in fluid balance. However, the exact mechanisms are not fully clear. We examined the effects of empagliflozin on fluid and electrolyte balance in a cohort of patients with DM2 and preserved kidney function (estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2), DM2 and concomitant CKD and non-diabetic CKD (both eGFR 20–60 ml/min/1.73 m2), respectively. Method A randomized double blind, placebo controlled cross-over trial. Participants were randomized to 4 weeks of empagliflozin 10 mg/day or matching placebo and crossed over to 4 weeks of the opposite treatment after a wash out. We measured body composition by bio-impedance using a Fresenius Body Composition Monitor, 24-hour ambulatory blood pressure (BP) using a Mobil-O-Graph, urinary sodium, potassium and glucose excretion, free water clearance, plasma levels of renin, aldosterone and copeptin and urinary excretion of epithelial sodium channels (ENaC), aquaporin-2 (AQP2) and sodium-chloride cotransporter (NCC). Results 49 participants completed the trial, 16 with DM2 and preserved renal function, 17 with DM2 and CKD and 16 with non-diabetic CKD. Mean age was 68, 8 ± 7.5 years, median eGFR was 42.2 ml/min/1.73 m2 (interquartile range: 34.5–73.5). 73% were male, 92% had concomitant arterial hypertension and 20% had ischemic heart disease. Empagliflozin reduced extracellular body water by 0.29 L (95% CI: −0.54; −0.03 L, P = 0.03) and tended towards reducing overhydration (mean difference: −0.23L, 95% CI: −0.51; 0.05L, P = 0.10). Systolic BP decreased by 6 mmHg and diastolic BP decreased by 3 mmHg during empagliflozin treatment compared to placebo (P < 0.001). Change in overhydration was correlated to changes in systolic BP (R = 0.38, P = 0.008). Sodium excretion and urine volume did not change, but empagliflozin increased glucose excretion (P < 0.0001) and fractional potassium excretion (P = 0.046). Furthermore, copeptin levels increased by 30% (P < 0.0001), urinary AQP2 excretion increased by 8% (P = 0.04) and free water clearance decreased (P = 0.0001). Renin levels also increased (P = 0.02) and there were borderline significant rises in aldosterone (P = 0.05) and urinary ENaC excretion (P = 0.08). Urinary excretion of NCC did not change (P = 0.63) Conclusion Our results indicate that SGLT2i exert a diuretic effect which, although compensated by increased activity of the renin-angiotensin system and antidiuretic hormone, leads to changes in fluid balance. Furthermore, the BP lowering effect of SGLT2i may be related to changes in fluid balance.